S-3 Leitlinie AWMF-Register-Nr. 043/044 Epidemiologie, Diagnostik, Therapie und Mana- gement unkomplizierter bakterieller ambulant erworbener Harnwegsinfektionen bei erwachsenen Patienten Erstellungsdatum: 2010 Nächste Überprüfung geplant: 2015 Kurzfassung 18. März 2010
Dans la pharmacie en ligne Viagra-représenté Paris large éventail de la dysfonction érectile anti-plus consommée. Générique Levitra (vardenafil), Cialis (tadalafil) et achat viagra pour homme, dont le prix est acceptable pour tous les budgets.1
En internet farmacia empecé a pedir porque en la farmacia de al lado nunca había deseado surtido de medicamentos cialis generico Muy cómodo en el uso de la farmacia. Estuvimos en el restaurante a. aquí la tableta con la entrega en el lugar de.
Guidelines for Common
The NB Provincial Health Authorities Anti-infective Stewardship Committee
under the direction of the Drugs and Therapeutics Committee
These clinical guidelines have been developed or endorsed by the NB Provincial Health Authorities Anti-infective Stewardship Committee and its Working Group, a sub- committee of the New Brunswick Drugs and Therapeutics Committee. Local antibiotic resistance patterns and input from local infectious disease specialists, medical microbiologists, pharmacists and other physician specialists were considered in their These guidelines provide general recommendations for appropriate antibiotic use in specific infectious diseases and are not a substitute for clinical judgment. Website Links
For Horizon Physicians and Staff:
For Vitalité Physicians and Staff:
To contact us:
When prescribing antimicrobials:
Carefully consider if an antimicrobial is truly warranted in the given clinical situation
Consult local antibiograms when selecting empiric therapy
Include a documented indication, appropriate dose, route and the planned duration of
therapy in all antimicrobial drug orders Obtain microbiological cultures before the administration of antibiotics (when possible) Reassess therapy after 24-72 hours to determine if antibiotic therapy is still warranted or effective for the given organism or clinical situation. Reassess based on relevant clinical data, microbiologic and/or radiographic information Assess for de-escalation as appropriate based on available microbiology culture and susceptibility results Antimicrobial Treatment Guidelines
For Common Infections
(Click arrow buttons to navigate) Section 1: Anatomical
Diabetic Foot Infectio Clostridium difficile Infecti Intra-Abdominal Infectio Respiratory
Acute Bacterial Rhinosinusiti Acute Exacerbation of Chronic Obstructive Pulmonary Disea Community Acquired Pneumoni Skin and Soft Tissue
Urinary Tract Infection Section 2: Drug Use Guidelines
Adult Dosing Tabl Penicil in and β-Lactam Al erg Antimicrobial Al ergy Evaluation T IV-to-PO Conversion Crit Nevirapine for Perinatal HIV Transmission Prophylaxi Section 3: Other
Splenectomy Vaccination K References
EMPIRIC ANTIMICROBIAL THERAPY FOR DIABETIC FOOT INFECTION
(Endorsed by NB Health Authorities Anti-Infective Stewardship Committee February 2016) Infection Severity
Preferred Empiric Regimens1
Wound less than 4 weeks duration
Wound less than 4 weeks duration
• Outpatient management • Cel ulitis less than 2 cm
• cephalexin 500 mg PO four times daily* • clindamycin 300 – 450 mg PO four times daily (only if and without involvement of Wound greater than 4 weeks duration
severe β-lactam allergy) • Tailor regimen based on C&S • sulfamethoxazole/trimethoprim 800/160 mg PO twice daily* + Wound greater than 4 weeks duration
results & patient response • Non-limb threatening metroNIDAZOLE 500 mg PO twice daily • amoxicillin/clavulanate 875/125mg PO twice daily* OR
• No signs of systemic toxicity • doxycycline 100 mg PO twice daily + metroNIDAZOLE 500 mg PO twice daily Moderate
Wound less than 4 weeks duration
Wound less than 4 weeks duration
• Initial management with • Cel ulitis greater than 2
• ceFAZolin 2 g IV q8h* OR
• levofloxacin 750mg IV/PO once daily* (only if severe outpatient parenteral therapy cm or involvement of deeper
• cefTRIAXone 2 g IV once daily (to facilitate outpatient management when β-lactam allergy) with rapid step-down to oral ambulatory administration of ceFAZolin not possible) Wound greater than 4 weeks duration
therapy after 48 to 72 hours • Non-limb threatening Wound greater than 4 weeks duration
• levofloxacin 750mg IV/PO once daily* + based on patient response • No signs of systemic toxicity • ceFAZolin 2 g IV q8h* + metroNIDAZOLE 500 mg PO twice daily OR
metroNIDAZOLE 500 mg PO twice daily (only if severe • Tailor regimen based on C&S • cefTRIAXone 2 g IV once daily + metroNIDAZOLE 500 mg PO twice daily β-lactam allergy) results & patient response (to facilitate outpatient management when ambulatory administration of ceFAZolin not possible) • piperacillin-tazobactam 3.375 g IV q6h* • imipenem/cilastatin 500 mg IV q6h* OR
• Inpatient management • Systemic signs of sepsis • levofloxacin 750 mg IV once daily* + metroNIDAZOLE • Limb or foot threatening 500 mg PO/IV twice daily (only if severe β-lactam • Urgent vascular assessment if • Extensive soft tissue • Tailor regimen based on C&S • Pulseless foot results & patient response Clinical Pearls:
Duration of Therapy
1 If high risk for MRSA, should include sulfamethoxazole/ • Soft tissue only – 2 weeks trimethoprim 800/160 mg PO twice daily * or doxycycline 100 • Bone involvement with complete surgical resection of all infected bone – 2 weeks mg PO twice daily for mild infections and vancomycin weight- • Bone involvement with incomplete surgical debridement of infected bone – 4-6 weeks IV based dosing to a target trough of 15 – 20 mg/L for moderate- severe infections • Bone involvement with no surgical debridement or residual dead bone postoperatively – 6 weeks IV, followed by 6 weeks PO • Debridement, good glycemic control and proper wound care are References:
important for the management of diabetic foot infections 1. Bowering K, Embil JM. Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in • Cultures: prefer tissue specimens post-debridement and Canada: Foot Care. Can J Diabetes 37(2013) S145-S149 cleansing of wound; surface or wound drainage swabs not 2. Lipsky BA, Berendt AR, Cornia PB et al. 2012 Infectious Disease Society of America Clinical Practice Guidelines for the Diagnosis and Treatment of Diabetic Foot Infections. CID 2012:54(12):132-173 • In a clinically infected wound a positive probe-to-bone (PTB) 3. Lipsky BA, Armstrong DG, Citron DM et al. Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP): prospective, test is highly suggestive of osteomyelitis randomized, controlled, double-blinded, multicentre trial. Lancet 2005; 366:1695 – 1703 • Imaging: recommend plain radiography (radionuclide imaging 4. Blond-Hill E, Fryters S. Bugs & Drugs An Antimicrobial/Infectious Diseases Reference. 2012. Alberta Health Services * Dose adjustment required in renal impairment Antimicrobial Management of Clostridium
(NB Provincial Health Authorities Anti-Infective Stewardship Committee, May 2014) Diarrhea: 3 or more unformed or watery stools in 24 hrs or less Send stool for Clostridium difficile testing Results pending but high clinical suspicion histopathologic findings of pseudomembranous colitis 1. Discontinue therapy with the inciting antimicrobial agent if possible
2. Stop all anti-peristaltic & pro-motility agents unless clearly indicated1
3. Begin Infection Control Precautions
- Accommodate patient in a private room (if possible) - Gowns and gloves (masks unnecessary) - Perform hand hygiene (preferably soap and water) 4. Classify & treat according to severity of CDI
Mild or Moderate
WBC greater than 15x109/L Hypotension or shock OR
WBC 15x109/L or less Serum creatinine level 1.5 x baseline Serum creatinine level less than 1.5 x baseline level level or greater OR
Clinical judgement (e.g. ICU Admission) Any Episode
vancomycin 125 mg2 PO/NG four times daily Any Episode
+/- metroNIDAZOLE 500 mg IV three times daily metroNIDAZOLE 500 mg PO vancomycin 125 mg PO (Add vancomycin 500 mg in 100mL NS three times daily x 10 - 14 days four times daily x 10 - 14 days retention enema four times daily if ileus) Duration: General y 10 - 14 days but may
extend depending on clinical scenario.
Recurrent Clostridium difficile Infection
Treat same as for initial episode and according to CDI severity
Vancomycin taper regimen: 125 mg PO four times daily x 14 days, then 125 mg PO twice daily x 7 days, then 125 mg PO once daily x 7
days, then 125 mg PO every 2 days x 2 weeks then discontinue
Consider ID consult
- Pregnancy/breast feeding: use vancomycin PO (avoid metroNIDAZOLE)
- Symptoms of CDI usual y begin 2 - 3 days after colonization - Test for cure is not recommended - Vancomycin administered intravenously is inef ective for CDI - Fidaxomicin is a non-formulary item that should only be considered under extenuating clinical circumstances, ID consultation required 1Examples: loperamide, diphenoxylate, opioids, metoclopramide, domperidone, etc 2For complicated severe episodes some authorities recommend vancomycin doses up to 500 mg; appropriate dose has not been established in clinical trials Adapted from: Vancouver Coastal Health Antimicrobial Stewardship Treatment Guidelines for Common Infections March 2011 1st Edition Antimicrobial Therapy for Intra-Abdominal Infections
(NB Provincial Health Authorities Anti-Infective Stewardship Committee, November 2015)
Origin/Severity of Intra-
ceFAZolin 2 g IV q8hg,* + CefOXitin 2 g IV q6hh,* Duration of Therapy, dependent
Infection, Mild to
Enterobacteriaceae metroNIDAZOLE 500 mg IV/PO on clinical picture:
(i.e. E.coli, Moderate severity:
gentamicin 5 – 7 mg/kg IV q24h* + o 5 – 7 days usually sufficient if Klebsiella spp, metroNIDAZOLE 500 mg IV/PO i.e. gastroduodenal Proteus spp, optimal source control obtained perforation, cholangitisa, Enterobacter spp.) o If intra-abdominal abscess: cholecystitisa, appendicitis, Anaerobes (i.e. B. Intravenous-to-Oral Conversionc:
antimicrobial therapy may be diverticulitisb, primary fragilis, Clostridium amoxicillin/clavulanate 875/125 mg ciprofloxacin 400 mg IV OR 500 mg prolonged, with duration dependant spp. etc…), (spontaneous) bacterial PO q12h* + metroNIDAZOLE 500 on resolution (up to 4 to 6 weeks) Streptococcus spp, ± Enterococcus o Day of intervention (drainage, • With no evidence of systemic spp (see below if surgery, etc.) considered as day 1 toxicity (APACHE II score less cefTRIAXone 2 g IV q24hg + piperacillin/tazobactam 3.375 g IV Stop antimicrobial within 24 hours
metroNIDAZOLE 500 mg IV/PO Infection, Severe:
acute stomach, duodenum &/or • As above with APACHE II proximal jejunum perforation if no score greater than or equal to ampicillin 2 g IV q6hh,* + acid-reducing therapy or 15, signs of systemic toxicity, gentamicin 5 – 7 mg/kg IV q24h* + malignancy and source control greater than 70 years old, metroNIDAZOLE 500 mg IV q12h achieved OR
o penetrating bowel trauma repaired secondary peritonitis, cancer, ciprofloxacin 400 mg IV q12h* + Intravenous-to-Oral Conversionc:
within 12 hours OR
poor nutritional status or metroNIDAZOLE 500 mg IV q12h As for mild to moderate above intraoperative contamination of a incomplete or delayed source surgical field from enteric contents o acute appendicitis without perforation, abscess or local Healthcare Associated
piperacillin/tazobactam 3.375 g IV imipenem-cilastin 500 mg IV peritonitis OR
• Hospitalized greater than 48 q6he,g,* (preferred if suspected MDR Gram-negative) o patients undergoing hours at time of onset, recent Multidrug Resistant cholecystectomy for acute cholecystitis unless evidence of post-operative infection, long infection outside wall of the ciprofloxacin 400 mg IV q12h* + term care, rehab, dialysis, gallbladder (ex. perforation) metroNIDAZOLE 500 mg IV q12h + nursing home, recent
vancomycin 15 mg /kg IV q12hf,* (continued on next page) Origin/Severity of Intra-
If MRSA Suspected
Add vancomycin 15 mg/kg IV q12h* (colonized or history of MRSA (for target trough of 15 – 20 mg/L) • micafungin preferred if Candida krusei or Add fluconazole 800 mg IV/PO then Candida glabrata isolated If Candida isolated
micafungin 100 mg IV q24h 400 mg IV/PO q24h* • Enterococcal coverage only necessary if: isolated as predominant organism in culture OR
healthcare associated infection OR
If Enterococci isolated
Add ampicillin 2 g IV q6hh,* penicillin allergy or penicillin
patient is immunocompromised OR
(not required if on piperacillin/tazobactam or resistant:
Blood culture positive imipenem-cilastin) vancomycin 15 mg/kg IV q12hf,* • If Enterococcus faecium isolated and criteria for treatment met, use vancomycinas empiric therapy and reassess based onsusceptibility results Clinical Pearls:
Antimicrobial therapy does not preclude source control (ex. percutaneous drainage or surgery) Patients with recent prolonged hospitalization (5 or more days) or recent antimicrobials (2 or more days) within the previous 3 months pose risk for resistance andtreatment failure, treat as healthcare associated Empiric Enterococci coverage is not recommended for mild-moderate severity community-acquired intra-abdominal infections. It should be reserved for patients inwhom this pathogen is more frequently found (healthcare-associated infections, particularly those with postoperative infection, presence of severeimmunosuppression, recurrent infection, patients who receive long-term cephalosporin treatment, and those with valvular heart disease or prosthetic intravascularmaterials) CAUTION: Significant E.coli resistance (greater than 20%) to fluoroquinolones and amoxicillin exist in some areas of the province; check local antibiogram andconfirm C&S results when available Pathogen directed therapy should be used when culture and susceptibility results are available Recommend blood, intraoperative and/or abscess fluid cultures in patients with post-operative or healthcare-associated infections; those with treatment failure and/orrequiring re-operation; or recently on antimicrobial therapy Blood cultures recommended if patient has sepsis syndrome Reassess initial empiric therapy based on clinical state & results of microbiological analysis a Anaerobic coverage not indicated for cholecystitis & cholangitis unless biliary-enteric anastomosis is present or aggravating factors (advanced age, immunosuppression or metabolic instability) b Most cases of diverticulitis can be managed with oral antibiotic therapy c Intravenous-to-Oral conversion: consider if infection well controlled, afebrile x 24 hrs., hemodynamically stable, tolerating oral intake and no clinical, radiographic or surgical sign of intra-abdominal collection from non-optimal drainage d For Pseudomonas aeruginosa infection, piperacillin/tazobactam dosage may be increased to 4.5 gm IV q6h e Anaerobic coverage adequate, addition of metroNIDAZOLE or clindamycin to piperacillin/tazobactam or imipenem-cilastin not necessary f Adjust vancomycin dose to target a trough level of 10 to 20 mg/L g Appropriate therapy option for patients with an immediate Type-1 (IgE-mediated) hypersensitivity reaction to penicillin (i.e. anaphylaxis, angioedema, laryngeal edema, urticaria) h Avoid in patients with immediate Type-1 (IgE-mediated) hypsensitivity reaction to penicillin, significant risk of cross-reactivity exists. *Dose adjustment required in renal impairment Antimicrobial Therapy for Acute Bacterial Rhinosinusitis (ABRS)
(NB Provincial Health Authorities Anti-Infective Stewardship Committee, November 2015)
Clinical diagnosis and differentiation of acute bacterial from viral rhinosinusitis is based on the characteristic patterns of clinical presentations taking
into account duration of symptoms, severity of illness, temporal progression and "double-sickening" in the clinical course
The following clinical presentations (any of the 3) are recommended for identifying patients with acute bacterial vs. viral rhinosinusitis:
1. Onset with persistent symptoms or signs compatible with acute rhinosinusitis, lasting for greater than or equal to 10 days without any evidence of clinical improvement2. Onset with severe symptoms or signs of high fever (greater than or equal to 39 °C) and purulent nasal discharge or facial pain lasting for at least 3 to 4 consecutive days at the beginning of illness 3. Onset with worsening symptoms or signs characterized by the new onset of fever, headache or increased in nasal discharge following a typical viral upper respiratory infection that lasted 5 – 6 days and were initially improving ("double sickening") Initiation of empiric antimicrobial therapy is recommended as soon as the clinical diagnosis of ABRS is established based on the above criteria; if
diagnosis is uncertain due to mild symptoms then consider observing without antibiotic therapy for 3 days
Mild – Moderate
Symptomatic therapy only +/- intranasal corticosteroids Symptoms less than 10
Consider intranasal saline irrigation days duration
Mild – Moderate
