Considerations for Dose Selection and Clinical Pharmacokinetics/Pharmacodynamics for the Development of Antibacterial Agents.

In June 2017, The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, organized a workshop entitled "Pharmacokinetics-Pharmacodynamics (PK/PD) for Development of Therapeutics against Bacterial Pathogens" to discuss details and critical parameters of various PK/PD methods and identify approaches for linking human pharmacokinetic (PK) data and drug efficacy analyses. The workshop participants included individuals from academia, industry, and government. This and the accompanying minireview on nonclinical PK/PD summarize the workshop discussions and recommendations. It is important to consider how information like PK/PD can support the clinical effectiveness of new antibacterial drugs, as PK/PD data have become central to antibacterial drug development programs. Key clinical considerations for antibacterial dose selection and clinical PK/PD characterization discussed in this minireview include a robust assessment of PK in the patient population of interest, critical considerations for assessing drug penetration in the lung for the treatment of pneumonia, and an emphasis on special populations, including patients with renal impairment and augmented renal function, as well as on dosing in obese and pediatric patients. Successful application of such approaches is now used to provide a more informative drug development package to support the approval of new antibiotics.

Relationship between vancomycin exposure and outcomes among patients with MRSA bloodstream infections with vancomycin Etest® MIC values of 1.5mg/L: A pilot study.

Data suggest that vancomycin is less effective for methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) with vancomycin Etest® MIC (MICEtest) ≥1.5 mg/L. No published studies have evaluated the relationship between vancomycin exposure and outcomes among patients with MRSA BSIs vancomycin MICEtest ≥1.5 mg/L. This study was a retrospective cohort of 71 hospitalized, adult, non-dialysis patients with MRSA BSIs treated with vancomycin. All but three patients had a vancomycin MICEtest of 1.5 mg/L. Achievement of CART-derived AUC24-48h of at least 550 mg*h/L (AUC24-48h/MIC of 366 mg*h/L) was associated with a lower incidence of treatment failure. In multivariate analyses, the risk ratio was 0.45 for the CART-derived AUC24-48h threshold, indicating that achievement of the CART-derived AUC24-48h threshold of 550 was associated with a 2-fold decrease in treatment failure. These findings suggest a potential association between vancomycin exposure and outcomes in patients with MRSA BSIs with MICEtest ≥1.5 mg/L. As this study was retrospective, these findings provide the basis for a future large-scale, multi-center prospective study.

Quantifying the matrix of relationships between reduced vancomycin susceptibility phenotypes and outcomes among patients with MRSA bloodstream infections treated with vancomycin .

OBJECTIVES: Several phenotypic characteristics of Staphylococcus aureus have been identified as aetiological factors responsible for adverse outcomes among patients receiving vancomycin. However, characterization of the outcomes associated with these reduced vancomycin susceptibility phenotypes (rVSPs) remains largely incomplete and it is unknown if these features contribute to deleterious treatment outcomes alone or in concert. This study described the interrelationship between rVSPs and assessed their individual and combined effects on outcomes among patients who received vancomycin for a methicillin-resistant S. aureus (MRSA) bloodstream infection. METHODS: An observational study of adult, hospitalized patients with MRSA bloodstream infections who were treated with vancomycin between January 2005 and June 2009 was performed. The rVSPs evaluated included the following: (i) Etest MIC; (ii) broth microdilution MIC; (iii) MBC : MIC ratio; and (iv) heteroresistance to vancomycin by the Etest macromethod. Failure was defined as any of the following: (i) 30 day mortality; (ii) bacteraemia ≥ 7 days on therapy; or (iii) recurrence of MRSA bacteraemia within 60 days of therapy discontinuation. RESULTS: During the study period, 184 cases met the study criteria and 41.3% met the failure criteria. There was a clear linear exposure-response relationship between the number of these phenotypic markers and outcomes. As the number of phenotypes escalated, the incidence of overall failure increased incrementally by 10%-18%. CONCLUSIONS: The data suggest that rVSPs contribute to deleterious treatment outcomes in concert.

Individualization of piperacillin dosing for critically ill patients: dosing software to optimize antimicrobial therapy.

