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Innovations in Pharmaceuticals and Pharmacotherapy
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Original Article Ciprofloxacin, oxacillin, piperacillin and sulfamethoxazole by systemic
administration for the control of severe infections: Is dose adjustment required
for critical burn patients?
1Cristina Sanches-Giraud, PhD*, 2David S Gomez, MD, 2Marcus C Ferreira, MD, 3Carlindo V Silva Jr,
Chemist, 3Silvia RCJ Santos, PhD
1Department of Pharmacy, Universidade Federal de São João del Rei–Divinópolis/MG, Brazil. 2 stract
Plastic Surgery and Burns, Hospital das Clinicas, Medical School,University of Sao Paulo–Sao Paulo/SP, ol of Pharmaceutical Sciences University of Sao Paulo - Sao Paulo/SP, Brazil. Aim: To investigate the kinetic disposition of ciprofloxacin, oxacillin, piperacillin, and
sulfamethoxazole and evaluate PK/PD target attainment in burn patients. Methods: Forty adult
burn patients, both genders (76 sets of plasma levels) from the Intensive Care Unit of Plastic
Surgery and Burns (ICU) were included in the study. Patients received antimicrobial therapy at
the recommended initial dose regimen as part of their medical care. Namely, ciprofloxacin (n =
8 patients/11 sets) and oxacillin (7/10) were prescribed in the early period of treatment; if
nosocomial infection was suspected, piperacillin/tazobactam (20/27) was prescribed;
sulfamethoxazole (15/28) was also prescribed for the control of documented or suspected
infections. Blood sampling was performed during the dosing intervals and drug plasma
measurements were performed. Pharmacokinetic data were derived by applying specific
software, and drug effectiveness was evaluated based on PK/PD target attainment. Finding:
Large variability in the pharmacokinetic data was observed for the investigated antimicrobial
agents. For sulfamethoxazole, significant differences were not detected among patients with
renal failure and those with preserved renal function. A PK/PD target greater than 60% was
attained when renal function was preserved in patients treated with ciprofloxacin, oxacillin,
piperacillin and sulfamethoxazole. Conclusion: Unpredictable pharmacokinetics were observed
for all of the investigated antimicrobial agents. Based on the PK/PD target attainments, once
dose adjustments were not required, the effectiveness of antimicrobial therapy against
susceptible common pathogens was guaranteed for burn patients with preserved renal function
receiving ciprofloxacin (0.5 mg/L, MIC), oxacillin, piperacillin and sulfamethoxazole for the
control of infections.
Keywords: Antimicrobial agents, pharmacokinetics, PK/PD correlation, critical burn patients
*Corresponding Author: Dr. Cristina Sanches Giraud, Av Sebastião Gonçalves Coelho, 400, Bairro
Chanadour 35501-296, Divinópolis, Minas Gerais, Brazil. E-mail: [email protected]
Innovations in Pharmaceuticals and Pharmacotherapy, All rights reserved
Cristina Sanches Giraud, IPP, Vol 1 (2), 133-144, 2013 1. Introduction
requirements related to PK/PD analysis for burn Infections remain the most frequent cause of patients have been reported, the aim of the morbidity and mortality in critical burn patients. present study was to investigate plasma drug The disruption of the normal skin barrier, immunocompromised state and prolonged hospital stay makes burn patients easier targets sulfamethoxazole by applying pharmacokinetics for microbial or fungal colonization. Thus, the and PK/PD target attainments to determine the diagnosis of infection and early administration of required dose adjustment. microbial agents are decisive factors for the 2. Materials and Methods
successful treatment and control of infections in burn patients [1]. Study Design and Patient Eligibility
Consequently, a significant number of factors The clinical protocol was a prospective, open- have an effect on burn patients, and the area label study and was approved by the Ethical and depth of burn injury, sepsis, degree of Committee (Protocol nº 0069/09) of the Hospital hydration, serum protein concentration, age, das Clinicas, Medical School, University of Sao renal function and period after thermal injury Paulo. The study was conducted from May of may affect the pharmacokinetics (PK) of drugs, 2009 to May of 2012, and informed written which alter antimicrobial plasma concentrations consent was obtained from all legally designated and affect antimicrobial activity. Variability in PK patient representatives. parameters has been observed, which makes it difficult to establish