doxycycline 100 mg po q12h amoxicillin 1000 mg po q8h* • Consider adjunctive intranasal saline irrigation Symptoms greater than 10
• Consider adjunctive intranasal corticosteroids in amoxicillin/clavulanate 875/125 mg days OR worsening after 5
patients with a history of allergic rhinitis to 6 days OR
If a patient has been on antibiotic therapy in the past month the antimicrobial therapy chosen Severe Symptoms for 3 to
should be based on a different mechanism of 4 consecutive days
800/160 mg po q12h* action regardless of the clinical success Failure of Initial Therapy
• Consider adjunctive intranasal saline irrigation (symptoms worsening after 48 – 72 amoxicillin/clavulanate 875/125 mg levofloxacin 500 mg po q24h* • Consider adjunctive intranasal corticosteroids in hrs. or failure to improve after 3 – 5 po q12h* + amoxicillin 1000 mg po patients with a history of allergic rhinitis days of initial empiric antimicrobial q12h* (high-dose amoxicillin with • Patients who fail to respond should be assessed for possible causes including infection with cefuroxime 500 mg po q12h* resistant organism, inadequate dosing andnoninfectious cause • Select an agent with broader spectrum of activity and from a different antimicrobial class Clinical Pearls
• Compatible Signs and Symptoms: purulent nasal discharge; nasal congestion or obstruction; facial swelling, congestion or fullness; facial pain or pressure; fever; hyposmia or anosmia;
• Majority of cases of acute sinusitis are viral and resolve within 5 to 7 days without the need for antibiotics; only 0.5 – 2% of viral upper respiratory infections are complicated by bacterial • Colour of nasal discharge or sputum is related to the presence of neutrophils, not bacteria, and should not be used to diagnose bacterial rhinosinusitis • Macrolides are not recommended for empiric therapy due to growing resistance rates for Streptococcus pneumoniae and Haemophilus influenzae within the Province • Respiratory fluoroquinolones (e.g. levofloxacin, moxifloxacin) should be reserved for failure of first-line options due to the potential for increasing resistance, risk of Clostridium difficile infection and their importance in the management of other infections • Respiratory fluoroquinolones (e.g. levofloxacin, moxifloxacin) have not been found to be superior to β-lactams in the management of ABRS • Antibiotics have not been shown to be beneficial in chronic rhinosinusitis without acute clinical deterioration• Consider ID consultation for refractory nosocomial rhinosinusitis • Decongestants (topical or oral) and/or antihistamines are not recommended as adjunctive therapy *Dose adjustment required in renal impairment Antimicrobial Therapy for Acute Exacerbation of Chronic Obstructive Pulmonary Disease
(NB Provincial Health Authorities Anti-Infective Stewardship Committee, November 2015)
The use of antibiotics in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is controversial Antimicrobial therapy is only recommended when AECOPD are accompanied by all 3 cardinal symptoms or at least 2 of the 3 cardinal symptoms, if increased sputum purulence is one of the 2 symptoms: 1. Increased dyspnea2. Increased sputum volume3. Increased sputum purulence Patients receiving invasive or non-invasive ventilation for AECOPD should be initiated on intravenous antimicrobial therapy Antibiotic selection should be based on patient symptoms and risk factors If infiltrate on chest x-ray or pneumonia suspected then treat as per pneumonia treatment guidelines Probable
Viral in most cases Antimicrobial therapy not
patients presenting with only 1 of Symptomatic therapy only the 3 cardinal symptoms Simple (Low-Risk Patients)
Streptococcus doxycycline 100 mg po q12h amoxicillin/clavulanate 875/125 mg po • If a patient has received an antibiotic • Less than 4 exacerbations per year pneumoniae in the last 3 months the therapy Haemophilus sulfamethoxazole/trimethoprim 800/160 chosen should be a regimen based influenzae mg po q12h* OR
on a different mechanism of action Moraxella catarrhalis cefuroxime 500 mg po q12h* OR
regardless of the clinical success clarithromycin 500 mg po q12h • Tailor antibiotic therapy for sputum culture results if available Complicated (High Risk
As in simple plus: • If a patient has received an antibiotic Patients)
Klebsiella spp and amoxicillin/clavulanate 875/125 mg po cefuroxime 500 mg po q12h* OR
in the last 3 months the therapy clarithromycin 500 mg po q12h* OR
chosen should be a regimen based At least one of: levofloxacin 750 mg po q24h* on a different mechanism of action Forced expiratory volume in 1 Increased probability regardless of the clinical success second (FEV1) less than 50% Intravenous Therapy: Intravenous Therapy: • Tailor antibiotic therapy for sputum cefTRIAXone 1-2 g IV q24h levofloxacin 750 mg IV q24h* (for levofloxacin) culture results if available Greater than or equal to 4exacerbations per year • Ischemic heart disease • Use of home oxygen • Chronic steroid use As in simple and • Tailor antibiotic therapy for
End-stage Lung Disease
complicated plus: amoxicillin/clavulanate 875/125 mg po levofloxacin 750 mg po q24h* sputum culture results (past or
Pseudomonas aeruginosa, Staphylococcus ciprofloxacin 500 -750 mg po q12h* aureus, MRSA (if Pseudomonas aeruginosa is suspected) Intravenous Therapy: Intravenous Therapy: levofloxacin 750 mg IV q24h* cefTRIAXone 1-2 g IV q24h negative bacilli OR
piperacillin/tazobactam 4.5 g IV q6h*
(if Pseudomonas aeruginosa is suspected)
• Macrolides are not recommended as first line empiric therapy due to growing resistance rates for Streptococcus pneumoniae and Haemophilus influenzae • Fluoroquinolones should be reserved for only severe cases, failure of first line options or β-lactam allergy in complicated cases due to the potential for increasing resistance, risk of Clostridium difficile infection and their importance in the management of other infections • Empiric therapy for atypical organisms (Mycoplasma pneumoniae & Chlamydophilia pneumoniae) not recommended • Consider obtaining cultures if not improving after 72 hours of antimicrobial therapy • Consider systemic corticosteroids for moderate to severe exacerbations of COPD (prednisone 40 mg po once daily for 5 days) • Influenza vaccination and pneumococcal vaccination recommended *Dose adjustment required in renal impairment Antimicrobial Therapy for Adult Community Acquired Pneumonia¶
(NB Provinical Health Authorities Anti-Infective Stewardship Committee, November 2014)
Having taken antibiotics within the past 3 months significantly increases the risk of resistant S. pneumoniae. Choose an antibiotic from a different class
¶Exclusion: patient with predisposing conditions such as cancer or immunosuppression, acute exacerbation of chronic obstructive pulmonary disease (COPD), bronchitis, macro-aspiration, or
Empiric Therapy (start antibiotics within 4 hours)
amoxicillin-clavulanate 875/125 mg PO bid* should be used instead of amoxicillin to provide coverage against Gram-negative bacilli and amoxicillin 500 mg – 1000 mg PO three times daily* aureus when required (e.g., post- influenza, alcoholism, COPD, nursing home) doxycycline 100 mg PO twice daily Amoxicillin is the oral beta-lactam that offers the best coverage against S. Macrolide PO (clarithromycin 500 mg PO twice daily* OR azithromycin 500 mg PO on day one then 250 mg once daily x 4 days) Microbiology Tests: None routinely (unless hospitalized, see below) amoxicillin 1000 mg PO three times daily* + [macrolide PO or doxycycline 100
Microbiology Tests: Moderate
ampicillin 2 g IV q6h* + [macrolide IV (azithromycin 500 mg IV once daily x 3
days) or doxycycline100 mg PO bid] -Blood cultures (2 sets) -Sputum culture Penicillin Allergy -Urine antigen for pneumococcus cefuroxime 1.5 g IV q8h + [macrolide IV or PO OR doxycycline100 mg PO bid]
and legionel osis‡ cefTRIAXone 2 g IV once daily + [macrolide IV or PO OR doxycycline 100 mg
(Depending on clinical context, consider investigation for atypical pathogens and viruses) levofloxacin 750 mg IV once daily* + ampicillin 2 g IV q6h*
For critically ill patients, combinations including doxycycline are not preferred If legionellosis strongly suspected, consider using levofloxacin S. aureus,)] Care with use of levofloxacin: association with C. difficile and nosocomial MRSA § CURB65 calculator, 1 point for any of the following:
IV-to-PO Step Down:
-Urea (greater than 7 mmol/L)
Suggested oral stepdown
-Respiration (greater than or equal to 30/min)
azithromycin or clarithromycin -Blood Pressure (less than 90 mm Hg systolic or less than or equal to 60 mm Hg diastolic)
Cephalosporin (any) amoxicillin + clavulanic acid Age ( 65 or greater)
Interpretation of CURB65 score levofloxacin + ampicillin in conjunction with clinical judgment. Too loose an interpretation of "severe pneumonia" levofloxacin alone ± amoxicillin contributes to overprescribing third generation cephalosporins and respiratory fluoroquinolones Please note, oral monotherapy vs combined therapy (atypicals) → clinical judgment. *Dose adjustment required in renal impairment ‡If antigen is positive for Legionella, efforts must be made to obtain sputum and advise laboratory that Legionella culture is required. This is important for epidemiological purposes in case of an outbreak. ∞If microbial cause of infection known, treat accordingly Treatment of Cellulitis/Skin Infection
(NB Provincial Health Authorities Anti-infective Stewardship Committee, May 2014)
Preferred Empiric Regimens
cephalexin 500 mg PO four times daily2 Work-up: None, unless there (no signs of systemic toxicity) β-lactam al ergy: is an associated fluctuant clindamycin 300 - 450 mg PO q6h pustule that can be drained - assess for clinical evidence of and sent for culture MRSA (e.g. purulent boil with spreading cel ulitis, previous MRSA sulfamethoxazole/trimethoprim 800/160 mg to 1600/320 infections or colonization) mg (1 or 2 DS tablets) PO twice daily2
doxycycline 100 mg PO twice daily ceFAZolin 2 g IV q8h2 Work-up: As above plus: (signs of systemic toxicity: documented soon as possible Blood cultures (2 sets) fever/hypothermia, tachycardia [HR Alternative for outpatient management: to PO (See options CBC, Creatinine, greater than 100 bpm] and hypotension (only when ambulatory administration of ceFAZolin is not [SBP less than 90 mm Hg or 20 mm Hg possible): usual y total 7-10 below baseline]) cefTRIAXone 2 g IV q24h β-lactam al ergy: clindamycin 600-900 mg IV q8h Progression on oral therapy1 vancomycin 15 mg/kg IV q12h2 (adjust based on levels to a trough target of 10-15 mg/L) piperacil in-tazobactam 3.375 g IV q6h2 AND
Work-up: As above plus: (sepsis syndrome, Necrotizing Fasci tis clindamycin 900 mg IV q8h urgent surgical assessment for [clinical features of NF include systemic diagnostic biopsy and/or toxicity, deep severe pain – more severe than expected for skin findings, violaceous bul ae, rapid spread along fascial planes, gas in soft tissues]) Clinical pearls: These guidelines are for basic skin infections only, any complicating features on history may require alternative management (Specific but not exclusive examples include: immunocompromised patients, diabetic foot infections, cel ulitis associated with a surgical site, trauma or animal/human bites) Consider looking for predisposing feature (e.g. Tinea pedis) as source of cel ulitis 1Assessment of clinical response within 48 hours should be based on pain and fever; mild progression of erythema expected during this timeframe
2 Dose adjustment required in renal impairment Treatment of Adult Urinary Tract Infections
(NB Provincial Health Authorities Anti-infective Stewardship Committee, May 2014)
(Tailor regimen based on urine/blood C&S results) Asymptomatic Bacteriuria
Antibiotic therapy only recommended for: • Asymptomatic bacteriuria with pyuria is not an -Prophylaxis for urological procedures when mucosal bleeding expected procedures: single indication for antimicrobial therapy -Treatment in pregnancy (Select antimicrobial therapy according to urine C&S) Others: 3 – 7 days Uncomplicated Cystitis (Lower UTI)
Preferred Regimen: (Female patients with dysuria, urgency, frequency, or nitrofurantoin monohydrate/macrocrystals 100 mg po twice daily (Not suprapubic pain with no fever or flank pain) recommended if CrCl less than 40 mL/min; avoid near term (36-42 weeks) due to risk of haemolytic anemia in the new born) Alternative Regimens:
amoxicillin/clavulanate 875/125 mg po twice daily3 OR
cefuroxime 500 mg po twice daily OR
sulfamethoxazole/trimethoprim 800/160 mg po twice daily1,3 (Not recommended in pregnant women) OR
fosfomycin 3 g po once
Acute Uncomplicated Pyelonephritis
Preferred Regimen: (Upper UTI)
Outpatient management an option if female, not cefixime 400 mg po once daily3 pregnant, no nausea/vomiting, no evidence of (Signs/Sx: fever, flank pain, costovertebral tenderness, abdominal/pelvic pain, nausea, vomiting dehydration, sepsis or high fever Alternative Regimens: with or without signs/sx of lower tract UTI) amoxicillin/clavulanate 875/125 mg po twice daily3 Treat for 14 days • May treat for 7 days if female, uncomplicated and Additional options if culture confirmed susceptibility: using ciprofloxacin or sulfamethoxazole/trimethoprim sulfamethoxazole/trimethoprim 800/160 mg po twice daily1,3 OR
• For treatment using oral β-lactams, consider an initial ciprofloxacin 500 mg po twice daily1,3 Complicated UTI
single intravenous dose of cefTRIAXone 1 g IV and (Complicating Factors: structural abnormality, use a 14 day total duration of antimicrobial therapy obstruction, recent urogenital procedure, male sex, Systemically Unwell:
immunosuppression, poorly controlled diabetes, spinal cefTRIAXone 1 g IV once daily2 OR
• Treat 7 days if prompt response, female and only cord injury, catheterization or Signs/Sx greater than 7 ampicillin 2 g IV q6h + gentamicin 5 mg/kg IV once daily2,3 OR
lower urinary tract infection piperacillin/tazobactam 3.375 g IV q6h2,3 (if at risk of MDR organisms) • Treat 14 days if male, delayed response, structural Pregnant:
abnormality, or upper tract symptoms cefTRIAXone 1 g IV once daily2 OR
ampicillin 2 g IV q6h + gentamicin 5 mg/kg IV once daily2,3 OR
• Pyuria not diagnostic, only treat if symptomatic piperacillin/tazobactam 3.375 g IV q6h2,3 (if at risk of MDR organisms) • Catheters frequently colonized, obtain culture through • Change catheter if in place for greater than 2 weeks Clinical Pearls:
• Cloudy & foul smelling urine alone is not considered an indication for a urine culture and sensitivity
• Therapy should be adjusted according to culture and sensitivity results • Blood cultures should be drawn if febrile, septic, signs and symptoms suggestive of pyelonephritis or immunocompromised • Post-treatment culture not recommended except in case of persistent or recurrent symptoms or pregnancy • nitrofurantoin and fosfomycin are not appropriate for men, complicated UTI or systemic infections 1CAUTION: Significant E.coli resistance (greater than 20%) to fluoroquinolones, sulfamethoxazole/trimethoprim and amoxicillin exist in some areas of the province; check local antibiogram and confirm urine C&S results when available 2De-escalate according to urine/blood C&S and switch IV to PO based on conversion criteria 3Dose adjustment required in renal impairment ADULT ANTIMICROBIAL DOSING TOOL
NB Provinical Health Authorities Anti-Infective Stewardship
Committee, November 2015
The dosing recommendations presented here are for adults with moderate-to-severe infections and are based on published literature, the Clinical & Laboratory Standards Institute's reference dosing for susceptibility interpretation and clinical experience. The recommended doses should only be used as a reference tool. Patient dosing should be individualized and based on pharmacokinetic and clinical evaluation where possible. Recommendations for renal dose adjustment are made according to estimated creatinine clearance (CrCl) calculated using the Cockroft-Gault equation, which is used in practice. Estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease 4 (MDRD4) equation, commonly reported with most serum creatinine levels, is NOT interchangeable with CrCl calculated using the Cockroft-Gault equation. The two equations may result in different antimicrobial dosing recommendations in up to 20 to 36% of cases with potential clinical significance.20 Recommendations for renal dose adjustment in the table below are for modifications of the maintenance doses; no adjustments required for loading doses where applicable. For patients on intermittent hemodialysis (IHD), antimicrobial dosages and
administration times may need to be adjusted. If an antimicrobial is significantly
removed by hemodialysis (HD) and recommended to be given post-HD then
administration of the dose prior to or during HD should be avoided because drug loss
could result in subtherapeutic levels post-HD. The dosing schedule should be adjusted
on dialysis days so that the scheduled dose is administered immediately after dialysis.