Piperacillin-tazobactam is frequently used for empirical and targeted therapy of infections in critically ill patients. Considerable pharmacokinetic (PK) variability is observed in critically ill patients. By estimating an individual's PK, dosage optimization Bayesian estimation techniques can be used to calculate the appropriate piperacillin regimen to achieve desired drug exposure targets. The aim of this study was to establish a population PK model for piperacillin in critically ill patients and then analyze the performance of the model in the dose optimization software program BestDose. Linear, with estimated creatinine clearance and weight as covariates, Michaelis-Menten (MM) and parallel linear/MM structural models were fitted to the data from 146 critically ill patients with nosocomial infection. Piperacillin concentrations measured in the first dosing interval, from each of 8 additional individuals, combined with the population model were embedded into the dose optimization software. The impact of the number of observations was assessed. Precision was assessed by (i) the predicted piperacillin dosage and by (ii) linear regression of the observed-versus-predicted piperacillin concentrations from the second 24 h of treatment. We found that a linear clearance model with creatinine clearance and weight as covariates for drug clearance and volume of distribution, respectively, best described the observed data. When there were at least two observed piperacillin concentrations, the dose optimization software predicted a mean piperacillin dosage of 4.02 g in the 8 patients administered piperacillin doses of 4.00 g. Linear regression of the observed-versus-predicted piperacillin concentrations for 8 individuals after 24 h of piperacillin dosing demonstrated an r(2) of >0.89. In conclusion, for most critically ill patients, individualized piperacillin regimens delivering a target serum piperacillin concentration is achievable. Further validation of the dosage optimization software in a clinical trial is required.

Comparative evaluation of serotonin toxicity among veterans affairs patients receiving linezolid and vancomycin.

Despite the theoretical risk of serotonin toxicity (ST) with linezolid, "real-world" clinical evaluations of the risk of ST in patients receiving linezolid have been limited to case reports and noncomparator studies. An observational, matched-cohort study was conducted to evaluate the risk of ST among hospitalized patients who received linezolid or vancomycin at the Upstate New York Veterans Affairs Healthcare Network (Veterans Integrated Service Network 2 [VISN-2]). Matching criteria included VISN-2 hospital, hospital ward, prior hospital length of stay, age, and baseline platelet counts. The patients' electronic medical records were evaluated for symptoms consistent with ST and the Hunter serotonin toxicity criteria (HSTC) using an intensive, natural word search algorithm. The study included 251 matched pairs. Demographics and comorbidities were similar between groups. Over half of the study population received at least one concurrent medication with serotonergic activity. Receipt of agents with serotonergic activity was more pronounced in the vancomycin group, and the higher frequency was due to concomitant antihistamine and antiemetic use. Antidepressant use, including selective serotonin reuptake inhibitors (SSRIs), was similar between groups. No patients in either group were found to meet the criteria using the word search algorithm for ST. Fewer linezolid patients than vancomycin patients met the HSTC overall (3.2% versus 8.8%) and when stratified by receipt of a concurrent serotonergic agent (4.3% versus 12.4%). Of the patients meeting the HSTC, most had past or present comorbidities that may have contributed to or overlapped the HSTC. This study of hospitalized patients revealed comparably low frequencies of adverse events potentially related to ST among patients who received linezolid or vancomycin.

Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter.

In an effort to maximize outcomes, recent expert guidelines recommend more-intensive vancomycin dosing schedules to maintain vancomycin troughs between 15 and 20 mg/liter. The widespread use of these more-intensive regimens has been associated with an increase in vancomycin-induced nephrotoxicity reports. The purpose of this systematic literature review is to determine the nephrotoxicity potential of maintaining higher troughs in clinical practice. All studies pertaining to vancomycin-induced nephrotoxicity between 1996 and April 2012 were identified from PubMed, Embase, Cochrane Controlled Trial Registry, and Medline databases and analyzed according to Cochrane guidelines. Of the initial 240 studies identified, 38 were reviewed, and 15 studies met the inclusion criteria. Overall, higher troughs (≥ 15 mg/liter) were associated with increased odds of nephrotoxicity (odds ratio [OR], 2.67; 95% confidence interval [CI], 1.95 to 3.65) relative to lower troughs of <15 mg/liter. The relationship between a trough of ≥ 15 mg/liter and nephrotoxicity persisted when the analysis was restricted to studies that examined only initial trough concentrations (OR, 3.12; 95% CI, 1.81 to 5.37). The relationship between troughs of ≥ 15 mg/liter and nephrotoxicity persisted after adjustment for covariates known to independently increase the risk of a nephrotoxicity event. An incremental increase in nephrotoxicity was also observed with longer durations of vancomycin administration. Vancomycin-induced nephrotoxicity was reversible in the majority of cases, with short-term dialysis required only in 3% of nephrotoxic episodes. The collective literature indicates that an exposure-nephrotoxicity relationship for vancomycin exists. The probability of a nephrotoxic event increased as a function of the trough concentration and duration of therapy.