a standard dosage regimen Adult patients with severe thermal and highlights the need for dose adjustment [2- injuries from the ICU of Plastic Surgery and Burns were eligible for inclusion. Patients with drug intolerance and pregnant patients were Ciprofloxacin, oxacillin, piperacillin and excluded. Sepsis diagnosis was based on clinical sulfamethoxazole are commonly prescribed to and laboratorial data according to the consensus burn patients in intensive care units (ICU); conference of the American Burn Association pharmacokinetic changes and effects on pharmacodynamics have not yet been reported Patients presented initially preserved renal despite the a considerable amount of data function and subsequently received intravenous related to others antimicrobial agents [6-10]. sulfamethoxazole as part of their medical care, in significantly affects the effectiveness of drug accordance with the following institutional therapy, permitting earlier clinical intervention for dose adjustment, especially in critical burn hospitalization, patients with a suspected or patients. In addition, dose adjustments based on confirmed diagnosis of infection received pharmacodynamics ciprofloxacin (400 mg, 12/12 h) and/or oxacillin (PK/PD) target attainments, in which key factors (2 g, 4 qh) until laboratory data were obtained include the time course of drug plasma levels (culture and susceptibility testing results); b) after dose administration and the minimum patients with nosocomial suspected infections of inhibitory concentration (MIC), are relevant to guarantee the control of infection [11]. piperacillin/tazobactam (4.5 g, 8 qh); c) patients with a documented or suspected diagnosis of Cristina Sanches Giraud, IPP, Vol 1 (2), 133-144, 2013 Stenotrophomonas maltophilia or Burkholderia 6.0 mm, 5 µm, Shimadzu). The mobile phase cepaciareceived sulfamethoxazole (80 mg/kg, consisted of 0.01 M phosphate buffer and daily). Ciprofloxacin, oxacillin, piperacillin and acetonitrile (68:32, pH 4.0, v/v) at a flow rate of sulfamethoxazole were infused over 0.5 to 1 0.5 mL/min. A UV detector was set at 280 nm (0- hours, based on dose regimen guidelines. If end 9.5 min) for ciprofloxacin and was changed to stage renal dysfunction was observed, an 210 nm (9.5-35.0 min) for oxacillin, piperacillin, empirical dose adjustment of sulfamethoxazole sulfamethoxazole, and IS measurements. The (20 mg/Kg, daily) was performed. (ciprofloxacin), 10.4 min (piperacillin), 13.6 min Decisions regarding the initial antimicrobial (oxacillin), 15.9 min (sulfamethoxazole) and 28.0 therapy and subsequent changes in dose min (IS). Endogenous compounds eluted up to regimens were made by the clinical team and 7.5 min of each chromatographic run, and a total were based on perceived clinical indications and run time of 35 minutes was required. The linear laboratory data including pharmacokinetics and range of the assay was 0.2-20.0 g/mL for PK/PD target attainments. The TBSA (total burn ciprofloxacin, 1.0-100 g/mL for oxacillin and surface area) was estimated by applying the Lund-Browder method [13]. Creatinine clearance sulfamethoxazole. Internal controls with high, was estimated by Cockcroft and Gault's method medium and low concentrations included 15, 8 [14], and all of the patients showed initially and 0.4 g/mL of ciprofloxacin, 75, 40 and 2 preserved renal function. g/mL of oxacillin and piperacillin, and 80, 40 Sample Collection for Pharmacokinetic Analysis
and 4 g/mL of sulfamethoxazole, respectively. In-process quality control samples showed a Blood samples (at least five samples) were mean inter-day imprecision and accuracy obtained from each patient at the steady state (expressed as the systematic error) of 1.83- level through a central catheter into sodium 4.67%/3.31-9.36% EDTA tubes (2 mL each) and was strategically 8.16%/3.01-14.01% planned based on the dosing interval. Collected 5.99%/3.86-7.57% for piperacillin, and 0.93- blood samples were centrifuged immediately 3.39%/4.25-9.39% sulfamethoxazole. after collection at 1800 g, and the plasma was Additionally, good drug plasma stability was transferred to labeled vials and stored (-20oC) demonstrated after three consecutive freezing- until the drug plasma assays were performed, thawing cycles. which was achieved by applying a recently reported bioanalytical method, as outlined Pharmacokinetic Analysis
concentration–time Bioanalytical Method