Other strategies may include supplementary doses administered post-HD to replace the
amount of antimicrobial removed during HD or intermittent post-HD administration (ex.
ceFAZolin 2 g IV post-HD 3 times weekly). Please consult your local pharmacy
department for guidance in patients receiving peritoneal dialysis, continuous veno-
venous hemofiltration, continuous veno-venous hemodiafiltration or continuous renal
replacement therapy. Dosing adjustment may also be necessary in patients with severe
In critically ill patients (ex: sepsis), antimicrobial pharmacokinetics can be significantly altered and unstable potentially resulting in sub-optimal dosing. A pharmacy consultation could be considered to optimize antimicrobial doses in this patient population. ADULT ANTIMICROBIAL DOSING TOOL - November 2015
Usual Adult Dose
(CrCl greater than
CrCl less than
or equal to 50
30 - 49 mL/min
10 - 29 mL/min
amoxicillin (PO)1,2,3,4,5,6 administer dose after dialysis on Do not use 875 mg tablets if CrCl <30 mL/min administer dose after dialysis on (dose listed as amoxicillin component) Less diarrhea with 875 mg given q12h vs.500 mg q8h Dose 2 g q4h for 1 – 2 g q12-24h; ampicillin (IV)1,3,5 endocarditis and other deep 1 – 2 g q8-12h 1 – 2 g q12-24h administer dose after dialysis on dialysis days cloxacillin (PO)1,5 500 – 1000 mg q6h Dose 2 g q4h for cloxacillin (IV)1,2,5 endocarditis and deep space infections‡ Dose 4 million units q4h for 20 – 50% of usual dose q4h; 2 – 4 million units 20 – 50% of usual penicillin G (IV)1,5 endocarditis and deep space 75% of usual dose q4h administer dose after dialysis on penicillin V (PO)2,5,8,9 300 – 600 mg q6h 300 – 600 mg q8h 2.25 g q6h (CrCl 20 – 40 mL/min) (CrCl less than 20 administer supplementary dose (dose listed as piperacillin plus tazobactam components) Hospital acquired pneumonia, febrile 3.375 g q6h (CrCl 20 – 40 mL/min) (CrCl less than 20 administer supplementary dose Pseudomonas spp infections piperacillin (IV)1,3,5 administer supplementary dose (CrCl 20-40mL/min) (CrCl less than 20 mL/min) of 1 g after dialysis session 1 – 2 g q24h; administer dose after dialysis on dialysis days ceFAZolin (1st) (IV)1,5,19 2 g after dialysis three times weekly if receiving dialysis three cephalexin (1st) (PO)1,3,5 administer dose after dialysis on 500 mg – 1 g three times weekly Dose 1 g twice daily for cefadroxil£ (1st) (PO)1,3,5 after dialysis if receiving dialysis three times weekly (continued on next page) ADULT ANTIMICROBIAL DOSING TOOL - November 2015
Usual Adult Dose
(CrCl greater than
CrCl less than
or equal to 50
30 - 49 mL/min
10 - 29 mL/min
250 mg q8h ; administer cefaclor£ (2nd) (PO)1,3,5 250 - 500 mg q8h supplementary dose of 250 mg after dialysis session 250 – 500 mg q24h; cefuroxime axetil (2nd) (PO)1,2,3,5 250 – 500 mg q24h administer dose after dialysis on cefuroxime (2nd) (IV)1,2,5 administer dose after dialysis on (CrCl greater than 20 mL/min) Dose 2 g q6h for moderate cefOXitin (2nd) (IV)1,5,10 to severe infections such as administer dose after dialysis on intra-abdominal infections cefprozil (2nd) (PO)1,3,5 administer supplementary dose of 250 mg after dialysis session cefixime (3rd) (PO)2,3 Dose 2 g q12h for CNS infections or Enterococcus cefTRIAXone (3rd) (IV)1 faecalis endocarditis in combination with ampicillin Moderate to severe infection administer dose after dialysis on cefotaxime (3rd) (IV)1,2,3 administer dose after dialysis on administer dose after dialysis on cefTAZidime (3rd) (IV)1,3,5 2 g after dialysis three times weekly if receiving dialysis three Uncomplicated mild to 1 – 2 g q8-12h moderate infections administer dose after dialysis on cefepime£ (4th) (IV)1,2 Severe infections including febrile neutropenia, hospital 2 g after dialysis three times acquire pneumonia deep weekly if receiving dialysis three space infections‡ or coverage for Pseudomonas aeruginosa (continued on next page) ADULT ANTIMICROBIAL DOSING TOOL - November 2015
Usual Adult Dose
(CrCl greater than
CrCl less than
or equal to 50
30 - 49 mL/min
10 - 29 mL/min
administer supplementary dose ertapenem£ (IV/IM)13,5 of 150 mg after dialysis session if daily dose given less than 6 hr before start of HD 250 – 500 mg q12h 250 – 500 mg q12h; Meropenem preferred for administer dose after dialysis on imipenem/cilastatinR (IV)1,11 CNS infections and when 500 – 1000 mg q6h CrCl less than 30 mL/min [consider
q6h dosing regimen: Caution: do NOT use this administer dose after dialysis on regimen for CNS infections meropenemR (IV)1,2,3,5 q8h dosing regimen: 500 mg – 1000 mg q24h; 500 mg – 1000 mg Dose 2 g q8h for CNS administer dose after dialysis on Aminoglycosides – Adjust dose for serum drug levels where applicable. For prolonged therapies consider pharmacy consult for appropriate dosing and monitoring
7 mg/kg for serious 5 – 7 mg/kg q48h start then use serial serum drug levels to 5 – 7 mg/kg q24h 5 – 7 mg/kg q36h gentamicin/tobramycin (IV) Dosing based on IBW, adjust (CrCl less (CrCl greater than or 1.5 – 2 mg/kg loading dose Extended Interval Dosing2,4,14 unless actual body weight equal to 60 mL/min) followed by 1 mg/kg greater than 20% above maintenance dose at the end of IBW, then use dosing weight each dialysis session; conventional dosing dose adjustments based on pre-dialysis levels (dosing based on patient's dry Dosing based on IBW, 1.5 – 2 mg/kg q8h weight if not obese; if dry weight unless actual body weight (CrCl greater than or 1.5 – 2 mg/kg q48-72hrs is greater than 20% of IBW then greater than 20% above equal to 80 mL/min) 1.5 – 2 mg/kg q24h dose is based off patients gentamicin/tobramycin (IV) IBW, then use dosing weight use serial drug levels to adjust; close Conventional Dosing 2,4,14 1.5 – 2 mg/kg q12h monitoring recommended Consider a loading dose of (CrCl less than 20 mL/min) 2 mg/kg to start 1 mg/kg at the end of each dialysis session;
1 mg/kg q8h (CrCl gentamicin/tobramycin (IV) 1 mg/kg q48-72hrs dose adjustments based on Dosing based on IBW, Synergy Dosing2,3,14 pre-dialysis levels unless actual body weight equal to 80 mL/min) (for Gram positive infections only; use serial drug levels to adjust; close (dosing based on patient's dry greater than 20% above tobramycin not for synergy against monitoring recommended weight if not obese; if dry weight IBW, then use dosing weight 1 mg/kg q12h (CrCl Enterococcus spp infections) (CrCl less than 20 mL/min) is greater than 20% of IBW then 50 – 79 mL/min) dose is based off patients (continued on next page) ADULT ANTIMICROBIAL DOSING TOOL - November 2015
Usual Adult Dose
(CrCl greater than
CrCl less than
or equal to 50
30 - 49 mL/min
10 - 29 mL/min
15 mg/kg to start Dosing based on IBW, serum drug levels to unless actual body weight 15 mg/kg q24h (CrCl 15 mg/kg q36h (CrCl adjust (CrCl less greater than 20% above 5 – 7.5 mg/kg at the end of each Extended Interval Dosing1,2,4 40 – 59 mL/min) IBW, then use dosing weight equal to 60 mL/min) dialysis session; dose adjustments based on pre-dialysis levels conventional dosing (dosing based on patient's dry Dosing based on IBW, 5 – 7.5 mg/kg q8h weight if not obese; if dry weight unless actual body weight (CrCl greater than or 5 – 7.5 mg/kg q48-72hrs is greater than 20% of IBW then greater than 20% above equal to 80 mL/min) 5 – 7.5 mg/kg q24h dose is based off patients IBW, then use dosing weight use serial serum drug levels to adjust; Conventional Dosing1,2,4 5 – 7.5 mg/kg q12h close monitoring recommended Consider a loading dose of (CrCl less than 20 mL/min) 7.5 mg/kg to start Macrolides
erythromycin (IV)1,2 500 – 1000 mg q6h 50 – 75% dose q6h Formulary products: •erythromycin base 250 mgcapsules containing EC erythromycin (PO)1,2,3 250 – 500 mg q6h 50 – 75% dose q6h pellets •erythromycin estolate 50mg/mL suspension azithromycin (IV)1 500 mg q24h x 3-5 days 500 mg q24h x 3 days Use with caution – No dose adjustment provided azithromycin (PO)1 500 mg on day one, then 250 mg daily for days 2 to 5 clarithromycin (PO)1,3,4 administer dose after dialysis on clarithromycin XL£ (PO)1,3 administer dose after dialysis on Quinolones
Uncomplicated UTI: ciprofloxacin (IV)1,2,8 administer dose after dialysis on Severe infections; infections due to Pseudomonas aeruginosa (continued on next page) ADULT ANTIMICROBIAL DOSING TOOL - November 2015
Usual Adult Dose
(CrCl greater than
CrCl less than
or equal to 50
30 - 49 mL/min
10 - 29 mL/min
UTI (uncomplicated): 250 – 500 mg q24h; Infection of the bone or skin, ciprofloxacin (PO)1,2,9 administer dose after dialysis on infections due to Pseudomonas spp or severe infections: 750 mg q12h 500 mg once then 500 mg once then 250 mg q48h (CrCl less than 20 mL/min or IHD) High dose for bacteremia, levofloxacin (PO/IV)1 complicated UTI, pyelonephritis, complicated skin infection, nosocomial 750 mg once then 500 mg q48h (CrCl less than 20 mL/min or IHD) pneumonia, intra-abdominal infections, infections due to Pseudomonas spp norfloxacin£ (PO)1,3 doxycycline (PO)1 200 mg then 100 mg minocycline£ (PO)1,3,5 Usual dose (Doxycycline preferred) 250 – 500 mg q6h 250 – 500 mg q24h 250 – 500 mg q8- 250 – 500 mg q12 – 24h tetracycline (PO)1,3,5 Use not recommended (Doxycycline preferred) tigecyclineR (IV)1 100 mg initially, then 50 mg q12h Other
600 – 900 mg q8h clindamycin (PO)1,12 300 – 450 mg q6-8h Skin and soft tissue infections: 4 mg/kg q24h Severe infections: Usual dose q48h if CrCl less than 30 Administer dose after dialysis on DAPTOmycinR (IV)1,3 8-10 mg/kg q24h 6 – 8 mg/kg q24h Monitor baseline and weekly creatine kinase levels (continued on next page) ADULT ANTIMICROBIAL DOSING TOOL - November 2015
Usual Adult Dose
(CrCl greater than
CrCl less than
or equal to 50
30 - 49 mL/min
10 - 29 mL/min
Uncomplicated UTI Administer dose after dialysis on linezolidR (PO/IV)1,2,3 Consider a supplemental dose Dose 500 mg q8h for after dialysis if administration metroNIDAZOLE (PO/IV)1,2 Clostridium difficile infection cannot be separated from the or CNS infection dialysis session nitrofurantoin monohydrate/macrocrystal sustained release capsules (MACROBID) (PO)1 Contraindicated if CrCl less than 40 mL/min nitrofurantoin regular release oral 50 – 100 mg q6h sulfamethoxazole + trimethoprim 8 – 20 mg TMP/kg/day divided q6-12h 50% of usual dose 2.5 – 10 mg/kg trimethoprim recommended, but if q24h; administer dose after •Each mL of injectable contains Dose listed as trimethoprim required: 4 – 6 dialysis on dialysis days sulfamethoxazole 80 mg and Pneumocystis jiroveci Treatment:
mg/kg/day divided trimethoprim 16 mg1,2,8 15 – 20 mg/kg/day divided q6-8h 5 – 20 mg/kg 3 times weekly (CrCl less than 15 after dialysis if receiving dialysis Use of sulfamethoxazole + three times weekly trimethoprim in moderate to severe renal dysfunction has sulfamethoxazole + trimethoprim not been not adequately Treatment (CrCl
studied, close monitoring of 15 – 30 mL/min):
sulfamethoxazole/trimethoprim 800/160 to patient response, 15 – 20 mg/kg/day jiroveci Treatment
•Each regular strength tablet 1600/320 mg q12h electrolytes and serum divided q6-8h for (CrCl less than15
contains sulfamethoxazole 400 mg creatinine recommended mL/min):
7 – 10 mg/kg after dialysis three and trimethoprim 80 mg mg/kg/day divided 7 – 10 mg/kg/day times weekly if receiving dialysis •Each mL of oral suspension Pneumocystis jiroveci Treatment:
three times weekly contains sulfamethoxazole 40 mg 15 – 20 mg/kg/day divided q6-8h and trimethoprim 8 mg1,2,8 CrCl less than 15 Administer dose after dialysis on trimethoprim (PO)2 (continued on next page) ADULT ANTIMICROBIAL DOSING TOOL - November 2015
Usual Adult Dose
(CrCl greater than
CrCl less than
or equal to 50
30 - 49 mL/min
10 - 29 mL/min
Consider a loading dose of 10 – 20 mg/L
Less than 70 kg: 25-30 mg/kg if severe Target Trough
1000 mg loading dose then 500 infection, adjusting 10 – 20 mg/L
10 – 20 mg/L
mg maintenance dose infused maintenance doses based (CrCl greater than on renal function Dosing based on actual 1250 mg loading dose then 750 Consider loading mg maintenance dose infused dose of 25 – 30 vancomycin (IV)2,8,13 Target Trough
Maximum of 2 g per dose for serial serum drug 15 – 20 mg/L
Greater than 100 kg: maintenance doses levels to adjust Target Trough
1500 mg loading dose then 15 – 20 mg/L
15 – 20 mg/L
1000 mg maintenance dose Adjust dose for serum drug (CrCl greater than infused after dialysis levels where applicable. For prolonged therapies (Adjust maintenance doses consider pharmacy consult based on pre-dialysis for appropriate dosing and vancomycin trough levels) C. difficile infection ONLY
See NB-ASC Clostridium
vancomycin (PO)1 125 – 500 mg q6h difficile Infection treatment guidelines for more details Antivirals
Dose based on ideal or dosing body weight Herpes zoster (shingles)/ Herpes simplex/ Varicella- 5 – 10 mg/kg q12h 5 – 10 mg/kg q24h Administer after dialysis on acyclovir (IV)1,2,3,9 zoster (chickenpox) in an 5 – 10 mg/kg q8h 2.5 – 5 mg/kg q24h immunocompromised host or patient with severe disease or encephalitis: 10 - 15 mg/kg q8h Herpes Zoster, and Administer dose after dialysis on Varicella: 800 mg five times 400 – 800 mg q8h to five times a day 400 – 800 mg q8h 200 – 800 mg q12h 250 mg after each dialysis Herpes zoster (shingles) (CrCl less than 20 250 mg after each dialysis famciclovir£ (PO)1,2,3,8 Primary genital herpes (CrCl greater than (CrCl less than 20 (CrCl 20 – 39 mL/min) 500 mg as a single 250 mg as a single dose after a dialysis session Recurrent Genital herpes (CrCl <20 mL/min) (continued on next page) ADULT ANTIMICROBIAL DOSING TOOL - November 2015
