Pharmacokinetics-Pharmacodynamics of Tazobactam in Combination with Piperacillin in an In Vitro Infection Model.

We have previously demonstrated the pharmacokinetic-pharmacodynamic (PK-PD) index best associated with the efficacy of tazobactam when used in combination with ceftolozane to be the percentage of the dosing interval during which tazobactam concentrations remained above a threshold value (%time>threshold). Using anin vitroinfection model and the same isogenic CTX-M-15-producingEscherichia colitriplet set genetically engineered to transcribe different levels ofblaCTX-M-15, herein we describe dose fractionation studies designed to evaluate the PK-PD index associated with tazobactam efficacy, when given in combination with piperacillin, and the impact of the presence of a different ß-lactam agent, or differentblaCTX-M-15transcription levels, on the magnitude of the tazobactam PK-PD index necessary for efficacy. The recombinant strains demonstrated piperacillin MIC values of 128, >256, and >256 µg/ml for the low-, moderate-, and high-level CTX-M-15-producingE. colistrains, respectively. The MIC value for piperacillin in the presence of 4 µg/ml of tazobactam was 2 µg/ml for all three strains. The PK-PD index associated with tazobactam efficacy was confirmed to be %time>threshold, regardless of ß-lactamase transcription (r(2)= 0.839). The tazobactam concentration thresholds, however, changed with the CTX-M-15 transcription level and were 0.25, 0.5, and 2 µg/ml for the low-, moderate-, and high-level CTX-M-15-producing strains, respectively (r(2)= 0.921, 0.773, and 0.875, respectively). The %time>threshold values for tazobactam necessary for net bacterial stasis and a 1- and 2-log10-unit CFU/ml decrease from baseline at 24 h were 44.9, 62.9, and 84.9%, respectively. In addition to verifying our previous study results, these results also demonstrated that the magnitude of bacterial-cell killing associated with a ß-lactam-ß-lactamase inhibitor combination is dependent on the amount of ß-lactamase produced. These data provide important information for the development of ß-lactam-ß-lactamase inhibitor combination agents.

An exploratory analysis of the ability of a cefepime trough concentration greater than 22 mg/L to predict neurotoxicity.

INTRODUCTION: Cefepime trough concentrations >22 mg/L (T(>22)) have been associated with neurotoxicity in a single study. PATIENTS AND METHODS: Neurotoxicity outcomes for 28 cefepime-treated adult patients with febrile neutropenia were abstracted from the literature. The precision of T(>22) to predict neurotoxicity was quantified using 95% confidence intervals. Thirty-two cefepime-treated patients contributed serum concentrations for a pharmacokinetic model, fit using the Nonparametric Adaptive Grid algorithm within the Pmetrics package for R. Concentration-time curves were simulated for common dosing schemes and 3 renal dispositions. Probabilities of neurotoxicity and numbers needed to harm were calculated from simulations according to the proposed pharmacokinetic/toxicodynamic threshold of T(>22). Bayesian modeling was utilized to explore other pharmacokinetic parameters relationships with neurotoxicity. RESULTS: The mean probability of neurotoxicity at T(>22) was 51.4% (95% CI: 16.4-85.0%). Among the schemes and renal dispositions simulated, the combination of cefepime 2 g every 8 h and a creatinine clearance of 60 mL/min produced the greatest probability of neurotoxicity (48.3%). Estimated numbers needed to harm according to T(>22) ranged from 2.1 to 18.5 persons. Explorations of maximal serum concentration and area under the curve demonstrated high levels of collinearity, making it impossible to identify trough concentrations as the driver of neurotoxicity. DISCUSSION: T(>22) had low precision as a predictive neurotoxic threshold. When a neurotoxic threshold of T(>22) was assumed, projected neurotoxicity rates and numbers needed to harm greatly exceeded observed neurotoxicity rates in the general population and in high risk subpopulations. Other drug exposure metrics should be explored.

Defining Clinical Exposures of Cefepime for Gram-Negative Bloodstream Infections That Are Associated with Improved Survival.