analyzed using non-compartmental analysis and PK Solutions 2.0 software (Summit, USA), and parameters at the steady state were obtained for the maximum (Cssmax) and minimum (Cssmin) piperacillin and sulfamethoxazole) by high drug plasma concentration. The estimated performance liquid chromatography (HPLC) parameters included the terminal elimination requires as internal standard (IS) ketoconazole rate constant (kel), biological half-life (t1/2 ), (100 g/mL). Plasma samples (200 L) were area under the plasma concentration-time added to acetonitrile (600 L), vortexed for 20 dosing interval curve ( ) (AUCss ), plasma seconds and centrifuged (8000 g, 5oC). Purified clearance (CLT) and apparent volume of plasma extract was concentrated to residue in a distribution (Vdss). water bath and dissolved in 200 L of an 8:2 v/v mixture of water: acetonitrile and 10 L was injected into the HPLC. Chromatographic analysis Target attainment
was performed on a LC10 Class VP (Shimadzu, PK/PD target attainments (target) were Japan) using a Shimpack CLC-CN column (150 x established according to each antimicrobial Cristina Sanches Giraud, IPP, Vol 1 (2), 133-144, 2013 characteristic as described below and were pair signed rank test. The level of statistical expressed as the percentage of desired target significance for all of the tests was defined as a sets achieved. PK/PD analysis was performed to p-value less than 0.05. evaluate the effective attained concentration range. Forty adult burn patients with preserved renal For ciprofloxacin, when the ratio between the area under the plasma concentration versus time hypermetabolic stage (48 h after thermal injury curve and the minimum inhibitory concentration and resuscitation) were included in the present was greater than 125 (AUCss0-24/MIC> 125), drug study. As part of their treatment, patients efficacy was predicted [15]. For investigated during the clinical follow-up period derivatives such as oxacillin and piperacillin, the in the ICU received antimicrobials alone or in PK/PD data indicated that the best parameter association, as described in Table I. In addition, was the percentage of the time dosing interval in five patients (9 sets) presented renal dysfunction which the drug plasma concentration remained during sulfamethoxazole therapy. above the minimum inhibitory concentration (% T>MIC). Data equivalent to 50% were required for antimicrobial activity against Demographic data, expressed as the mean Staphylococcus aureus, while 70% was required and standard deviation, are presented in Table II. for other strains [16]. For sulfamethoxazole, A high percentage of inhalation injuries by AUCss0-24/MIC values greater than 25 were thermal accident were registered and thermal injuries were predominant compared to effectiveness [17]. electrical accidents. Pharmacokinetic parameters Concerning potential common pathogens, the (median/quartile) for antimicrobial agents are also described in Table II. In addition, only data concerning sulfamethoxazole were distributed in two groups of sets, according to the patient's renal function (preserved or renal impairment). Susceptibility Testing database. The MIC for Statistical significant differences were not sulfamethoxazole was 38 mg/L for susceptible observed (p>0.05) between groups. [18]. effectiveness was estimated according to the percentage of target attainment. PK/PD data were plotted against the MIC Statistics
values (Table II) of the investigated antimicrobial agents, considering the predictive index for drug Demographic and pharmacokinetic data were efficacy, as expressed for ciprofloxacin (AUCss0- analyzed with GraphPadPrisma, Version 5.0 (50-70% T>MIC), (GraphPad Software, Inc., Chicago, IL) software. (50-70% T>MIC) sulfamethoxazole (AUCss0-24/MIC>25 for NRF and pharmacokinetic parameters (biological half-life, RF), and the percentages of PK/PD target plasma clearance and apparent volume of attainment were determined. distribution) were analyzed by the Shapiro-Wilk normality test. Discussion
To reduce morbidity and mortality in critically For sulfamethoxazole, dose and kinetic data ill patients with severe infections, source control were compared by applying Wilcoxon's matched Cristina Sanches Giraud, IPP, Vol 1 (2), 133-144, 2013 Table I. Patients' individual characteristics in different periods of follow up in the ICU
Abbreviations - ICU: Intensive Care Unit; F: Female; M: Male; TBSA: total burn surface area; CLcr: creatinine clearance; Injury - T:
thermal; I: inhalation; E: electrical; Antimicrobials - 1: ciprofloxacin; 2: oxacillin; 3: piperacillin; 4: sulfamethoxazole