Usual Adult Dose
(CrCl greater than
CrCl less than
or equal to 50
30 - 49 mL/min
10 - 29 mL/min
2.5 mg/kg q12h if 1.25 mg/kg 3 times weekly (following dialysis, if receiving dialysis three times weekly) ganciclovir (IV)1,8 2.5 mg/kg q24 h if 0.625 mg/kg three times weekly (following dialysis, if 0.625 mg/kg q24h receiving dialysis three times weekly) Use with caution: 75 mg after each dialysis (CrCl greater than oseltamivir (PO)1,2,15 An initial 30 mg dose may be given prior to HD if exposed Use with caution: during the 48 hours between (for 10 to 14 days) dialysis sessions. Then administer 30 mg after alternate dialysis sessions 1 g three times weekly after Herpes zoster (shingles) dialysis, if receiving dialysis three times weekly 500 mg as a single Administer dose after a dialysis 2g q12h x 2 doses Administer dose after dialysis on Primary genital herpes valACYclovir (PO)1,2,16 Administer dose after dialysis on Recurrent genital herpes 1g q24h x 3 days Herpes simplex/ Varicella 1 g three times weekly after zoster Treatment in dialysis, if receiving dialysis oncology patients three times weekly Herpes simplex/ Varicella Administer dose after dialysis on zoster prophylaxis in oncology patients (CrCl greater than or Consider ID or Transplant Consult equal to 60 mL/min) valGANciclovir (PO)1,2,8 (CrCl greater than or Consider ID or Transplant Consult equal to 60 mL/min) (CrCl 25-39 mL/min) (continued on next page) ADULT ANTIMICROBIAL DOSING TOOL - November 2015
Usual Adult Dose
(CrCl greater than
CrCl less than
or equal to 50
30 - 49 mL/min
10 - 29 mL/min
10 mg inhaled orally q12h zanamivir£ (inhaled)1,15 10 mg inhaled orally q24h Antifungals
amphotericin B (IV)1,2,4,8
0.5-1 mg/kg q24h amphotericin B, lipid complex (IV)1,4,8 amphotericin B, liposomal£ (IV)1,8 3 – 6 mg/kg q24h 200 mg once then 100 mg q24h anidulafungin£ (IV)1 caspofungin£ (IV)1 70 mg once, then 50 mg q24h micafungin (IV)1,17 Esophageal candidiasis OR invasive aspergillosis Administer usual dose after Candidemia: 800 mg loading dialysis on dialysis days; on fluconazole (PO/IV)1 dose on day 1 then 400 mg 400 – 800 mg q24h 50% of the dose if CrCl 50 mL/min or less non-dialysis days, reduce dose Capsules and oral solution NOT bioequivalent itraconazole (PO)1 Aspergillosis: Consider 100 – 200 mg q24h loading dose of 200 mg q8h x 3 days; then 200 mg q12h Loading dose, 300 mg IV infusion q12h on day 1, followed Accumulation & resultant toxicity of the diluent can occur if CrCl less than 50 mL/min. posaconazole (IV)1,8,9 by 300 mg IV infusion q24h starting on day 2 Delayed-Release Tablet Loading dose of 300 mg q12h on day 1 followed by 300 mg q24h starting on day 2 posaconazole (PO)1,8,9 **Delayed release tablet and oral Prophylaxis: 200 mg three times daily suspension are NOT bioequivalent Treatment of invasive fungal infections: 400 mg q12h or 200 mg four times daily for patients unable to tolerate a meal or nutritional supplement Therapeutic drug 6 mg/kg q12h x 2 monitoring may be Accumulation & resultant toxicity of the diluent can occur if CrCl less than 50 mL/min. voriconazole (IV)1 doses then 4 mg/kg Use oral voriconazole at normal doses (continued on next page) ADULT ANTIMICROBIAL DOSING TOOL - November 2015
Usual Adult Dose
(CrCl greater than
CrCl less than
or equal to 50
30 - 49 mL/min
10 - 29 mL/min
400 mg q12h x 2 doses then 200 mg q12h for patients weighing greater than or equal to 40 kg; OR 200 mg q12h x 2 doses Therapeutic drug then 100 mg q12h for patients less than 40 kg voriconazole (PO)1,18 monitoring may be IDSA recommendations for invasive aspergillosis: may consider oral therapy in place of IV with dosing of 4 mg/kg rounded up to convenient tablet dosage form every 12 hours. IV administration preferred in serious infections as comparative efficacy with the oral route has not been established. Legend:
R: restricted antimicrobial
£: antimicrobial not listed on NB Hospital Formulary
‡: deep space infections include meningitis, septic arthritis,complicated abscesses, etc
IBW: ideal body weight
Dry body weight in hemodialysis: defined as the lowest tolerated post-dialysis weight at which there are minimal signs or symptoms of hypovolemia or hypervolemia.21
Obesity: defined as an actual body weight greater than 20% above patient's calculated ideal body weight.
Cockcroft-Gault equation for estimated creatinine clearance (mL/min): CrCL (females) = (140 – age) x weight (kg)* serum creatinine (mcmol/L) CrCl (males) = CrCl (females) x 1.2 *For weight, use ideal body weight unless actual body weight is greater than 20% of ideal body weight, in which case use dosing body weight.
Ideal body weight (IBW):
IBW (females) = 45.5 kg + 0.92 x (height in cm – 150 cm) OR 45.5 kg + 2.3 × (height in inches – 60 inches)
IBW (males) = 50 kg + 0.92 x (height in cm – 150 cm) OR 50 kg + 2.3 × (height in inches – 60 inches)
Dosing weight (kg) = IBW + 0.4 × (actual body weight – IBW) ADULT ANTIMICROBIAL DOSING TOOL - November 2015
Lexi-Comp Drug Information: (See specific drug monograph) Accessed online May 2015 Blondel-Hill E and Fryters S. Bugs and Drugs An Antimicrobial/Infectious Diseases Reference2012 The Johns Hopkins POC-IT ABX Guide The Unbound Plateform: (See Specific drug monograph)Accessed online May 2015 Antimicrobial Handbook – 2012. Editor: Dr Kathy Slayter. Antimicrobial Agents Subcommittee.
Capital Health, Nova Scotia.
Aronoff GR, Bennett WM, Berns JS, Brier ME, Kasbekar N et al. Drug Prescribing in RenalFailure Dosing Guidelines for Adults and Childeren. 5th Ed. American College of PhysiciansPhiladelphia 2007 Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD et al. Infectious DiseasesSociety of America/American Thoracic Society Consensus Guidelines on the Management ofCommunity-Acquired Pneumonia in Adults. Clinical Infectious Diseases 2007; 44:S27-72 RxFiles Drug Comparison Charts. 10th Ed. October 2014 DrugDex: (See specific product monograph). Accessed online May 2015 e-CPS Drug Monographs:(see specific drug monograph). Accessed online May 2015 10. Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJC et al. Diagnosis and Management of Complicated Intra-abdominal Infection in Adults and Children: Guidelines by theSurgical Infection Society and the Infectious Diseases Society of America. Clinical InfectiousDiseases 2010;50:133-164 11. Parenteral Drug Therapy Manual. Horizon Health Network – Moncton Area. Accessed online 12. Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJ et al. Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by theInfectious Diseases Society of America. Clinical Infectious Diseaseshttp://www.idsociety.org/Organ_System/#Skin & Soft Tissue Accessed online May 2015 13. Rybak M, Lomaestro B, Rotschafer JC, Moellering R Jr., Craig W et al. Therapeutic drug monitoring of vancomycin in adult patients: A consensus review of the American Society ofHealth-System Pharmacists, the Infectious Diseases Society of America, and the Society ofInfectious Diseases Pharmacists. Am J Health-Syst Pharm. 2009; 66:82-98 14. Horizon Health Network Standard Operating Practice Nephrology & Hypertension Services, Hemodialysis. Vancomycin and Aminoglycoside Dosing and Monitoring Guidelines. Effectivedate: 03/02/2012 15. Stiver HG, Evans GA, Aoki FY, Allen UD and Laverdiere M. Guidance on the use of antiviral drugs for influenza in acute care facilities in Canada, 2014-2015. Ca J Infect Dis Med Microbiol26(1):e5-e8 16. NCCN Clinical Practice Guidelines in Oncology Prevention and Treatment of Cancer Related Infections Version 2.2015.
17. Enoch DA, Idris SF, Aliyu SH, Micallef C, Sule O and Karas JA. Micafungin for the treatment of invasive aspergillosis. Journal of Infection 2014 68;507-526 18. Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP et al. Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America. ClinicalInfectious Diseases 2008;46:327-60 19. Turnidge, JD. Cefazolin and Enterobacteriaceae: Rationale for Revised Susceptibility Testing Breakpoints. Clinical Infectious Diseases 2011;52(7):917-924 20. Wargo KA, Eiland EH, Hamm W, English TM and Phillippe HM. Comparison of the Modification of Diet in Renal Disease and Cockcroft-Gault Equations for Antimicrobial Dosage Adjustments.
Ann Pharmacother 2006; 40:1248-1253.
21. Agarwal R and Weir MR. Dry Weight: A Concept Revisited in an Effort to Avoid Medication- Directed Approaches for Blood Pressure Control in Hemodialysis Patients. Clin J Am SocNephrol. 2010 Jul;5(7):1255-1260 Management of Penicillin and Beta-Lactam Allergy
(NB Provincial Health Authorities Anti-Infective Stewardship Committee, February 2016) Key Points
• Beta-lactams are generally safe; allergic and adverse drug reactions are over diagnosed and reported • Nonpruritic, nonurticarial rashes occur in up to 10% of patients receiving penicillins. These rashes are usually not allergic and are not a contraindication to the use of a different beta-lactam • The frequently cited risk of 8 to 10% cross-reactivity between penicillins and cephalosporins is an overestimate based on studies from the 1970's that are now considered flawed • Expect new intolerances (i.e. any allergy or adverse reaction reported in a drug allergy field) to be reported after 0.5 to 4% of all antimicrobial courses depending on the gender and specific antimicrobial. Expect a higher incidence of new intolerances inpatients with three or more prior medication intolerances.1 • For type-1 immediate hypersensitivity reactions (IgE-mediated), cross-reactivity among penicillins (table 1) is expected due to similar core structure and/or major/minor antigenic determinants, use not recommended without desensitization.
• For type-1 immediate hypersensitivity reactions, cross-reactivity between penicillins (table 1) and cephalosporins is due to similarities in the side chains; risk of cross-reactivity will only be significant between penicillins and cephalosporins with similarside chains • Only type-1 immediate hypersensitivity to a penicillin manifesting as anaphylaxis, bronchospasm, angioedema, hypotension, urticaria or pruritic rash warrant the avoidance of cephalosporins with similar side chains and other penicillins • Patients with type-1 immediate hypersensitivity to a penicillin may be safely given cephalosporins with side chains unrelated to the offending agent (See figure 1 & 2 below)
For example, ceFAZolin does not share a side chain with any beta-lactam and is not expected to cross react with otheragents • Cross-reactivity between cephalosporins is low due to the heterogeneity between side chains; therefore, a patient with a cephalosporin allergy may be prescribed another cephalosporin with a dissimilar side chain • Cross-reactivity between penicillins and carbapenems is low. Carbapenems would be a reasonable option when antibiotics are required in patients with type-1 immediate hypersensitivity reaction to penicillins • Patients with reported Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, immune hepatitis, hemolytic anemia, serum sickness or interstitial nephritis secondary to beta-lactam use should avoidbeta-lactams and not receive beta-lactam skin testing, re-challenging or desensitization • Penicillin skin tests can be used to predict penicillin sensitivity and have a 97-99% negative predictive value • Any patient with possibility of type-1 immediate hypersensitivity to a beta-lactam should be referred for allergy confirmation Management of the Beta-Lactam Allergy (Figure 1 & Figure 2) 1,2,3,4
Avoid the unnecessary use of antimicrobials, particularly in the setting of viral infections.
Complete a thorough investigation of the patient's allergies, including, but not limited to: the specific drug the patientreceived, a detailed description of the reaction, temporal relationship of the onset of the reaction with respect towhen the drug was given, concomitant drugs received when the reaction occurred, the time elapsed since thereaction occurred and tolerability of any structurally related compounds Patient reports intolerance (e.g. nausea, vomiting, diarrhea, headache) – likely not allergic, attempt beta-lactam therapy Patient has a documented severe non-IgE mediated hypersensitivity reaction to a beta-lactam (e.g.
interstitial nephritis, immune hepatitis, hemolytic anemia, serum sickness, severe cutaneous reactions suchas Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia andsystemic symptoms (DRESS), etc…) – avoid all beta-lactam antibiotics including their use for allergytesting, desensitization and re-challenge.
Treatment options include non-beta-lactam antibiotics Patient has a documented severe type-1 immediate hypersensitivity reaction to a penicillin (e.g.
anaphylaxis, urticaria, angioedema, hypotension, bronchospasm, stridor, pruritis) – avoid other penicillinsand cephalosporins with similar side chain, unless patient undergoes desensitization.
Treatment options include cephalosporins with dissimilar side chains or carbapenems or non- beta-lactam antibiotics – Note: ceFAZolin does not share a side chain with any beta-lactam agent.
Patient has a documented severe type-1 immediate hypersensitivity reaction to a cephalosporin (e.g.
anaphylaxis, urticaria, angioedema, hypotension, bronchospasm, stridor, pruritis) – avoid cephalosporinswith similar side chains and penicillins with similar side chains (see figure 2) unless desensitization isperformed.