Population pharmacokinetics of extended-infusion piperacillin-tazobactam in hospitalized patients with nosocomial infections.

While extended infusions of piperacillin-tazobactam (TZP) are increasingly used in practice, the effect of infusion on the pharmacokinetic (PK) profile of TZP has not been widely assessed. To assess its effect on the pharmacokinetic profile of TZP, seven serum samples were collected from 11 hospitalized patients who received 3.375 g TZP intravenously for 4 h every 8 h. Population pharmacokinetic models were fit to the PK data utilizing first-order, Michaelis-Menten (MM), and parallel first-order/MM clearance. A population PK model with first-order clearance was fit to the tazobactam PK data. Monte Carlo simulations (MCSs) were used to determine the most effective administration schedule to ensure that free piperacillin concentrations were above the MIC for at least 50% of the dosing interval (50% fT>MIC) and to quantify the extent of the nonlinear clearance. The model incorporating parallel linear/MM clearance best fit the piperacillin PK data. The MCSs demonstrated that approximately 50% of the administered piperacillin is cleared by the nonlinear clearance mechanism. The results of the MCSs also revealed that more intensive TZP extended infusion dosing schemes (3.375 to 4.5 g intravenously [3-h infusion] every 6 h) than those commonly used in clinical practice were needed to maximize the 50% fT>MIC for MICs of ≥8 mg/liter. This study suggests that extended infusion of TZP is the most effective method of administration for patients with nosocomial infections. Due to the hyperclearance nature of the hospitalized patient populations studied, more intensive TZP dosing regimens may be needed to maximize fT>MIC in certain hospitalized populations.

The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: a systematic review and meta-analysis.

BACKGROUND: Emerging data suggest that vancomycin may be less effective against serious methicillin-resistant Staphylococcus aureus (MRSA) infections with minimum inhibitory concentration (MIC) values at the higher end of the susceptibility range. The purpose of this review is to examine the strength of these associations. METHODS: All relevant studies pertaining to treatment outcomes or mortality associated with vancomycin MIC were retrieved from the medical literature from January 1996 through August 2011 and analyzed according to Cochrane guidelines. RESULTS: Of the 270 studies identified, 48 studies were reviewed, with 22 studies included in the final meta-analysis. Vancomycin MIC was significantly associated with mortality for MRSA infection irrespective of the source of infection or MIC methodology (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.14-2.37; P < .01). This mortality association was predominantly driven by bloodstream infections (BSIs; OR, 1.58; 95% CI, 1.06-2.37; P = .03) and isolates with a vancomycin MIC of 2 µg/mL by Etest (OR, 1.72; 95% CI, 1.34-2.21; P < .01). Vancomycin MIC was significantly associated with treatment failure irrespective of source of infection or MIC methodology (OR, 2.69; 95% CI, 1.60-4.51; P < .01). CONCLUSION: High vancomycin MIC was associated with a higher mortality rate in MRSA BSI. Thus, institutions should consider conducting Etest MICs on all MRSA BSI isolates. Although these data highlight concerns about vancomycin, currently, there are no data to support better survival rates with alternative antibiotics. Data are sorely needed to determine whether other agents can remedy these outcomes observed with vancomycin for MRSA infections with elevated vancomycin MIC values.

Telavancin pharmacokinetics and pharmacodynamics in patients with complicated skin and skin structure infections and various degrees of renal function.