of the pathogen and early and appropriate important interventions that the clinician can Cristina Sanches Giraud, IPP, Vol 1 (2), 133-144, 2013 antimicrobial dosing regimen is key for the lactams would provide better bactericidal eradication of infection-causing bacteria and an activity based on their short half lives [23,24]. important factor in the emergence and Surprisingly, in the present study, the biological proliferation of antibiotic-resistant strains. half-life of oxacillin was prolonged in burn Within this context, drug plasma monitoring patients compared to data reported by Kampf in coupled with drug effectiveness prediction tools 1983 for non-burn patients [23]. Thus, the by PK/PD target attainments are key issues to results obtained in the present study were ensure adequate drug therapy. An adequate attributed to an increase in the biological half- bioanalytical method must also be developed to life and volume of distribution, which does not ensure the safe use of these tools and to change the drug plasma clearance in critically ill implement interventions in a timely manner [23]. burn patients with preserved renal function. These changes support target attainment by The pharmacokinetics of several drugs has PK/PD target attainments (50% T to 70% T been studied in burn patients, including >MIC) for strains with MICs ranging from 0.5 to 2 antimicrobial agents, and wide variability within mg/L, corresponding to drug effectiveness and among patients has been reported. Thus, ratesof100% (0.5mg/L MIC) and greater than the unpredictability of the pharmacokinetics of 70% (1 – 2mg/L MIC). Consequently, oxacillin antimicrobial agents in burn patients must be dose adjustments were not required after the highlighted [4,5,9,19,20]. drug was administered via short infusion every 4 hours. Pharmacokinetic data obtained in the present study for ciprofloxacin were in accordance with Concerning piperacillin, several studies have the data reported for burn patients by Garrelts shown that a continuous infusion is required in (1996) and was in agreement with data related to the plasma clearance and volume of pharmacokinetic data obtained in the present distribution in critically ill patients without burns study were in accordance with those previously reported byand Bourget et al .for burn patients [10,27]. In addition, increases in Regarding the attainment of effective drug the apparent volume of distribution of plasma concentrations for the recommended piperacillin were obtained more often in burn dose of ciprofloxacin (800 mg/daily), data from patients than in non-burned, critically ill patients the present study was based on PK/PD target with sepsis, as reported by Roberts et al. [25]. AUCss0-24/MIC>125. Finally, the data obtained in the present study ciprofloxacin, 73% target attainment was indicated that dose adjustments for piperacillin guaranteed for 0.5 mg/L (MIC) versus the were required for burn patients. Dose inefficacy for strains with the same reported MIC adjustments were performed once for strains values [9,22]. Based on the data obtained in the with MICs of 2 –16 mg/L, and PK/PD target present study, dose adjustments were not attainments greater than 80% were attained required for strains with a MIC of 0.5 mg/L. However, as suggested by van Zantenet al., the against the recommended index of 50% T>MIC. daily dose of ciprofloxacin (800 mg) should be Considering 70% T>MIC, the percentage of increased to 1200 mg to achieve the desired target attainment was less than 80% and was target [22]. In contrast, target attainment was equal to 59% in the follow-up periods for strains 64% for a MIC of 1.0 and 36% for a MIC of 2.0 with MICs of 16 mg/L. In the last twenty years, despite the lack of research concerning oxacillin pharmacokinetics and PK/PD target attainments, researchers have suggested that a continuous infusion of Cristina Sanches Giraud, IPP, Vol 1 (2), 133-144, 2013 Table no 2: Demographic data, Pharmacokinetics and PK/PD target attainment
Oxacillin
Sets of plasma levels (N) Age, yrs (mean ± SD) Weight, kg (mean ± SD) Thermal accident N/total (%) Inhalation injury N/total (%) Electrical accident no/total (%) Renal Failure no/total (%) PK Parameters and Oxacillin
Cristina Sanches Giraud, IPP, Vol 1 (2), 133-144, 2013 Pharmacokinetic-Pharmacodynamic Correlation -PK/PD target attainment (%)
parameter
0-24/ MIC>125 50% T>MIC
70% T>MIC
50% T>MIC
70% T>MIC
AUCss0 -24/MIC>25

Statistics: Wilcoxon matched pair signed rank test. Data expressed as median (Quartiles 25-75%) for kinetic data and as mean (CI95%): confidence interval
95% for daily dose.