Treatment options include penicillins with dissimilar side chains, cephalosporins with dissimilar side chains, carbapenems or non-beta-lactam antibiotics.
Figure 1: Management Diagram
Reported Penicil in Allergy
Assess the nature of the allergy Onset after more
Onset within 1-72
hours of administration
than 72 hours of
Intolerance such as:
Onset after more
than 72 hours of
bronchoconstriction, epidermal necrolysis, allergic rhinitis, immune hepatitis, early onset urticaria, morbiliform rash, maculopapular rash sickness hemolytic anemia or interstitial Further assess the
desensitizing and re- challenging with all beta-lactam antibiotics What specific agent? Penicillin skin testing available?
Convincing history of
Avoid all penicillins as reaction:
well as beta-lactams Avoid all penicillins as with a similar side monitored setting; if well as beta-lactams chain (see figure 2) or negative, penicillin with a similar side class antibiotics may chain (see figure 2) or desensitization or select a non-beta- desensitization or lactam antibiotic select a non-beta- lactam antibiotic. Figure 2: Matrix of Beta-Lactam Cross Allergy (based on similar core and/or side chain structures) 5, 6, 7, 8, 9
Each ‘X' in the matrix indicates side-chain and/or major/minor antigenic similarity between two antibiotics. For type-1 immediate hypersensitivity there is a risk of cross-allergenicity between pairs due to similar side-chains and/or major/minor antigenic determinants, use NOT recommended without desensitization.
For example: a patient allergic to amoxicillin would likely manifest a reaction to ampicillin, cloxacillin, piperacillin, ticarcillin, cefadroxil, cephalexin, cefaclor and cefprozil but NOT to ceFAZolin, cefuroxime or cefTRIAXone, etc.
4TH GEN CEPH
Beta-lactam antibiotics are the most commonly prescribed class of antimicrobials and include penicillins, cephalosporins, carbapenems and monobactams (table 1).9 Due to similarities in their beta-lactam ring structure it has been widely accepted that penicillins, cephalosporins and carbapenems have significant cross-reactivity with other classes of beta-lactams.5,9,10,11 Historically it has been reported that approximately 10% of patients allergic to penicillins are also allergic to cephalosporins and up to 50% cross-reactivity has been reported between penicillins and carbapenems.4,5,9,10,11 Therefore, it has been commonly recommended that patients with a severe allergic reaction to one class of beta-lactam antibiotic should not receive any beta-lactam antibiotic.9 This historic over-estimation of cross-sensitivity between classes of beta-lactams is inaccurate and based on flawed methodologies.12 Studies have shown that physicians are more likely to prescribe antimicrobials from other classes when patients have a documented penicillin or cephalosporin allergy.13,14 Non beta-lactam alternatives may be: less effective, more toxic, broader spectrum, more expensive and more likely to lead to infection or colonization with resistant organisms.4,13,15,16,17 The inaccurate documentation of a penicillin allergy can lead to undesirable patient outcomes. For example, one study showed that patients with a documented penicillin allergy at admission spend more time in hospital and are more likely to be exposed to antibiotics associated with C.difficile and vancomycin resistant Enterococcus.18 In addition they had increased prevalence rates for infections secondary to C.difficile, vancomycin-resistant Enterococcus and methicillin-resistant Staphylococcus aureus.18 Practice however is changing because allergies have been better defined and the role of the chemical structure on the likelihood of cross-reactivity is now better understood. Recent data shows that the rate of allergic cross-reactivity between penicillins and other beta-lactams is much lower than previous estimates.4,5,9,11 Determining the nature of the patient's reaction is an important step in differentiating between an allergic reaction and an adverse drug reaction such as nausea, vomiting, diarrhea and headache.5,9 Immunologic reactions to medications are generally classified according to the Coombs and Gell classification of hypersensitivity reactions (see table 2).5,9 The onset and presentation of the reaction can be used to help classify the reaction and determine whether or not a beta-lactam antibiotic may be used (table 2).5,9 Type-1, immediate hypersensitivity reactions, are immunoglobulin (Ig) E-mediated reactions and are the only true allergic reactions where the potential risk of cross-reactivity between beta-lactams should be considered.5,9 Type-1 immediate hypersensitivity reactions usually occur within 1 hour of exposure and typically manifest as anaphylaxis, bronchospasm, angioedema, stridor, wheezing, hypotension, urticaria or a pruritic rash.5 The incidence of these reactions is very low.19 Nonurticarial and nonpruritic rashes are almost certainly not IgE-mediated.5 Penicillins
Penicillin is the most frequently reported drug allergy and is reported in 5-10% of the population.20,21,22 Studies have shown that between 80 and 95% or more of those patients reporting a penicillin allergy do not in fact have true hypersensitivity reactions and the vast majority of these patients can tolerate beta-lactams.1,10,21,22,23,24,25 The use of penicillins can be associated with a nonimmediate, nonpruritic, nonurticarial rash in up to 10% of patients that is unlikely to be IgE-mediated and most often idiopathic or T-cell mediated.5,26 While inconvenient, these reactions have not been associated with anaphylaxis and pose no risk of cross reactivity with other beta-lactams.26 An example is the nonpruritic maculopapular rash commonly seen after the administration of ampicillin or amoxicillin to children suffering from infectious mononucleosis secondary to the Epstein-Barr virus.27 Only a type-1 immediate (IgE-mediated) hypersensitivity reaction to a penicillin manifesting as: anaphylaxis, bronchospasm, angioedema, hypotension, urticaria or pruritic rash warrants the avoidance of other penicillins and cephalosporins with similar side chains.4,5,9,11 Cross-reactivity between penicillins (figure 2) may be due to shared common antigenic determinants based on similarities in their core ring structure that is common to all penicillins and/or the side chains that distinguish different penicillins from one another; therefore, cross-reactivity cannot be based on side chain similarities alone. Currently, there is one Health Canada-approved standardized penicillin skin test. PRE-PEN contains the major antigenic determinant of penicillin and is used to rule out a type-1 immediate (IgE-mediated) penicillin allergy. Available literature suggests that the skin test using both major and minor antigenic determinants are roughly 50-60% predictive of penicillin hypersensitivity with a 97-99% negative predictive value.4 When penicillin skin testing is not available, the approach to penicillin allergic patients is based on their reaction history and the need for treatment with a penicillin.28 While patients with a convincing reaction history are more likely to be allergic, those with vague histories cannot be discounted as they may also be penicillin allergic.28 The time passed since the reaction is useful because 50-80% of penicillin allergic patients lose their sensitivity after 5 and 10 years respectively.2,29,30 Skin testing, desensitization or re-challenge with a beta-lactam should not be performed in those patients with a history of Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, serum sickness, immune hepatitis, hemolytic anemia or interstitial nephritis.5 Cephalosporin-induced skin reactions, described as urticarial, rash, exanthema and pruritus, occur in approximately 1 to 3% of patients.31 Early analysis of cephalosporin use in penicillin allergic patients was complicated by the uncritical evaluation of "allergic reaction".5,9,11 Any adverse reaction to cephalosporins was often classified as "allergic".5,9,11 This, accompanied with possible penicillin contamination in early cephalosporin production, resulted in overestimations of cross sensitivity.5,9 In addition, penicillin allergic patients are more likely to have an allergy to any drug when compared to other patients.4,5,9,10,11 Investigations have shown that individuals with a penicillin allergy are three times more likely to develop new allergies to unrelated compounds, leading to further overestimations of cross-reactivity.5,9,10 Cross-reactivity between penicillins and cephalosporins is due to similarities in side chains at the C-3 or C-7 position as shown in table 3 and not similarities in beta-lactam ring structure as previously speculated.4,5,9,11 The American Academy of Pediatrics states that the likelihood of a penicillin allergic patient reacting to a cephalosporin with a different side chain is similar to that of a non-penicillin allergic patient.5 A prospective study with skin test or challenge dose confirmed penicillin allergy demonstrated a 0% cross-reactivity to ceFAZolin, cefuroxime and cefTRIAXone. None of these agents share a side chain with penicillin.32 Meanwhile the risk of cross-reactivity may be up to 40% between penicillins and cephalosporins with the similar R-group side chains.3,33 Cross-reactivity between cephalosporins is low because of the significant heterogeneity of the side chains at the C-3 and C-7 positions.9,34 Therefore, if a patient has a cephalosporin allergy, one can safely prescribe another cephalosporin that has dissimilar side chains at both C-3 and C-7 positions.34 CeFAZolin is not expected to cross react with any penicillin or cephalosporin as it does not share a side chain with any beta-lactam.4,34 Carbapenems
Early studies evaluating the risk of cross-reactivity between penicillin and carbapenems found rates upwards of 47%. However, these studies had poor definitions of allergy and variable methods for determining allergy status.9 A more recent systematic review was completed to collect and combine all published data on pediatric and adult patients reported to have a clinical history of type-1 immediate hypersensitivity (IgE-mediated) to a penicillin and/or cephalosporin who were then given a carbapenem.35 Within the study allergic reactions were classified as proven, suspected or possible IgE-mediated and non-IgE-mediated.35 Overall, for patients with a history of proven, suspected or possible IgE-mediated reaction to a penicillin; 4.3% (36/838) had a suspected hypersensitivity reaction to a carbapenems but only 20 were compatible with an IgE-mediated reaction and only one was considered to be proven.35 The authors concluded that carbapenems would be a reasonable option when antibiotics are required in patients with IgE-mediated reactions to penicillins.35 They advise that clinicians proceed with caution by administering the first dose of carbapenem in a setting where anaphylaxis can be managed and to consider giving via a graduated challenge.35 If at any stage the patient reacts then the options are to use a carbapenem desensitization protocol or switch to a non-beta-lactam antibiotic.35 Desensitization, or temporary induction of drug tolerance, is used for patients with a documented or convincing history of type-1 immediate (IgE-mediated) beta-lactam allergy and/or positive skin test and a serious infection where non-cross-reacting alternatives are not appropriate.2,28 The goal of desensitization is to modify a patient's immune response to allow safe treatment with the allergenic drug.28 Desensitization will not prevent non-IgE mediated reactions and should never be attempted in patients with reactions involving major organs or severe cutaneous reactions (e.g. interstitial nephritis, SJS, TEN, DRESS, etc.).2 Desensitization is performed by administering incremental doses of the allergenic drug.3 Usually the procedure is complete within hours and starts in the microgram range.28 Dosages are usually doubled every 15 to 30 minutes until therapeutic doses are achieved.28 When the desensitization process is complete, treatment with the select beta-lactam should be started immediately and must not be interrupted during the treatment course.2,28 Desensitization is usually lost within two days of cessation and must be repeated if the beta-lactam is required in the future.2,28 Graduated Challenge
Graduated challenges are used when there is a low likelihood of drug allergy and differ from desensitization in that they do not alter the patient's underlying immune response to the drug in question.28 Their purpose is to allow cautious administration in patients unlikely to be allergic when there is no intention to alter the patient's immune response.28 If the graduated challenge is tolerated the patient is then considered not to be allergic and not at increased risk for future reactions.28 Graduated challenges should never be performed in patients with reactions involving major organs or non-IgE mediated severe cutaneous reactions (e.g. interstitial nephritis, SJS, TEN, DRESS, etc…).28 The starting dose of a graduated challenge is often higher than that used for desensitization and usually only involves 2 to 3 steps and completed within hours.28 For a graduated challenge for an intravenous antibiotic, 1% of the full dose is administered, then 10 % of the full dose, then the full dose, separated by 30 minutes to 1 hour each and under careful observation.2,3 If at any point a reaction occurs the graduated challenge is stopped. The decision to use a graduated challenge is based on the risk of cross-reactivity and the description and remoteness of the allergic reaction in question. Treatment options requiring desensitization or graduated challenge should be avoided in severe infections (ex. febrile neutropenia, sepsis, meningitis, etc.) where delays in appropriate drug therapy are associated with poor patient outcome, in these scenarios a non-beta lactam treatment option should be considered for empiric therapy. Table 1: Classification of Beta-Lactams
piperacillin ticarcillin Table 2: Coombs and Gell Classification of Hypersensitivity Reactions4,5
I - Immediate and Acute hypersensitivity (Rarely up to 72 hypotension, bronchospasm, stridor, pruritis Avoid the offending
agent and side chain
(See Figure 2)
II – Delayed cytotoxic Hemolytic anemia, Drug specific, avoid antibody-mediated thrombocytopenia, the offending agent hypersensitivity III – Antibody complex- Antibody-antigen glomerulonephritis, complexes precipitate hypersensitivity vasculitis, drug potentially affect any IV – Delayed type Contact dermatitis, Incidence is low. hypersensitivity Ex: Eosinophilia, bullous exanthems, severe exfoliative dermatoses (ex. SJS/TEN), interstitial nephritis, immune hepatitis and some morbilliform or maculopapular rashes Idiopathic Reactions Maculopapular or 1 – 4% of patients morbilliform rashes receiving beta-lactams Not a contraindication to future use of beta-lactam antibiotics *Anaphylaxis: defined as serious hypersensitivity reaction that is rapid in onset and may cause death, typically involving theskin, mucosal tissue or both and either respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia) or reduced blood pressure or the associated symptoms and signs of end-organ dysfunction. Table 3: Beta-Lactam Groups with Similar Side-Chains
Similar C-7Side Chain
Similar C-3 Side Chain
(Cross Reactions between agents (Cross reactions between agents within one group is possible) within one group is possible) cephalexin cefadroxil cefprozil • CeFAZolin does not share a side chain with any beta-lactam and is not expected to cross react with other agents• Amoxicillin, ampicillin, penicillin, cloxacillin, piperacillin and ticarcillin share common major allergic determinants based on similarities in their core structure and/or side chains; therefore, cross-reactivity cannot be based on sidechain similarities alone Macy E and Ngor E. Recommendations for the Management of Beta-Lactam Intolerance. Clinic RevAllerg Immunol 2014; 47:46-55 Blondel-Hill and Fryters. B-Lactam Allergy. Bugs and Drugs: An antimicrobial/infectious diseasereference. 2012:87-90.
PL Detailed-document, Allergic Cross-reactivity Among Beta-lactam Antibiotics: An Update.
Pharmacist's Letter/Prescriber's Letter. October 2013 Terico AT and Gallagher JC. Beta-lactam allergy and cross-reactivity. J Pharm Pract. 2014Dec;27(6):530-44.
Pichichero, Michael E. A review of evidence supporting the American Academy of Pediatricsrecommendations for prescribing cephalosporin antibiotics in penicillin allergic patients. Pediatrics.
DePestel DD, Benninger MS, Danziger L, LaPlante KL, May C, et al. Cephalosporin use in treatment ofpatients with penicillin allergies. J Am Pharm Assoc. 2008; 48:530-540 Mirakian R, Leech SC, Krishna MT, Richter AG, Huber PAJ, et al. Management of allergy to penicllinsand other beta-lactams. Clinical & Experimental Allergy45:300-327 Pichichero ME and Zagursky R. Penicillin and Cephalosporin Allergy. Ann Allergy Asthma Immunol112(2014):404-412 Lagacé-Wiens P. and Rubinstein E. Adverse reactions to B-Lactam antimicrobials. Expert Opin. DrugSaf. 2012(11):381-99.
10. Herbert ME, Brewster GS, Lanctot-Herbert M. Medical Myth: Ten percent of patients who are allergic to penicillin will have serious reactions if exposed to cephalosporins. West J Med 2000;172:341 11. Pichichero ME. Use of selected cephalosporins in penicillin allergic patients. A paradigm shift.
Diagnostic Microbiology and Infectious Disease. 2007(52):13-18.