The percentage of time that free drug concentrations remain above the MIC (fT>MIC) that is necessary to prevent mortality among cefepime-treated patients with Gram-negative bloodstream infections (GNBSI) is poorly defined. We conducted a retrospective study of adult patients with GNBSI. Eligible cases were frequency matched to ensure categorical representation from all MICs. Organism, MIC, infection source, gender, age, serum creatinine, weight, antibiotic history, and modified APACHE II score were collected from hospital records. Two population pharmacokinetic models (models 1 and 2) were used to impute exposures over the first 24 h in each patient from mean model parameters, covariates, and dosing history. From the imputed exposures, survival thresholds for fT>MIC were identified using classification and regression tree (CART) analysis and analyzed as nominal variables for univariate and multivariate regressions. A total of 180 patients were included in the analysis, of whom 13.9% died and 86.1% survived. Many patients (46.7% [n = 84/180]) received combination therapy with cefepime. Survivors had higher mean (standard deviation [SD]) fT>MIC than those who died (model 1, 74.2% [29.6%] versus 52.1% [33.8%], P < 0.001; model 2, 85.9% [24.0%] versus 64.4% [31.4%], P < 0.001). CART identified fT>MIC threshold values for greater survival according to models 1 and 2 at >68% and >74%, respectively. Survival was improved for those with fT>MIC of >68% (model 1 adjusted odds ratio [aOR], 7.12; 95% confidence interval [CI], 1.90 to 26.7; P = 0.004) and >74% (model 2 aOR, 6.48; 95% CI, 1.90 to 22.1) after controlling for clinical covariates. Similarly, each 1% increase in cefepime fT>MIC resulted in a 2% improvement in multivariate survival probability (P = 0.015). Achieving a cefepime fT>MIC of 68 to 74% was associated with a higher odds of survival for patients with GNBSI. Regimens targeting this exposure should be aggressively pursued.

Dual beta-lactam therapy for serious Gram-negative infections: is it time to revisit?

We are rapidly approaching a crisis in antibiotic resistance, particularly among Gram-negative pathogens. This, coupled with the slow development of novel antimicrobial agents, underscores the exigency of redeploying existing antimicrobial agents in innovative ways. One therapeutic approach that was heavily studied in the 1980s but abandoned over time is dual beta-lactam therapy. This article reviews the evidence for combination beta-lactam therapy. Overall, in vitro, animal and clinical data are positive and suggest that beta-lactam combinations produce a synergistic effect against Gram-negative pathogens that rivals that of beta-lactam-aminoglycoside or beta-lactam-fluoroquinolone combination therapy. Although the precise mechanism of improved activity is not completely understood, it is likely attributable to an enhanced affinity to the diverse penicillin-binding proteins found among Gram negatives. The collective data indicate that dual beta-lactam therapy should be revisited for serious Gram-negative infections, especially in light of the near availability of potent beta-lactamase inhibitors, which neutralize the effect of problematic beta-lactamases.

Pharmacokinetics-pharmacodynamics of tazobactam in combination with ceftolozane in an in vitro infection model.

Despite ß-lactamase inhibitors being available for clinical use for nearly 30 years, a paucity of data exists describing the pharmacokinetic-pharmacodynamic (PK-PD) determinants of efficacy for these agents. Herein, we describe dose fractionation studies designed to determine the exposure measure most predictive of tazobactam efficacy in combination with ceftolozane and the magnitude of this measure necessary for efficacy in a PK-PD in vitro infection model. The challenge organism panel was comprised of an isogenic CTX-M-15-producing Escherichia coli triplet set, genetically engineered to transcribe different levels of bla(CTX-M-15). These recombinant strains exhibited ceftolozane MIC values of 4, 16, and 64 µg/ml representing low, moderate, and high levels of CTX-M-15, respectively. Different bla(CTX-M-15) transcription levels were confirmed by relative quantitative real-time PCR (qRT-PCR) and ß-lactamase hydrolytic assays. The exposure measure associated with efficacy was the percentage of the dosing interval that tazobactam concentrations remained above a threshold (%Time>threshold), regardless of enzyme expression (r(2) = 0.938). The threshold concentrations identified were 0.05 µg/ml for low and moderate and 0.25 µg/ml for the high-ß-lactamase expression strain constructs. The magnitudes of %Time>threshold for tazobactam associated with net bacterial stasis and a 1- and 2-log10 CFU reduction in bacteria at 24 h were approximately 35, 50, and 70%, respectively. These data provide an initial target tazobactam concentration-time profile and a paradigm to optimize tazobactam dosing when combined with ceftolozane.