Abbreviations - NRF: normal renal function; RF: renal failure; t1/2b: half-life; CLT: total body clearance; Vdss: volume of distribution at the steady state; TA:
target attainment; MIC: minimum inhibitory concentration; AUCss0-24: daily area under the curve; % T>MIC: time above MIC; NRF: normal renal function;
RF: renal failure; NAP: Not applicable
Cristina Sanches Giraud, IPP, Vol 1 (2), 133-144, 2013 If resistance patterns and other clinical of sulfamethoxazole must be increased to maximize the efficacy, while doses must be sulfamethoxazole remains a highly useful carefully decreased for patients with renal expanded-spectrum generation agents [23]. Sulfamethoxazole is mainly prescribed in ICU HIV patients with Pneumocystis (AUC/MIC>25) recommended by Cheng et al.[17] for sulfamethoxazole and the observed MIC of Burkholderiacepacia infections [17]. 38 mg/L, a high percentage of target attainment was obtained in the present study for patients Due to the large kinetic variability in the data, with preserved renal function; however, a lower significant differences were not observed for percentage of target attainment was obtained sulfamethoxazole for burn patients with renal impairment . pharmacokinetic parameters obtained in renal impairment sets versus preserved renal function Although PK/PD studies are not the only sets. Consequently, prolonged half-lives in criteria used to determine when therapeutic patients with renal impairment were not decisions are necessary, these studies enable detected, as previously reported [28,29]. In clinicians to consider the in vitro activity related addition, the total amount of drug eliminated via to the pharmacokinetic profile of a given antimicrobial dosing regimen. Coupled with the approximately 15% of the administered dose. knowledge of clinical trial results, resistance Thus, significant changes in drug clearance were mechanisms, local susceptibility patterns and not expected for patients with renal impairment characteristics, enhances the clinical decision to ensure delivery for optimal care. In contrast, for burn patients with preserved renal function, a similar increase in the volume Limitations of the study must also be of distribution and total body clearance was considered, including (i) the use of a calculated observed. Reduced plasma levels were expected creatinine clearance determined by Cockcroft in patients with preserved renal function, as and Gault's method [14] as a renal function previously reported by Hutabaratet al. [31]. measurement instead of a 24 hour creatinine Controversial data related to sulfamethoxazole measurement; (ii) assumptions that weight on dose regimen based on renal function were admission is reflective of the patients' weight previously reported; once, if drug plasma throughout their entire stay in the ICU; and (iii) clearance did not change, no decreases on daily the use of the MIC value from surveillance dose was required in renal failure [28,29]. databases instead of clinical laboratorial data when documented infections did not occur Decreases in the daily dose have been during the dose adjustment time course (iv) total drug plasma measurements. dysfunction based on prolonged time-dose intervals [32,33]. pharmacokinetics was observed for all of the Meanwhile, based on the data obtained in investigated antimicrobials, highlighting the need the present study, when the dose regimen was for therapeutic drug plasma monitoring in burn adjusted in patients with renal dysfunction by patients. Regarding the attainment of effective effectiveness was achieved in a lower recommended dose of ciprofloxacin, 73% target percentage compared to those with preserved attainment was only guaranteed for a MIC of 0.5 renal function. Thus, for patients with preserved mg/L versus the inefficacy for common renal function, the initial empirical dose regimen pathogens, which was 1-2mg/L (MICs). In Cristina Sanches Giraud, IPP, Vol 1 (2), 133-144, 2013 addition, based on these findings, dose [7] Rybak M., Llomaetro B., Totschafer J., et al. adjustments were not required for oxacillin, 2009. Therapeutic monitoring of vancomycin piperacillin and sulfamethoxazole in burn in adult patients: a consensus review of patients with preserved renal function once Pharmacists, the Infectious Diseases Society recommended dosing regimens, as evaluated by of America, and the society of Infectious Diseases Pharmacists. Am J Health Syst adjustment must be carefully considered for Pharm; 66:82-98. sulfamethoxazole in burn patients for renal [8] Moise P.,Forrest A.,Bhavnani S.,et al. 2004. Area under the inhibitory curve and Conflict of interest: Authors have no conflict of
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