12. Pichichero ME and Casey JR. Safe use of selected cephalosporins in penicillin-allergic patients: A meta-analysis. Otolaryngology-Head and Neck Surgery 2007; 136:340-347 13. Lee CL, Zembower TR, Fotis MA, Postelnick MJ; Greenberger PA, et al. The Incidence of Antimicrobial Allergies in Hospitalized Patients. Arch Intern Med 2000; 160:2819-2822 14. Solensky R., Earl, H.S., Gruchalla R.S. Clinical Approach to Penicillin-Allergic Patients: A Survey. Ann Allergy Asthma Immunol 2000. Mar; 84(3):329-333 15. MacLaughlin EJ, Saseen JJ and Malone DC. Cost of β-Lactam Allergies: Selection and Costs of Antibiotics for patients with a Reported β-lactam Allergy. Arch Fam Med. 2000; 9:722-726 16. Schweizer ML, Furuno JP, Harris AD, Johnson JK, Shardell MD, et al. Comparative effectiveness of nafcillin or cefazolin versus vancomycin in methicillin-susceptible Staphylococcus aureus bacteremia.
BMC Infectious Diseases 2011; 11:279 17. Stryjewski ML, Szczech LA., Benjamin, Jr DK., Inrig JK., Kanafani ZA., et al. Use of vancomycin or first- generation cephalosporins for the treatment of hemodialysis-dependent patients with methicillin-susceptible Staphylococcus aureus bacteremia. Clin Infect Dis 2007; 44:190-196 18. Macy E. and Contreras R. Health care use and serious infection prevalence associated with penicillin "allergy" in hospitalized patients: A cohort study. J Allergy Clin Immunol 2014;133:790-796 19. Romano A and Caubet JC. Antibiotic Allerigies in Children and Adults: From Clinical Symptoms to Skin Testing and Diagnosis. J Allergy Clin Immuinol Pract 2014;2:3-12) 20. Solensky R. Allergy to β-lactam Antibiotics. J Allergy Clin Immunol. 2012; 130(6):1442-1442.e5.
21. Macy E, Schatz M, Lin CK and Poon KY. The Falling Rate of Positive Penicillin Skin Tests from 1995 to 2007. The Permanente Journal 2009;13(2):12-18 22. Borch JE., Anderson KE, Bindslev-Jensen C. The Prevalence of Suspected and Challenge-Verified Penicillin Allergy in a University Hospital Population. Basic & Clinical pharmacology & Toxicology 2006;98:357-362 23. Frumin J and Gallagher JC. Allergic Cross-Sensitivity Between Penicillin, Carbapenem and Monobactam Antibiotics: What are the Chances? The Annals of Pharmacotherapy 2009 Feb; 43:304-315 24. Jost BC., Wener HJ and Bloomberg GR. Elective Penicillin Skin Testing in a Pediatric Outpatient Setting. Ann Allergy Asthma Immunol 2006 Dec; 97(6):807-812 25. Wong BB., Keith PK., Waserman S. Clinical History as a Predictor of Penicillin Skin Test Outcome. Ann Allergy Asthma Immunol. 2006 Aug;97(2):169-174 26. Schiavino D., Nucera E., De Pasquale T., Roncoallo C., Pollastrini E., et al. Delayed allergy to aminopenicillins : clinical and immunological findings. Int J Immunopathol Pharmacol 2006 Oct-Dec ;19(4) :831-840 27. Aronson MD and Awwaerter PG. Up-to-Date Infectious mononucleosis in adults and adolesants. In.
Accessed online August 2015 28. Solensky R. and Khan DA. (Editors) Joint Task Force on Practice Parameters. Drug Allergy: an Updated Practice Parameter. Ann Allergy Asthma Immunol 2010; 105:259-273 29. Blanca M, Torres MJ, Garcia JJ et al. Natural evolution of skin test sensitivity in patients allergic to beta- lactam antibiotics. J Allergy Clin Immunol. 1999; 103:918-924.
30. Sullivan TJ, Wedner HJ, Shatz GS, et al. Skin testing to detect penicillin allergy. J Allergy Clin Immunol.
31. KelKar P.S. and Li J.T.C. Cephalosporin Allergy. N Engl J Med 2001; 345(11):804-80932. Novalbos A, Sastre J, Cuesta J et al. Lack of allergic cross-reactivity to cephalosporins among patients allergic to penicillins. Clin Exp Allergy. 2001;31(3):438-443 33. Miranda A, Blanca M, Vega JM et al. Cross-reactivity between a penicillin and a cephalosporin with the same side chain. J Allergy Clin Immunol 1996;98(3):571-677 34. MSH+UHN Antimicrobial Stewardship Program. Antimicrobial Stewardship Clinical Summaries-Beta- lactam Allergy.accessed March 5, 2015) 35. Kula B, Djordjevic G, and Robinson JL. A Systematic Review: Can one Prescribe Carbapenems to Patients with IgE-Mediated Allergy to Penicillins or Cephalosporins? CID 2014;59(8):1113-1122 Antimicrobial Allergy Evaluation Tool
(NB Provincial Health Authorities Anti-Infective Stewardship Committee, May 2016)
Reaction (as indicated in the patient's chart or described by the patient )
Asthma Autoimmune disease Atopic dermatitis Latex allergy Prior anaphylaxis Multiple drug intolerance syndrome Multiple drug allergy syndrome Food allergy: Other: _ Patient questionnaire
1. When did the reaction take place? _ 2. How old was the patient at the time of the reaction? _ 3. Does the patient recall the reaction? If not, who informed them of the reaction? 4. Does the patient remember which medication? _ 5. What was the medication prescribed for? 6. What was the route of administration? 7. How long after starting the medication did the reaction begin? _ 8. Describe the reaction: _ 9. Did the patient seek medical care due to the reaction? _ 10. Was the medication discontinued? If so, what happened after it was discontinued? _ 11. Did the patient have any other ongoing medical problem at the time of the reaction? 12. What other medications was the patient taking? Why and when were they prescribed? 13. Has the patient taken any similar medications before or after the reaction? If so, what was the result? 14. Has the patient ever experienced this reaction without intake of the suspected medication? Assessment
Probable non-severe delayed hypersensitivity
Probable type 1 immediate hypersensitivity reaction
reaction (non-IgE mediated)
Probable non-allergic adverse reaction or
Probable severe delayed hypersensitivity reaction
Completed by: _ Date/time: _ Table 1: Patient questionnaire1,2,4,5,6,7,12,13,14
When did the reaction take place? Patients with type 1 immediate (IgE-mediated) hypersensitivity reactions to penicillin may lose their sensitivity over time (50% after 5 years, and 80% after 10 years) How old was the patient at the time of the Certain confounding factors may be more common depending on the patient's age. (Example: viral exanthems in pediatric patients) Does the patient recall the reaction? If not, Vague histories do not rule out serious reactions. However, it is less
who informed them of the reaction? likely to be a serious hypersensitivity reaction if the patient or family cannot recall the specifics of the reaction. Does the patient remember which medication? Knowing the specific antimicrobial which caused the reaction can help in determining safe alternatives. What was the medication prescribed for? Sometimes patients confuse symptoms of the condition with adverse reactions of the medication. (e.g.: Strep. pyogenes scarlet fever rash being confused as a drug-reaction) What was the route of administration? Hypersensitivity reactions can be more common when medications are administered intravenously compared to orally. How long after starting the medication did the Timeframe is essential to distinguish between an IgE-mediated immediate hypersensitivity reaction or non-IgE mediated delayed reaction. Describe the reaction. Obtain specific information from the patient. (Ex: if a rash; determine location, morphology, etc.) Did the patient seek medical care due to the Can be of value to stratify how severe the reaction was. Was the medication discontinued? If so, what Discontinuing the medication will have varying results. (e.g.: depending happened after it was discontinued? on the type of skin reaction, symptoms may or may not improve after discontinuation) Did the patient have any other ongoing Certain viral infections [e.g. Epstein-Barr virus (EBV), Herpes simplex medical problem at the time of the reaction? virus (HSV), Human immunodeficiency virus (HIV), Cytomegalovirus (CMV)] are associated with non-IgE mediated cutaneous drug reactions that are often misdiagnosed as "allergic reactions". What other medications was the patient Concomitant medications could cause or contribute to the reaction. taking? Why and when were they prescribed? Has the patient taken any similar medications Tolerance of structurally similar medications is not always indicative of before or after the reaction? If so, what was tolerance of the suspected medication; however, it can assist in determining safe alternatives. Has the patient ever experienced this reaction If the same reaction has occurred without exposure to the suspected without intake of the suspected medication? medication, it may be caused by other factors. Allergy evaluation is an essential component of patient care. Beta-lactams, as a class, are generally safe; allergic and adverse reactions are over diagnosed and over reported. For example, up to 10% of the population will report a penicillin allergy; but up to 95% (or more) of these patients do not have a true allergy.4,6,11 Fearing a potential anaphylaxis secondary to beta-lactam use, many clinicians will over diagnose penicillin allergy or simply accept a diagnosis of penicillin allergy from patients without a proper history of the reaction.2 Studies have shown that physicians are more likely to prescribe antimicrobials from other classes when patients have a documented penicillin or cephalosporin allergy.2,9 Non beta-lactam alternatives may be: less effective, more toxic, broader spectrum, more expensive and more likely to lead to infection or colonization with resistant organisms.6,9 Unfortunately, a penicillin allergy label is not benign. Simply being labelled as having an allergy to penicillin increases the likelihood of prolonged hospital stay and increases the risk of infections due to Clostridium difficile, vancomycin-resistant Enterococcus (VRE), and methicillin-resistant Staphylococcus Aureus (MRSA).10 Most patients have no current physical findings that can either prove or disprove their allergy label.2 The initial probability of a true allergy is almost always determined by the allergy history.2 The included patient questionnaire can assist clinicians in obtaining a detailed allergy history. A detailed investigation of the patient's allergy history is necessary to differentiate between true type 1 (IgE-mediated) immediate hypersensitivity reactions (true allergic reactions) and non IgE-mediated hypersensitivity reactions or intolerances/adverse reactions. While some of the non IgE-mediated reactions are minor, other types of reactions can be severe (e.g. interstitial nephritis, immune hepatitis, hemolytic anemia, serum sickness, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, etc.). Table 2 below subdivides the reactions based on the Coombs and Gell classification of hypersensitivity reactions: Table 2: Coombs and Gell Classification of Hypersensitivity Reactions 6,7
I - Immediate and Acute Anaphylaxis, urticaria, Anaphylaxis: Penicillins hypersensitivity (Rarely up to 72 hypotension, bronchospasm, stridor, Cephalosporins 0.0001- II – Delayed cytotoxic Hemolytic anemia, antibody-mediated thrombocytopenia, hypersensitivity III – Antibody complex- Antibody-antigen complexes mediated hypersensitivity glomerulonephritis, precipitate in tissues and small vessel vasculitis, potentially affect any end IV – Delayed type Contact dermatitis, Incidence is low. hypersensitivity Ex: Eosinophilia, bullous exanthems, severe exfoliative dermatoses (ex. SJS/TEN), interstitial nephritis, immune hepatitis and some morbilliform or maculopapular rashes Idiopathic Reactions Usually greater than Maculopapular or 1 – 4% of patients receiving morbilliform rashes The time to onset of the reaction can be a helpful tool in determining if the reaction was in fact a true type 1 immediate (IgE-mediated) hypersensitivity reaction. Type 1 reactions usually occur within an hour of exposure, with the possibility of occurring up to 72 hours post-exposure, and can include anaphylaxis, urticaria, angioedema, hypotension, bronchospasm, stridor and pruritis.5,6,7 Cutaneous reactions
Many patients may report a "rash" as an allergic reaction; however more information should be sought to assist in defining the true nature of the reaction. Cutaneous reactions can range from non-severe delayed maculopapular rashes to life-threatening toxic epidermal necrolysis; therefore it is essential to further question the patient. Certain infections can either cause cutaneous reactions or predispose patients to reacting to antimicrobials. Patients suffering from certain bacterial infections (e.g. Streptococcus pyogenes, Mycoplasma pneumoniae) can develop cutaneous symptoms, irrespective of which antibiotic is used.18,22 Certain viral infections [e.g. Epstein-Barr virus (EBV), Herpes simplex virus (HSV), Human immunodeficiency virus (HIV), Cytomegalovirus (CMV)] can also directly cause cutaneous symptoms.14,18,22 Patients suffering from these viral infections may also be at a higher risk to react to certain antimicrobials.2,4,12,13 A notable example is the delayed morbilliform rash that often develops when patients suffering from EBV are treated with an aminopenicillin, such as amoxicillin.4,18 Please see table 3 below for a brief description of certain cutaneous reactions. Table 3 – Cutaneous reactions 1,2,15,16,18,19,20,21
Type of skin reaction
Region(s) affected: Lips, eyelids, earlobes, tongue, mouth, larynx, Morphology: Skin-coloured circumscribed edema involving the subcutaneous tissues. (can be asymmetrical/unilateral) Resolution within 24-72 hours More details: Non-pruritic; often very frightening for patients; can be painful DRESS syndrome
Onset: 1-8 weeks Region(s) affected: Classic distribution: Face, upper trunk, (Drug Rash with
extremities (but can progress anywhere on the surface of the skin Eosinophilia and Systemic
and can sometimes have mucosal involvement) Symptoms)
Duration: Weeks- months (even after Morphology: Most commonly begins as an erythematous, pruritic, discontinuing the morbilliform rash suspected medication) More details: Pruritis and fever usually precede cutaneous eruptions. Can cause facial edema, which can be mistaken for angioedema. Systemic systems involved: - Lymphatic: lymphadenopathy is very common - Hematologic: leukocytosis, eosinophilia, lymphocytosis - Hepatic: hepatosplenomegaly, hepatitis, elevated liver transaminases, elevated alkaline phosphatase - Renal: hematuria, proteinuria, elevated BUN and creatinine - Other: pulmonary, cardiac, neurologic Erythema multiforme
Onset: Within 3-5 Region(s) affected: Often appear on the extremities (hands, palms, extensor of the forearms, soles of the feet, etc.) and can spread inwards towards the trunk. May involve mucous membranes of the mouth and genitalia. symptoms of an upper respiratory Morphology: Well-demarcated, circular, erythematous papules; often "target" or "iris"-like. - Can be difficult to discern from Stevens-Johnson Syndrome - Often associated with HSV or mycoplasma infections - Fever, if present, is usually mild Type of skin reaction
Maculopapular rash /
Region(s) affected: Commonly begin on head, neck or upper torso, Morbilliform rash /
(often more than 72 and progress downward to the extremities. Exanthems
hours), within the first 2-4 weeks Morphology: Often bilateral and symmetrical. Usually flat, barely following the initial raised, erythematous patches (one to several mm in diameter). Can also include papules. Duration: Usually - With or without pruritis - Can develop into confluent areas - Can be the result of several mechanisms (ex: viral infection, idiopathic, etc.) - Mild eosinophilia is possible, but not common - Fever rarely associated; but is mild if present Photosensitivity /
Onset: 5-20 hours Region(s) affected: Areas most often exposed to the sun (ex: face, back of the hands, back and sides of the neck, extensor surfaces of the forearm, etc.). Classical presentation spares shaded areas, such as under the chin, under the nose, behind the ears. Morphology: Often resembles exaggerated sunburn, sometimes with blisters. Sharp demarcation at sites where clothing or jewelry were present during light exposure. More details: Not common with beta-lactam antibiotics Pruritis
Region(s) affected: Localized or generalized itching; more often generalized when drug induced. Morphology: Does not require visible cutaneous signs of a reaction. More details: Mechanism not always clear Region(s) affected: Less than 10% of the body surface is affected. syndrome
(within 8 weeks of Can affect the skin, eyes, and mucous membranes; such as the first exposure), but lips, mouth, and genital mucous membranes. with abrupt onset of symptoms. Morphology: Often begins with dusky red, flat lesions (sometimes target-like, similar to erythema multiforme), progressing to bullae Duration: Up to 6 and necrotic lesions. Leads to blisters and dislodgement of the More details: - Is accompanied by any (or all) of: high fever, malaise, myalgia, arthralgia, headache, ocular involvement, painful stomatitis - A medical emergency; in-hospital mortality = 5-12 % Toxic epidermal necrolysis Onset: Delayed
Region(s) affected: Greater than 30% of the body surface is (within 8 weeks of affected. Can affect the skin, eyes, and mucous membranes; such first exposure), but as the lips, mouth, and genital mucous membranes. Hairy regions with abrupt onset of of the skin are often spared. Morphology: See Stevens-Johnson Syndrome; eventually can Duration: Up to 6 resemble extensive second degree burns More details: - Is accompanied by any (or all) of: high fever, fatigue, vomiting, diarrhea, malaise, myalgia, angina, arthralgia, headache, ocular involvement, painful stomatitis - A medical emergency; in-hospital mortality more than 30% Type of skin reaction
Onset: Immediate, Region(s) affected: Can occur in any location. Involves the usually within 36 superficial portion of the dermis, and not subcutaneous tissues. Morphology: Raised, erythematous areas of edema (wheals), Duration: Rarely sometimes with central pallor. Will often blanch with pressure. persist for more than 24 hours More details: - Often pruritic - May or may not be accompanied by angioedema, can progress to anaphylaxis For more information, please see the Management of Penicillin and Beta-Lactam Allergy guideline prepared by the NB
Provincial Health Authorities Anti-Infective Stewardship Committee.