This study characterized the pharmacokinetic/pharmacodynamic profiles of the Food and Drug Administration (FDA)-approved telavancin renal dose adjustment schemes. A previously published two-compartment open model with first-order elimination and a combined additive and proportional residual error model derived from 749 adult subjects in 11 clinical trials was used to simulate the individual concentration-time profiles for 10,260 subjects (NONMEM). The dosing regimens simulated were 10 mg/kg of body weight once daily for individuals with creatinine clearances (CL(CR)s) of >50 ml/min, 7.5 mg/kg once daily for individuals with CL(CR)s of 30 to 50 ml/min, and 10 mg/kg every 2 days for those with CL(CR)s of <30 ml/min. The area under the concentration-time curve (AUC) under one dosing interval (AUC(τ)) was computed as dose/CL. The probability of achieving an AUC(τ)/MIC ratio of ≥ 219 was evaluated separately for each renal dosing scheme. Evaluation of the dosing regimens demonstrated similar AUC values across the different renal function groups. For all renal dosing strata, >90% of the simulated subjects achieved an AUC(τ)/MIC ratio of ≥ 219 for MIC values as high as 2 mg/liter. For patients with CL(CR)s of <30 ml/min, the probability of target attainment (PTA) exceeded 90% for both the AUC0₋24 (AUC from 0 to 24 h) and AUC24₋48 intervals for MICs of ≤ 1 mg/liter. At a MIC of 2 mg/liter, the PTAs were 89.3% and 23.6% for the AUC0₋24 and AUC24₋48 intervals, respectively. The comparable PTA profiles for the three dosing regimens across their respective dosing intervals indicate that the dose adjustments employed in phase III trials for complicated skin and skin structure infections were appropriate.

Meropenem penetration into epithelial lining fluid in mice and humans and delineation of exposure targets.

Pseudomonas aeruginosa pneumonia remains a most-difficult-to-treat nosocomial bacterial infection. We used mathematical modeling to identify drug exposure targets for meropenem in the epithelial lining fluid (ELF) of mice with Pseudomonas pneumonia driving substantial [2 to 3 log(10) (CFU/g)] killing and which suppressed resistant subpopulation amplification. We bridged to humans to estimate the frequency with which the largest licensed meropenem dose would achieve these exposure targets. Cell kills of 2 and 3 log(10) (CFU/g) and resistant subpopulation suppression were mediated by achieving time > MIC in ELF of 32%, 50%, and 50%. Substantial variability in meropenem's ability to penetrate into ELF of both mice and humans was observed. Penetration variability and high exposure targets combined to prevent even the largest licensed meropenem dose from achieving the targets at an acceptable frequency. Even a highly potent agent such as meropenem does not adequately suppress resistant subpopulation amplification as single-agent therapy administered at maximal dose and optimal schedule. Combination chemotherapy is likely required in humans if we are to minimize resistance emergence in Pseudomonas aeruginosa pneumonia. This combination needs evaluation both in the murine pneumonia model and in humans.

Penetration of meropenem into epithelial lining fluid of patients with ventilator-associated pneumonia.

Antibiotic penetration to the infection site is critical for obtaining a good clinical outcome in patients with ventilator-associated pneumonia (VAP). Surprisingly few studies have quantified the penetration of ß-lactam agents into the lung, as measured by the ratio of area under the concentration-time curve (AUC) in epithelial lining fluid (ELF) to AUC in plasma (AUC(ELF)/AUC(plasma) ratio). These have typically involved noninfected patients. This study examines the penetration and pharmacodynamics of meropenem in the ELF among patients with VAP. Meropenem plasma and ELF concentration-time data were obtained from patients in a multicenter clinical trial. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer (big nonparametric adaptive grid [BigNPAG]). A Monte Carlo simulation was performed to estimate the range of ELF/plasma penetration ratios one would expect to observe in patients with VAP, as measured by the AUC(ELF)/AUC(plasma) ratio. The range of AUC(ELF)/AUC(plasma) penetration ratios predicted by the Monte Carlo simulation was large. The 10th percentile of lung penetration was 3.7%, while the 90th percentile of penetration was 178%. The variability of ELF penetration is such that if relatively high ELF exposure targets are required to attain multilog kill or resistance suppression for bacteria like Pseudomonas aeruginosa, then even receiving the largest licensed dose of meropenem with an optimal prolonged infusion may not result in target attainment for a substantial fraction of the population.