Evaluation of once-daily vancomycin against methicillin-resistant Staphylococcus aureus in a hollow-fiber infection model.

For methicillin-resistant Staphylococcus aureus (MRSA) infections, data suggest that the clinical response is significantly better if the total vancomycin area under the concentration-time curve (AUC)/MIC ratio is ≥400. While the AUC/MIC ratio is the accepted pharmacokinetic/pharmacodynamic (PK/PD) index for vancomycin, this target has been achieved using multiple daily doses. We are unaware of a systematically designed dose fractionation study to compare the bactericidal activity of once-daily administration to that of traditional twice-daily administration. A dose fractionation study was performed with vancomycin in an in vitro hollow-fiber infection model against an MRSA USA300 strain (MIC of 0.75 µg/ml) using an inoculum of ∼10(6) CFU/ml. The three vancomycin regimens evaluated for 168 h were 2 g every 24 h (q24h) as a 1-h infusion, 1 g q12h as a 1-h infusion, and 2 g q24h as a continuous infusion. Free steady-state concentrations (assuming 45% binding) for a total daily AUC/MIC ratio of ≥400 were simulated for all regimens. A validated liquid chromatography-tandem mass spectrometry method was used to determine vancomycin concentrations. Although once-daily and twice-daily dosage regimens exhibited total trough concentrations of <15 µg/ml, all regimens achieved similar bactericidal activities between 24 and 168 h and suppressed the amplification of nonsusceptible subpopulations. No colonies were found on agar plates with 3× MIC for any of the treatment arms. Overall, the results suggest that once-daily vancomycin administration is feasible from a PK/PD perspective and merits further inquiry in the clinical arena.

In vitro pharmacodynamics of simulated pulmonary exposures of tigecycline alone and in combination against Klebsiella pneumoniae isolates producing a KPC carbapenemase.

Multidrug-resistant Klebsiella pneumoniae strains that produce a serine carbapenemase (KPC) are emerging worldwide, with few therapeutic options that retain consistent susceptibility. The objective of this study was to determine the effect of combination therapy with tigecycline versus tigecycline alone against KPC-producing isolates (KPC isolates). An in vitro pharmacodynamic model was used to simulate adult steady-state epithelial lining fluid concentrations of tigecycline (50 mg every 12 h) given alone and in combination with either meropenem (2 g by 3-hour infusion every 8 h) or rifampin (600 mg every 12 h). Five KPC isolates with various phenotypic profiles were exposed over 48 h. Time-kill curves were constructed, and the areas under the bacterial killing and regrowth curves (AUBCs) were calculated. No regimens tested were able to maintain bactericidal reductions in CFU over 48 h. The AUBCs for tigecycline and meropenem monotherapies at 48 h ranged from 375.37 to 388.11 and from 348.62 to 383.83 (CFU-h/ml), respectively. The combination of tigecycline plus meropenem significantly reduced the AUBCs at 24 and 48 h for isolates with tigecycline MICs of ≤ 2 µg/ml and meropenem MICs of ≤ 16 µg/ml (P < 0.001) but added no additional activity when the meropenem MIC was 64 µg/ml (P = 0.5). Rifampin provided no additional reduction in CFU or AUBC over tigecycline alone (P = 0.837). The combination of tigecycline with high-dose, prolonged-infusion meropenem warrants further study as a potential treatment option for these multidrug-resistant organisms.

Optimization of meropenem dosage in the critically ill population based on renal function.