Demoly P, et al. Drug hypersensitivity: questionnaire. Allergy 1999, 54, 999-1003 Salkind AR, et al. Is This Patient Allergic to Penicillin? An Evidence-Based Analysis of the Likelihood of Penicillin Allergy. JAMA,2001; 285;19: 2498-2505 Management of Penicillin and Beta-Lactam Allergy. NB Provincial Health Authorities Anti-Infective Stewardship Committee. 2016 Lagace-Wiens P. and Rubinstein E. Adverse reactions to B-Lactam antimicrobials. Expert Opin. Drug Saf. 2012(11):381-99.
Blondel-Hill and Fryters. B-Lactam Allergy. Bugs and Drugs: An antimicrobial/infectious disease reference. 2012:87-90.
Teirico, Terry et al. Beta-lactam allergy and cross-reactivity. Journal of Pharmacy Practice. 2014(27): 330-41.
Pichichero, Michael E. A review of evidence supporting the American Academy of Pediatrics recommendations for prescribingcephalosporin antibiotics in penicillin allergic patients. Pediatrics. 2005(115):1048-55.
Solensky R., Earl, H.S., Gruchalla R.S. Clincal Approach to Penicillin-Allergic Patients: A Survey. Ann Allergy Asthma Immunol2000. Mar; 84(3):329-333 Lee, C.L., Zembower, T.R., Fotis M.A., Postelnick, M.J.; Greenberger, P.A., et al. The Incidene of Antimicrobial Allergies inHospitalized Patients. Arch Intern Med 2000; 160:2819-2822 10. Macy E. and Contreras R. Health care use and serious infection prevalence associated with penicillin"allergy" in hospitalized patients: A cohort study. J Allergy Clin Immunol 2014;133:790-796 11. Solensky R. Allergy to β-lactam Antibiotics. J Allergy Clin Immunol. 2012; 130(6):1442-1442.e512. Stokes S and Tankersle M. HIV: Practical implications for the practicing allergist-immunologist. Ann Allergy Asthma Immunol. 2011; 13. Aota N and Shiohara T. Viral connection between drug rashes and autoimmune diseases: How autoimmune responses are generated after resolution of drug rashes. Autoimmunity Reviews. 2009; 8: 488-494 14. Tohyama M and Hashimoto K. New Aspects of drug-induced hypersensitivity syndrome. Journal of dermatology. 2011; 38: 222- 15. UpToDate: An approach to the patient with drug allergy. Last updated 04-2015. Accessed online 10/201516. UpToDate: Penicillin allergy: Immediate reactions. Last updated 31-05-2015. Accessed online 10/201517. Trubiano J, Phillips E. Antimicrobial stewardship's new weapon? A review of antibiotic allergy and pathways to "de-labeling". Curr Opin Infect Dis. 2013; Dec; 26(6) 18. Goldsmith LA,et al. Fitzpatrick's Dermatology in General Medicine, 8e. 201219. Litt JZ. Litt's D.E.R.M. Drug Eruptions & Reactions Manual. 18th edition. 2012.
20. 21. Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: Part I. Clinical perspectives. J Am Acad Dermatol 2013; 68:693.e1.
22. Hardy R. Infections Due to Mycoplasmas. Harrison's Principles of Internal Medicine, 19e. 2015 Antimicrobial Route of Administration (IV to PO)
Patients on the targeted IV antimicrobials should be assessed within 72 hours of the start of IV therapy and regularly
thereafter for the appropriateness of IV to PO conversion based on the following criteria (see below for list of targeted
antimicrobials and their renal dose adjustments).
is tolerating food, enteral feeds and/or other oral medications AND is not showing evidence of malabsorption (e.g.diarrhea/vomiting) AND does not have continuous nasogastric suctioning, gastrectomy, malabsorption syndrome, GI obstruction or ANTIMICROBIAL CRITERIA
is clinically improving (which may include documented improved clinical signs and symptoms of infection, normalizing white blood cell count, etc…) AND is hemodynamically stable AND has been afebrile for at least 48 hours (i.e. temperature less than 38°C) AND is not being treated for a condition where parenteral therapy is clinically indicated, including but not limited to: endocarditis, CNS infection, osteomyelitis, S. aureus bacteremia, undrained or complicated abscess, cystic fibrosis, febrile neutropenia AND doesn't have a pathogenic isolate showing resistance to the suggested antibiotic Table 1: Route of Administration (IV to PO)
Conversion Protocol for Targeted Antimicrobials
250 or 500 mg q24h azithromycin 250 mg cephalexin1,2 500 mg (For community-acquired pneumonia or acute exacerbation of COPD) 400 mg q12h or q24h ciprofloxacin1 500 mg ciprofloxacin1 750 mg 600-900 mg q8h or q12h clindamycin 450 mg 500 mg q8h or q12h metroNIDAZOLE1 500 mg moxifloxacin 400 mg levofloxacin1 (dose same as IV) 1Dose adjustment required in renal impairment 2Assess for true penicillin allergy Table 2: Antimicrobial Dosing in Renal Impairment
Usual adult dose
CrCl 30 - 49
(CrCl equal to or greater
CrCl 10 - 29 mL/min
CrCl less than 10 mL/min
than 50 mL/min)
amoxicillin + clavulanate 250–500 mg q12h extend interval to q24h extend interval to q24h ciprofloxacin PO ciprofloxacin IV 500 mg q8h or q12h CrCl 20-49 mL/min
CrCl less than 20 mL/min
CrCl 20-49 mL/min
CrCl less than 20 mL/min
Provincial Drugs & Therapeutics Committee
"April 28, 2014" Communication
Topic: Nevirapine (VIRAMUNE) for Perinatal HIV Transmission Prophylaxis
A decision was made in October 2013 to list nevirapine (VIRAMUNE) 10 mg/mL oral suspension on the New Brunswick Hospital Formulary. The oral suspension dosage form of nevirapine is only available in Canada via Health Canada's Special Access Programme. Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with an established role in the prevention of vertical transmission of HIV to neonates born to mothers who received no antenatal anti- retroviral therapy or with a recent or projected HIV viral load greater than 1000 copies/mL.1 Nevirapine is used in combination with other antiretroviral drugs for this indication. National Institutes of Health (NIH, 2012) guidelines recommend that HIV-exposed infants of women who received no antepartum antiretroviral prophylaxis receive 3 doses of nevirapine in the first week of life (1st dose at birth, 2nd dose 48 hours after the 1st, 3rd dose 96 hours after the 2nd). Infants weighing 1.5- 2 kg at birth receive 8 mg/dose by mouth, while those weighing greater than 2 kg receive 12 mg/dose by mouth.2 For women who did not receive any antiretroviral therapy during pregnancy, the British Columbia (BC, 2013) guidelines recommend a single intrapartum dose of nevirapine 200 mg as soon as possible after the onset of labour or at least 2 to 3 hours prior to caesarian section. This recommendation varies from the updated NIH guidelines, which no longer includes maternal single dose nevirapine. The BC guidelines recommend the same infant dose and schedule of nevirapine as recommended by NIH. Canadian guidelines (2003)3 are currently being updated.
As the likelihood of its use is deemed to be low, but the time-sensitivity for acquisition is high, a
small centrally-located supply of nevirapine oral suspension is being held at the Dr. Everett
Chalmers Hospital pharmacy department in Fredericton for use on request by any facility in the
Requests to ship nevirapine to other facilities can be made by calling the DECH pharmacy department at (506) 452-5284 (inventory) or (506) 452-5280 (dispensary) or (506) 452-5700 (switchboard after hours, ask for Administrative Officer). Discussion with an Infectious Diseases physician is strongly encouraged. 1 Money D, Tullock K, Boucoiran I, Alimenti A et al. British Columbia Guidelines for the Care of HIV Positive Pregnant Women and Interventions to Reduce Perinatal Transmission. July 23, 2013; CMA Infobase. 2 Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1- Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. 3 Burdge DR, Money DM, Forbes JC, Walmsley SL, Smaill FM, Boucher M, et al. on behalf of the Canadian HIV Trials Network Working Group on Vertical HIV Transmission. Canadian Consensus Guidelines for the management of pregnancy, labour and delivery and for postpartum care in HIV-positive pregnant women and their offspring [online appendix]. CMAJ 2003; 168(13): Online-1 to Online 14. Available: www.cmaj.ca/cgi/data/168/13/1671/DC1/1 Prevention of Overwhelming Postsplenectomy Infection
The spleen is the largest lymphatic organ in the body and its primary functions are to filter
damaged red blood cells and micro-organisms from the blood and to aid in the production of
antibodies to enhance the immune response.1 Asplenic patients or patients who suffer from
functional asplenia have an increased risk of infection and are at risk of contracting a syndrome
known as overwhelming postsplenectomy infection (OPSI).2 Overwhelming postsplenectomy
infection has been defined as "septicaemia and/or meningitis, usually fulminant but not
necessarily fatal, occurring at any time after removal of the spleen".3 The incidence of OPSI has
been difficult to establish due to a wide variation in occurrence rates among different groups of
patients, but lifetime risk has been estimated at 5%.2 Risk of OPSI has been found to be
dependant on age at which splenectomy occurs, time interval from splenectomy, cause for
asplenia and immune status of the patient.4 Although the incidence of OPSI is low the
estimated mortality is high (38 – 69%).2 Therefore, prevention and early identification of OPSI
has been identified as key strategies to improve patient outcome.2 Some of the current
strategies being used and recommended to decrease a patient's risk of OPSI include
vaccination, communication of hyposplenic state to other healthcare providers and patient
education.1,2,5 In addition, some groups recommend either short term or lifelong prophylactic
antibiotics to reduce the risk of OPSI. 8 However, the use of antibiotics for the prevention of
OPSI is not evidence based and is often limited by poor compliance and antibiotic resistance;
therefore, its use should be assessed on a case-by-case basis.8 The Provincial Anti-infective
Stewardship Committee (ASC) has prepared resources to facilitate recommended vaccination
orders, vaccine distribution, patient education and communication to the primary care physician.
Asplenic patients are at risk of OPSI with any micro-organism but particularly encapsulated
bacteria such as Streptococcus pneumoniae, Haemophilus influenzae and Neisseria
meningitidis.2,4 Encapsulated bacteria are more difficult for the body to clear because they
resist antibody binding and their clearance is primarily completed by the spleen.4 Therefore, it is
important that attention be paid to providing optimal protection against encapsulated bacteria
using appropriate immunizations.6 The National Advisory Committee on Immunization (NACI)
currently recommends the following vaccines for adult asplenic or hyposplenic patients:
pneumococcal 13-valent conjugate vaccine, pneumococcal 23-valent polysaccharide vaccine,
Haemophilus influenzae type b conjugate vaccine, meningococcal ACYW-135 conjugate
vaccine, all routine immunizations and yearly influenza vaccine.6,7
Streptococcus pneumoniae is responsible for 50 – 90% of all cases of OPSI. 4 Pneumococcal polysaccharide vaccine (PNEUMOVAX 23) provides protection against 23 serotypes of Streptococcus pneumoniae and is the vaccine of choice for adult patients at high risk of invasive pneumococcal disease (IPD). 6 The pneumococcal polysaccharide vaccine has been found to have an efficacy of 50 to 80% against IPD among the elderly and high risk groups.6 However, after immunization with pneumococcal 23-valent polysaccharide vaccine antibody levels begin to decline after 5 to 10 years and the duration of immunity is unknown.6 In an effort to improve the duration of immunity the current NACI guidelines recommend for adults with asplenia or hyposplenia, one dose of pneumococcal 13-valent conjugate vaccine (PREVNAR 13) followed at least 2 months later by one dose of pneumococcal 23-valent polysaccharide vaccine.6 If pneumococcal 23-valent polysaccharide vaccine has been previously received then wait 1 year before giving pneumococcal 13-valent conjugate vaccine. 10 In the case where only one vaccine can be given then it should be the pneumococcal 23-valent polysaccharide vaccine. A single life time booster of pneumococcal 23-valent polysaccharide vaccine is recommended 5 years after the initial dose. 6 The Center for Disease Control and Prevention's Advisory Committee on Immunization Practices released a statement in October 2012 with similar recommendations for all adult patients 19 years of age or greater.10 A single dose of Haemophilus influenzae type b (HiB) conjugate vaccine is recommended in all patients who are functionally or anatomical y aslpenic and greater than 5 years of age regardless of previous Hib immunization.5,6 Current Hib vaccine should be given at least one year after any previous dose.6 This is despite limited efficacy data and a low overall risk of Haemophilus influenzae sepsis in patients greater than 5 years of age.6 Meningococcal ACYW-135 conjugate vaccine, MENACTRA or MENVEO, is recommended for all
groups at high risk of meningococcal infection when long-term protection is required.6,7
Recommendations are to give 2 doses of meningococcal ACYW-135 conjugate vaccine at least
8 weeks apart for patients with anatomic or functional asplenia between the ages of 1 – 55.6
Based on limited evidence and expert opinion current NACI guidelines recommend that 2 doses
of meningococcal ACYW-135 conjugate vaccine given 8 weeks apart is appropriate for
individuals greater than 55 years of age despite lacking authorization for use in this age
group.6,7 Booster doses are recommended every 3 - 5 years in individuals vaccinated at 6 years
of age or younger and every 5 years for individuals vaccinated at greater than 6 years of age.6
In addition, all routine immunizations and yearly influenza vaccination should be given as there are no contraindications to the use of any vaccine in patients with functional or anatomical hyposplenia. 6 When an elective splenectomy is planned, the necessary vaccines are recommended to be given two weeks before removal of the spleen. 6 In the case of an emergent splenectomy, vaccines should be given two weeks post-splenectomy or prior to hospital discharge if there is a concern that the patient may not return for vaccination. 6 Asplenic patients are at increased risk of travel related infectious diseases, including malaria and babesiosis.9 Expert advice should be sought prior to travel to endemic areas. Patient Education
Education has also been cited as an essential component for successful prevention of OPSI. 2
Patients should be educated regarding their increased risk of developing life threatening sepsis,
what to do at the first sign of infection, to inform al healthcare professionals of their hyposplenic
state and to take appropriate precautions to prevent OPSI.2 Education may be provided
through thorough discussion and provision of appropriate reading materials.2
Document Updated by: Tim MacLaggan, BSc(Pharm), ACPR
Document reviewed and approved by: New Brunswick Anti-infective
Stewardship Committee - September 2013
Jones P, Leder K, Woolley I, et al. Postsplenectomy Infection: Strategies For Prevention In GeneralPractice. Australian Family Physician 2010; 39(6):383-386 Moffett S. Overwhelming postsplenectomy infection: Managing Patient's at risk. JAAPA 2009; 22(7):36-39 Waghorn DJ. Overwhelming Infection in Asplenic Patients: Current Best Practice Measures Are Not BeingFollowed. J Clin Pathol 2001; 54:214-218 Okabayashi T, Hanazaki K. Overwhelming Postsplenectomy Infection Syndrome in Adults – A Clinically Preventable Disease. World J Gastroenterol 2008;14(2):176-179 Spelman D, Buttery J, Daley A, Isaacs D, Jennens I, Kakakios A, Lawrence R, Roberts S, Torda A, Watson D, Woolley I, Anderson T, Street A. Guidelines for the Prevention of Sepsis in Asplenic and Hyposplenic Patients. Int Med Journal National Advisory Committee on Immunization (NACI). Canadian Immunization Guide. Evergreen Edition. Ottawa (ON): Public Health Agency of Canada; http://www.phac-aspc.gc.ca/publicat/cig-gci/ Accessed September 5, 2013 National Advisory Committee on Immunization (NACI). Statement on Conjugate Meningococcal Vaccine for Serogroups A, C, Y and W135. Can Commun Dis Rep 2007; 33;(ACS-3):1-24 Sabatino AD, Carsetti R, Corazza GR. Post-Splenectomy and Hyposplenic States. Lancet. 2011 Apr 5.[Epubahead of print] doi:10.1016/S0140-6736(10)61493-6 Watson D. Pretravel Health Advice for Asplenic Individuals. J Travel Med 2003; 10:117-121 10. Use of 13-valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine for Adults with Immunocompromising conditions: Recommendations of the Advisory Committee on Immunization Practices.