Identification of optimal renal dosage adjustments for traditional and extended-infusion piperacillin-tazobactam dosing regimens in hospitalized patients.

This study examined the effect of various levels of renal impairment on the probability of achieving free drug concentrations that exceed the MIC for 50% of the dosing interval (50% fT > MIC) for traditional and extended-infusion piperacillin-tazobactam (TZP) dosing strategies. It also identified optimal renal dosage adjustments for traditional and extended-infusion dosing schemes that yielded probability of target attainment (PTA) and exposure profiles that were isometric to those of the parent regimens. Data from 105 patients were analyzed using the population pharmacokinetic modeling program BigNPAG. To assess the effect of creatinine clearance (CL(CR)) on overall clearance, TZP clearance was made proportional to the estimated CL(CR). A Monte Carlo simulation (9,999 subjects) was performed for the traditional dosing scheme (4.5 g infused during 30 min every 6 h) and the extended-infusion TZP dosing scheme (3.375 g infused during 4 h every 8 h). The fraction of simulated subjects who achieved 50% fT > MIC was calculated for the range of piperacillin MICs from 0.25 to 32 mg/liter and stratified by CL(CR). The traditional TZP regimen displayed the greatest variability in PTA across MIC values, especially for MIC values exceeding 4 mg/liter, when stratified by CL(CR). In contrast, the PTA for the extended-infusion TZP regimen exceeded >or=80% for MIC values of or=32 mg/liter irrespective of the CL(CR). The CL(CR) adjustments for traditional and extended-infusion TZP dosing regimens should be considered at a CL(CR) of

Correlation between vancomycin MIC values and those of other agents against gram-positive bacteria among patients with bloodstream infections caused by methicillin-resistant Staphylococcus aureus.

An increase in the distribution of vancomycin MIC values among methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) isolates has been noted. It is postulated that the shift in vancomycin MIC values may be associated with a concurrent rise in the MIC values of other anti-MRSA agents. Scant data are available on the correlation between vancomycin MIC values and the MIC values of other anti-MRSA agents. This study examined the correlation between vancomycin MIC values and the MIC values of daptomycin, linezolid, tigecycline, and teicoplanin among 120 patients with bloodstream infections caused by MRSA at a tertiary care hospital between January 2005 and May 2007. For each included patient, the MIC values of the antibiotics under study were determined by the Etest method and were separated into the following two categories: day 1 (index) and post-day 1 (subsequent). For subsequent isolates, the MIC values for each antibiotic from the post-day 1 terminal isolate were used. Among the index isolates, there was a significant correlation (P value, <0.01) between the MIC values for vancomycin and daptomycin and between the MIC values for vancomycin and teicoplanin. The MIC values for daptomycin were significantly correlated with linezolid, tigecycline, and teicoplanin MIC values. Among the 48 patients with subsequent isolates, vancomycin MIC values were significantly correlated with MIC values for daptomycin, linezolid, and teicoplanin (rho value of >or=0.38 for all comparisons). This study documented an association between vancomycin MIC values and the MIC values of other anti-MRSA antibiotics among patients with bloodstream infections caused by MRSA primarily treated with vancomycin.

Predictors of high vancomycin MIC values among patients with methicillin-resistant Staphylococcus aureus bacteraemia.

BACKGROUND: Recent evidence suggests that vancomycin demonstrates reduced activity against methicillin-resistant Staphylococcus aureus (MRSA) infections when vancomycin MIC values are at the high end of the susceptibility range (> or = 1.5 mg/L). However, scant research exists on factors predictive of high vancomycin MICs (> or = 1.5 mg/L) among MRSA bacteraemic patients. Empirical therapy decisions would greatly benefit from such information. OBJECTIVES: To identify the parameters predictive of high vancomycin MICs (> or = 1.5 mg/L) among MRSA bacteraemic patients and to develop an evidence-based clinical prediction tool. METHODS: This observational cohort study included adult patients with MRSA bloodstream infections between January 2005 and May 2007. Demographics, co-morbid conditions, and microbiology and antibiotic exposure data were collected. Vancomycin MICs were determined by Etest. Stepwise logistic regression was used to identify independent predictors of high vancomycin MICs. RESULTS: Of the 105 patients who met the inclusion criteria, 77 patients (73.3%) exhibited a high vancomycin MIC (> or = 1.5 mg/L). In the bivariate analysis, prior vancomycin exposure within 30 days of index culture collection [15 patients (19.5%) versus 1 patient (3.6%), P = 0.05] and residence in an intensive care unit (ICU) at the onset of infection [27 patients (35.1%) versus 3 patients (10.7%), P = 0.02] were both significantly associated with a high vancomycin MIC value and both were independent predictors of high MICs in the logistic regression. CONCLUSIONS: Patients with MRSA bloodstream infections in the ICU or with a history of vancomycin exposure should be considered at high risk of infection with strains for which vancomycin MICs are elevated. Appropriate and aggressive empirical therapy is required for these patients.

Relationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin.

There is growing concern that vancomycin has diminished activity for methicillin-resistant Staphylococcus aureus (MRSA) infections, with vancomycin MICs at the high end of the CLSI susceptibility range. Despite this growing concern, there are limited clinical data to support this notion. To better elucidate this, a retrospective cohort study was conducted among patients with MRSA bloodstream infections who were treated with vancomycin between January 2005 and May 2007. The inclusion criteria were as follows: at least 18 years old, nonneutropenic, with an MRSA culture that met the CDC criteria for bloodstream infection, had received vancomycin therapy within 48 h of the index blood culture, and survived >24 h after vancomycin administration. Failure was defined as 30-day mortality, bacteremia >or=10 days on vancomycin therapy, or a recurrence of MRSA bacteremia within 60 days of vancomycin discontinuation. Classification and regression tree (CART) analysis identified the vancomycin MIC breakpoint associated with an increased probability of failure. During the study period, 92 patients met the inclusion criteria. The vancomycin MIC breakpoint derived by CART analysis was >or=1.5 mg/liter. The 66 patients with vancomycin MICs of >or=1.5 mg/liter had a 2.4-fold increase in failure compared to patients with MICs of or=1.5 mg/liter was independently associated with failure (adjusted risk ratio, 2.6; 95% confidence interval, 1.3 to 5.4; P = 0.01). These data strongly suggest that patients with MRSA bloodstream infections with vancomycin MICs of >or=1.5 mg/liter respond poorly to vancomycin. Alternative anti-MRSA therapies should be considered for these patients.

Pharmacodynamics of ceftazidime and meropenem in cerebrospinal fluid: results of population pharmacokinetic modelling and Monte Carlo simulation.

BACKGROUND: Ceftazidime and meropenem are frequently used in the empirical treatment of hospital-acquired cerebrospinal fluid (CSF) infections. Although their dispositions in CSF have been described, the ability of these agents to achieve critical pharmacodynamic targets against the array of nosocomial CSF Gram-negative bacteria encountered in practice has not been reported. METHODS: Serum and CSF pharmacokinetic data were obtained from hospital patients with external ventricular drains and who received ceftazidime or meropenem. Concentration-time profiles in serum and CSF were modelled using a three-compartment model with zero-order infusion and first-order elimination and transfer. The model parameters were identified using population pharmacokinetic analysis [Big Non-Parametric Adaptive Grid (BigNPAG)]. A Monte Carlo simulation (9999 subjects) estimated the probability of target attainment (PTA) for total drug CSF concentrations at 50% and 100% T(>MIC) for ceftazidime 2 g intravenously every 8 h and meropenem 2 g intravenously every 8 h. The Gram-negative infection isolates of the seven most prevalent Gram-negative bacilli from the Meropenem Yearly Susceptibility Test Information Collection Program were used as a measure of contemporary MIC distribution. RESULTS: Post-Bayesian measures of bias and precision, observed-predicted plots and R(2) values were highly acceptable for both drugs. Although the PTA in CSF was approximately one dilution higher for ceftazidime compared with meropenem at a given MIC value, the cumulative fraction of response (CFR) in CSF against all Gram-negatives was markedly higher for meropenem when compared with ceftazidime secondary to the higher occurrence of lower MIC values for meropenem. Both agents had a low CFR against Pseudomonas aeruginosa. CONCLUSIONS: The pharmacodynamics of meropenem was superior to that of ceftazidime against Gram-negative pathogens in the CSF.