PURPOSE: To develop a meropenem population pharmacokinetic model in critically ill patients with particular focus on optimizing dosing regimens based on renal function. METHODS: Population pharmacokinetic analysis was performed with creatinine clearance (CrCl) and adjusted body weight to predict parameter estimates. Initial modeling was performed on 21 patients (55 samples). Validation was conducted with 12 samples from 5 randomly selected patients excluded from the original model. A 5,000-patient Monte Carlo simulation was used to ascertain optimal dosing regimens for three CrCl ranges. RESULTS: Mean ± SD age, APACHE, and CrCl were 59.2 ± 16.8 years, 13.6 ± 7, and 78.3 ± 33.7 mL/min. Meropenem doses ranged from 0.5 g every 8 h (q8h)-2 g q8h as 0.5-3 h infusions. Median estimates for volume of the central compartment, K12 and K21 were 0.24 L/kg, 0.49 h⁻¹, and 0.65 h⁻¹, respectively. K10 was described by the equation: K10= 0.3922 + 0.0025 × CrCl. Model bias and precision were -1.9 and 8.1 mg/L. R², bias, and precision for the validation were 93%, 1.1, and 2.6 mg/L. At minimum inhibitory concentrations (MICs) up to 8 mg/L, the probability of achieving 40% fT > MIC was 96, 90, and 61% for 3 h infusions of 2 g q8h, 1 g q8h, and 1 g q12h in patients with CrCl ≥50, 30-49, and 10-29, respectively. Target attainment was 75, 65, and 44% for these same dosing regimens as 0.5 h infusions. CONCLUSIONS: This pharmacokinetic model is capable of accurately estimating meropenem concentrations in critically ill patients over a range of CrCl values. Compared with 0.5 h infusions, regimens employing prolonged infusions improved target attainment across all CrCl ranges.

Length of stay and hospital costs associated with a pharmacodynamic-based clinical pathway for empiric antibiotic choice for ventilator-associated pneumonia.

STUDY OBJECTIVE: To determine hospital costs associated with the use of a clinical pathway implemented in our intensive care units (ICUs) to optimize antibiotic regimen selection for patients with ventilator-associated pneumonia (VAP) compared with costs in a historical control group treated according to prescriber preference. DESIGN: Retrospective cost analysis from the hospital perspective. SETTING: Single, tertiary-care medical center. PATIENTS: One hundred sixty-six adults with VAP from the medical, surgical, and neurotrauma ICUs (73 historical control patients [2004-2005] and 93 patients given an empiric antibiotic clinical pathway for VAP [2006-2007]). MEASUREMENTS AND MAIN RESULTS: The VAP clinical pathway consisted of an ICU-specific three-drug regimen that considered local minimum inhibitory concentration distributions and a pharmacodynamically optimized dosing strategy. Hospital cost data were collected and inflated to 2007 according to the consumer price index. The VAP-related length of treatment, hospitalization costs, and antibiotic costs were compared between groups. The median VAP length of treatment was 24 days (interquartile range [IQR] 13-35 days] and 11 days (IQR 7-17 days) for historical and clinical pathway groups, respectively (p<0.001). Daily hospital costs were similar for both cohorts over the first 7 days, after which costs declined significantly for patients treated with the clinical pathway (p<0.001). When controlling for baseline differences between groups and length of stay before development of VAP, patients treated with the clinical pathway had shorter lengths of ICU stay after VAP, shorter total hospital lengths of stay after VAP, and lower hospital costs after the treatment of VAP. Median total antibiotic costs for individual patients were similar between groups ($535 [IQR $261-998] vs $482 [IQR $222-985] clinical pathway vs control, p=0.45), and the proportion of VAP hospital resources consumed by antibiotics for both groups was low. CONCLUSION: Although aggressive dosing of more costly antibiotics was empirically prescribed using the clinical pathway, patients in this group exhibited a shorter duration of treatment, reduced hospital length of stay after VAP, and lower hospital costs without any significant increase in antibiotic expenditures.

Pharmacodynamic-based clinical pathway for empiric antibiotic choice in patients with ventilator-associated pneumonia.