Morbidity and Mortality Weekly Report 61(40);816-819 October 12, 2012 **The following clinical order set is provided as a sample only and would have to be modified to an
individual zone's format for local use**
Clinical Order Set
Post-Splenectomy Vaccinations – Adult
Provincial Anti-infective Stewardship Committee
1. The following orders will be carried out by a nurse only on the authority of a physician/nurse practitioner.
2. A bullet preceding an order indicates the order is standard and should always be implemented.
3. A check box preceding an order indicates the order is optional and must be checked off to be implemented.
4. Applicable boxes to the right of an order must be checked off and initialed by the person implementing the order.
5. Date and time of administration must be recorded
Hypersensitivity to any vaccine component Anaphylactic reaction to previous dose of any of the vaccines listed below Vaccinations (if not received pre-operatively for elective surgeries or if not received previously)
Haemophilus influenzae type b conjugate vaccine (ACT-HIB) 0.5 mL intramuscularly in deltoid Meningococcal ACYW-135 conjugate vaccine (MENACTRA or MENVEO) 0.5 mL intramuscularly in deltoid (additional dose of meningococcal ACYW-135 conjugate vaccine required in 2 months followed by a booster every 5 years) Pneumococcal Vaccination:
-If pneumococcal 23-valent polysaccharide vaccine (PNEUMOVAX 23) not previously received or
received greater than one year ago:
Pneumococcal 13-valent conjugate vaccine (PREVNAR 13) 0.5 mL intramuscularly in deltoid (Pneumococcal 23-valent polysaccharide vaccine (PNEUMOVAX 23) required 8 weeks later if not previously received. Single lifetime booster of Pneumococcal 23-valent polysaccharide (PNEUMOVAX 23) required 5 years after first dose.) -If Pneumococcal 23-valent polysaccharide vaccine (PNEUMOVAX 23) previously received but less than one year ago then wait 1 year from that date to give Pneumococcal 13-valent conjugate vaccine (PREVNAR 13). Single lifetime booster of Pneumococcal 23-valent polysaccharide (PNEUMOVAX 23) required 5 years after first dose. Seasonal Influenza Vaccine (if not already received) -Vaccinations should be given two weeks post-operatively (if patient remains hospitalized) or on hospital discharge -Al vaccinations may be administered simultaneously. Separate syringes and separate injection sites should be used if more than one vaccine is administered on the same day. Adapted with permission from Antimicrobial Handbook-2010 Capital Health, Nova Scotia Revised and Approved Feb 2014 Adult Splenectomy Vaccines
Documentation for Primary Care Provider and Public Health
Please complete and forward to patient's primary care provider and local public health office on discharge. To: Local Public Health Office
Re. Patient Name: Asplenic patients are known to be at risk of infection, and are particularly susceptible to encapsulated organisms. Vaccinations are recommended to reduce the risk of infection in this patient population. Your patient received the following vaccinations while in hospital after splenectomy. Please update your records, and note the patient's need for future vaccinations. Meningococcal ACYW-135 conjugate vaccine (MENACTRA or MENVEO) (2 doses, 2 months apart) Date 1st dose given: Administration Site: Date 2nd dose given: Administration Site: A booster is recommended every 5 years
Haemophilus influenzae type b conjugate vaccine (ACT-HIB) Date given: Administration Site: Pneumococcal 13-valent conjugate vaccine (PREVNAR 13) Date given: Administration Site: Pneumoccocal polysaccharide vaccine (PNEUMOVAX 23) due 8 weeks after pneumococcal 13-valent conjugate vaccine (PREVNAR 13) Date given: Administration Site: A single booster dose of pneumococcal polysaccharide vaccine is recommended after 5 years.
- Yearly influenza vaccine recommended.
If you have any questions regarding these vaccinations please call the numbers above, or contact the Department of Public Health for further information. This message is CONFIDENTIAL. If you received this fax by mistake, please notify us immediately. Adapted with permission from Antimicrobial Handbook-2010 Capital Health, Nova Scotia Approved Sept 2013 Splenectomy
Information for Patients
Role of the spleen:
The spleen has many functions, including removal of damaged blood cells. It also plays an important role in removal of certaintypes of bacteria.
The spleen may be removed (splenectomy) if it becomes overactive, stops working or is ruptured in an accident.
Life without a spleen:
Adults can live a normal life without a spleen. However, you may be at risk of developing infections caused by certaintypes of bacteria which are normally removed by the spleen.
The most serious possible infection is called overwhelming post-splenectomy infection (OPSI). This infection is rare, but can progress rapidly and may result in the loss of limbs ordeath.
How to reduce the risk of infection:
Inform all doctors, dentists and other health care professionals that you do not have a A series of vaccinations are recommended for patients who have their spleen removed.
These vaccines are two doses of meningococcal quadrivalent conjugate vaccine,pneumococcal conjugate vaccine, pneumococcal polysaccharide vaccine (due 2 monthsafter pneumococcal conjugate vaccine), and haemophilus influenzae type b conjugatevaccine.
You should receive a single booster of pneumonococcal polysaccharide vaccine in 5 years.
You should receive a booster dose of meningococcal conjugate vaccine every 5 years.
You should receive a yearly flu shot.
Your family doctor will receive a letter explaining the vaccinations you received in hospital,
as well as recommendations for future vaccinations.
Seek expert medical advice before travel. Patients without a spleen are at increased risk of travel related infectious diseases, including severe malaria. Additional vaccines and/or oneor more medications may be recommended to prevent or treat travel-related infectiousdiseases. Where malaria is endemic, preventative measures including antimalarialmedications, insect repellent and barrier precautions should be used.
Wal et card (included with this information) includes information on vaccinations you have Medic-Alert™ bracelet should be worn. It should indicate that you had your spleen When to seek medical attention:
If you receive a tick or animal bites/scratches. You may be at risk of developing a serious If you notice any signs of infection, including fever, sore throat, chil s, unexplained cough, vomiting or diarrhea. Contact your family doctor as soon as possible for further instructions.
Adapted with permission from Antimicrobial Handbook-2010 Capital Health, Nova Scotia Approved Sept 2013 Wallet card for Asplenic Patients
Please complete card and give to patient on hospital discharge.
Patient Name: _
Physician Name: _
Physician Phone: _
Patient is at risk of potentially fatal, overwhelming infections. Medical attention required for: Signs of infection- fever > 38ºC, sore throat, chills, unexplained cough.
Tick and animal bites/scratches.
Patient has received the following vaccinations:
Meningococcal ACYW-135 conjugate vaccine
(MENACTRA or MENVEO)
2 doses 8 weeks apart Date 1st dose given: Date 2nd dose given: Meningococcal ACYW-135 conjugate vaccine booster
(MENACTRA or MENVEO)
Dates due: every 5 years Pneumococcal 13-valent conjugate vaccine (PREVNAR 13)
Pneumococcal polysaccharide vaccine (PNEUMOVAX 23)
Date due: 8 weeks after pneumococcal 13-valent conjugate vaccine(PREVNAR 13) Date given: Pneumoccal polysaccharide booster (PNEUMOVAX 23)
Date due: single dose 5 years after initial vaccine Date given: Haemophilus influenzae type b conjugate vaccine (ACT-HIB)
Adapted with permission from Antimicrobial Handbook-2010 Capital Health, Nova Scotia Approved Sept 2013
Splenectomy Vaccine Checklist
1) Post-Splenectomy Vaccinations Clinical Order Set 2) Vaccines as per clinical order set plus package inserts 3) Splenectomy Vaccines – Documentation for Primary Care Provider and Public Health Form 4) Splenectomy – Information for Patients Sheet 5) Wallet Card for Asplenic Patients Sheet Adapted with permission from Antimicrobial Handbook-2010 Capital Health, Nova Scotia Approved Sept 2013 References
Clostridium difficile Infection Cohen SH., Dale NG, Stuart J, Ciaran PK, Vivian GL, McDonald LC, Pepin J &Wilcox MH. Clinical Practice Guidelines for Clostridium difficile Infection in Adults: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010; 31(5):431-455 Antimicrobial Stewardship Treatment Guidelines for Common Infections. 1st Edition Vancouver Coastal Health. March 2011 McFarland LV, Elmer GW & Surawicz CM. Breaking the Cycle: Treatment Strategies for 163 Cases of Recurrent Clostridium difficile Disease. Am J Gastroenterol 2002;97:1769-1775 Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH, McFarland LV, Mellow M & Zuckerbraun BS. Guidelines for the Diagnosis, Treatment and Prevention of Clostridium difficile Infections. Am J Gastroenterol 2013; 108:478-498 Debast SB, Bauer MP & Kuijper EJ. European Society of Clinical Microbiology and Infectious Diseases: Update of the Treatment Guidance Document for Clostridium difficile Infection. Clin Microbiol Infect 2014; 20(suppl. 2): 1 – 26 Intra-Abdominal Infections Ball, C., Hansen, G., Harding, G., Kirkpatrick, A., Weiss, K. & Zhanel, G. (2010). Canadian practice guidelines for surgical intra-abdominal infections. Canadian Journal of Infectious Disease and Medical Microbiology, 21(1), 11-37. Doyle, J., Nathens, A., Morris, A., Nelson, S., & McLeod, R. (2011). Best practice in general surgery guideline #4: Management of Intra-abdominal infections. Toronto, ON: University of Toronto, Faculty of Medicine. INESSS. Antibiotic Treatment Guide: Intra-abdominal Infections in Adults. June 2012 So, M. (2010). Intra-abdominal infections education module. Toronto, ON: Mount Sinai Hospital and University Health Network. Solomkin, J., Mazuski, J., Bradley, J, et al. (2010). Diagnosis and management of complicated intra- abdominal infections in adults and children: Guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clinical Infectious Disease, 50 (15 January)., 133-163. Blondel-Hill E. & Fryters S. (2012). Bugs & Drugs. An Antimicrobial/Infectious Diseases Reference. Alberta Health Services. Young-Fadok T. & Pemberton J. (2014). Treatment of acute diverticulitis. UpToDate. Retrieved from Antimicrobial Stewardship Treatment Guidelines for Common Infections. 1st Edition Vancouver Coastal Health. March 2011 Antimicrobial Handbook – 2012. Editor: Dr Kathy Slayter. Antimicrobial Agents Subcommittee. Capital Health, Nova Scotia Sawyer RG, Claridge JA, Nathens AB, Rotstein OD, Duane TM et al. Trial of Short-Course Antimicrobial Therapy for Intraabdominal Infection. 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Adrian Howe (Australia) Title: "Emotional Law—Provocation and the Cultural Politics of Law Reform." Abstract: "This paper analyses the cultural politics of criminal law reform, focusing on 21st century efforts to reform partial defences to murder in jurisdictions in Australia and the UK. Subjecting the case law and conventional black-letter law commentaries to critiques offered by feminist law scholarship and contemporary emotion theory, it explores deeply emotional reactions to the provocation defence—western societies' most emotional law. A comparative analysis is provided of the different options canvassed in debates that have raged in recent law commission inquiries into whether provocation is capable of reform or whether it should be abolished outright. It is argued that reforms which retain the defence but limit its use or which more ‘radically' abolish the defence but retain provocation as a sentencing discretion are destined to fail because they do not get to the heart of the problem—the deeply ingrained cultural script that men who kill in the heat of ‘passion' deserve some compassion. All contributors to the debate have emotional investments in their positions, but it is the passionate attachments of provocation's ardent apologists for this antediluvian defence that are the paper's analytical focus." Agnieszka Kubal (UK) Title: "Recognizing the Place of Legal Culture in Legal Integration Research. Polish post-2004 EU Enlargement Migrants in the United Kingdom." Abstract: "The paper is placed at the intersection of migration and legal studies. Enquiring into the study of the immigrants in the new socio-legal environment suggests existing gaps and certain shortcomings in the current knowledge on the various aspects of legal integration. This research, engaging critically with the reviewed literature, offers a new approach to studying legal integration, taking Polish post-2004 EU Enlargement migrants in the UK as a case study. It suggests a combined focus on structural factors stemming from the host country's legal environment as well as migrants' cultural background – their values, accustomed patterns of legal behaviour, attitudes to law (legal culture) – in the process of shaping – and possibly re-shaping – their relationship to law during the settlement process. This paper aims to offer an understanding of how people in their daily interactions gradually change their behaviour, views and attitudes engaging in the complex interplay between the new environment and their cultural background during the process of integration. This study makes the claim for the proper recognition of the cultural background of immigrants while investigating their modes and strategies of legal integration. It acknowledges the legal culture of immigrants as a significant factor in empirical research, accounting for nuances and bringing out the subtle differences and therefore revealing the bigger, richer picture of immigrant integration, than one solely relying on structural factors and government policies of immigrant incorporation. The approach to legal culture adopted in this research acknowledges the diversity of sub-cultures and sub-groups within it, at the same time stressing a general, distinguishable and largely shared pattern of accustomed behaviour, thinking and experience of law." Ahti Laitinen (Finland) Title: "Arson: Crime Rates, Offenders, and Prevention in Finland." Abstract: "This paper deals with arson and its prevention in Finland. Arson will first be viewed in the light of history and criminological theory. The second part of the paper contains the results of an empirical study on arson. The material has been collected from different official sources. For example, the offenses data base of the police, the so-called "Accident data base" of the Ministry of the Interior, and the data base of trials have been used. In addition, the documents of the preliminary investigations of the police have been utilized. According to the preliminary results, approximately one-third of all fires are arson. Most often the offenders are young, undereducated males. What is surprising is that arson is more common in some prosperous cities, where, for example, the unemployment rate is unusually low. During 2005-2007 many arson of historical and valuable buildings, like