BACKGROUND: Because of the high frequency of multidrug resistant bacteria in our intensive care units (ICUs), we implemented a ventilator-associated pneumonia (VAP) clinical pathway based on unit-specific minimum inhibitory concentration (MIC) distributions and pharmacodynamic modeling in 3 of our ICUs. METHODS: This was a prospective, observational evaluation with a historical control group in adult patients (n = 168) who met clinical and radiologic criteria for VAP. Monte Carlo simulation was used to determine antibiotic regimens having the greatest likelihood of achieving bactericidal exposures against Pseudomonas aeruginosa. Antibiotic regimens were incorporated into an ICU-specific computerized clinical pathway as empiric agents of choice. RESULTS: Pharmacodynamic modeling found 3-hour infusions of cefepime 2 g every 8 hours or meropenem 2 g every 8 hours plus tobramycin and vancomycin would provide the greatest probability of empirically treating VAP in these ICUs. Infection-related mortality was reduced by 69% (8.5% vs 21.6%; P = .029), infection-related length of stay was shorter (11.7 +/- 8.1 vs 26.1 +/- 18.5; P < .001), and fewer superinfections were observed in patients treated on the pathway. A number of patients with nonsusceptible P aeruginosa were successfully treated with high-dose, 3-hour infusion regimens. CONCLUSIONS: In our ICUs where multidrug resistant bacteria are common, an approach considering ICU-specific antibiotic MICs coupled with pharmacodynamic dosing strategies resulted in improved outcomes and shorter duration of treatments.

Elevated vancomycin minimum inhibitory concentrations among methicillin-resistant Staphylococcus aureus isolated from patients with ventilator-associated pneumonia at a Connecticut hospital.

Emerging evidence suggests that vancomycin minimum inhibitory concentrations (MICs) within methicillin-resistant Staphylococcus aureus (MRSA) are increasing. The objective of this surveillance study was to determine vancomycin MIC distributions for MRSA isolates collected from the respiratory tract of patients with ventilator-associated pneumonia (VAP) at a large community hospital in Hartford, Connecticut. The frequency of heteroresistant vancomycin intermediate S. aureus (hVISA) was also assessed for select isolates. Vancomycin MICs and hVISA screening were conducted using standard inoculum and macromethod Etest methodology, respectively, for isolates collected between November 2005 and August 2007. Fifty-eight isolates of MRSA were collected over the two-year period. The MIC50 and MIC90 were both 2 microg/ml; 31.0% and 58.6% of isolates had vancomycin MICs of 1.5 microg/ml and 2 microg/ml, respectively. None of the isolates tested were positive for hVISA; four isolates were VISA. Vancomycin MICs for respiratory MRSA at this Connecticut hospital are elevated. Institution-specific surveillance in the state is warranted.

In vivo pharmacodynamic profile of tigecycline against phenotypically diverse Escherichia coli and Klebsiella pneumoniae isolates.

Tigecycline is a glycylcycline with activity against Enterobacteriaceae, including multidrug-resistant isolates of Klebsiella pneumoniae and Escherichia coli producing extended-spectrum beta-lactamase (ESBL) and carbapenemases. Herein, we used an in vivo murine thigh model to characterize the pharmacodynamic profile of tigecycline against genotypically and phenotypically diverse K. pneumoniae and E. coli isolates. Doses of 3.125 to 300 mg/kg, divided 1 to 6 times daily, were administered subcutaneously against six (two nonresistant, one carbapenemase, and three ESBL producing) K. pneumoniae strains and five (two nonresistant and three ESBL producing) E. coli strains. The phenotypic profile (reported tigecycline MIC) for all isolates ranged from 0.125 to 2 microg/ml. Mean correlation coefficients of free (f) drug exposures (percentage of the dosing interval that free drug concentration remained above the MIC [fT>MIC], the ratio of the free drug area under the concentration-time curve/MIC [fAUC/MIC], and the ratio of maximum concentration of free drug in serum/MIC) for all 11 isolates were 0.595, 0.969, and 0.897, respectively. The fAUC/MIC was the pharmacodynamic parameter that best described the efficacy of tigecycline against both E. coli and K. pneumoniae. Interestingly, reductions in the number of CFU were noted even though doses achieved an fT>MIC of 0%. With respect to fAUC/MIC in the neutropenic model, the cumulative 80% and 50% effective pharmacodynamic indexes (EI(80) and EI(50)) for all 11 isolates were 8.4 and 4.7, respectively. An experiment in nonneutropenic mice infected with an ESBL-producing E. coli and K. pneumoniae isolate resulted in the lowest tigecycline fAUC/MIC EI(80) and EI(50) values at 1.8 and 1.0 for E. coli and 1.7 and 1.6 for K. pneumoniae. While the phenotypic profile of tigecycline appeared to drive efficacy irrespective of ESBL or carbapenemase production, the presence of a competent immune system markedly reduced this required exposure.

Population pharmacokinetics of high-dose, prolonged-infusion cefepime in adult critically ill patients with ventilator-associated pneumonia.

A population pharmacokinetic model of cefepime was constructed from data from adult critical care patients with ventilator-associated pneumonia (VAP). A total of 32 patients treated with high-dose cefepime, 2 g every 8 h (3-h infusion) or a renal function-adjusted equivalent dose, were randomized into two groups--26 for the initial model and 6 for model validation. Serum samples of cefepime were collected at steady state. Nonparametric adaptive grid population modeling was employed using a two-compartment K(slope) pharmacokinetic model relating the elimination rate constant (K(10)) to renal function, as defined by creatinine clearance (CL(CR)), and central distribution volume (V(1)) to total body weight (TBW). The final model was described by the following equations: K(10) = 0.0027 x CL(CR) + 0.071 h(-1) and V(1) = TBW x 0.21 liter/kg. The median intercompartmental transfer constants K(12) and K(21) were 0.780 h(-1) and 0.472 h(-1), respectively. Using these median parameter estimates, the bias, precision, and coefficient of determination for the initial model were 11.3 microg/ml, 24.0 microg/ml, and 26%, respectively. The independent validation group displayed a bias, precision, and coefficient of determination of -1.64 microg/ml, 17.1 microg/ml, and 62%, respectively. Time-concentration profiles were assessed for various dosing regimens, using 5,000-patient Monte Carlo simulations. Among the regimens, the likelihoods of 2 g every 8 h (3-h infusion) achieving free drug concentrations above the MIC for 50% of the dosing interval were 91.8%, 78.1%, and 50.3% for MICs of 8, 16, and 32 microg/ml, respectively. This study provides a pharmacokinetic model capable of predicting cefepime concentrations in critically ill patients with VAP.

Bronchopulmonary disposition of micafungin in healthy adult volunteers.

By way of bronchoscopy and bronchoalveolar lavage, intrapulmonary steady-state concentrations of micafungin administered at 150 mg daily to 15 healthy volunteers were determined at 4, 12, and 24 h after the third dose. The micafungin disposition was predominantly intracellular, with approximately 106% penetration into alveolar macrophages and 5% penetration into epithelial lining fluid.

Influence of automated screening and confirmation of extended-spectrum beta-lactamase-producing members of the Enterobacteriaceae on prescribing of antibiotics.

This study investigated the clinician response to the extended-spectrum beta-lactamase (ESBL) confirmation report generated by an automated detection system, MicroScan Walkaway. The study compared two cohorts (pre- and post-automated detection) of patients with an ESBL-producing Escherichia coli or Klebsiella species non-urinary infection over the period October 2001-December 2006. Acceptance of the report, as defined by the initiation of carbapenem therapy, was observed in 69.2% of the post-automated detection cohort (n=78) versus 20% in the pre-automated detection period (n=15) (P

The current state of multidrug-resistant gram-negative bacilli in North America.

Although much of today's media focuses on multidrug-resistant gram-positive bacteria such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus, resistance within gram-negative bacilli continues to rise, occasionally creating situations in which few or no antibiotics that retain activity are available. Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella sp are emerging threats nationally. Although carbapenems are considered the antibiotic class of choice to treat ESBL-producing Enterobacteriaceae, the ability of these organisms to produce carbapenemases has now become apparent in some regions throughout the United States. Although still rare, Klebsiella sp that produce KPC-2 retain susceptibility only to tigecycline, polymyxins, and occasionally aminoglycosides. Multidrug resistance among Pseudomonas aeruginosa and Acinetobacter sp has always been apparent across many hospitals in the United States. Recent surveillance indicates increasing resistance to all currently available antibiotics, including carbapenems, cephalosporins, penicillins, fluoroquinolones, and aminoglycosides. Against many strains, only polymyxins retain activity; however, resistance has also been reported to these agents. Fortunately, resistance mechanisms such as metallo-beta-lactamases are still rare in the United States. As no new antibiotics with novel mechanisms against many of these gram-negative bacilli are expected to be developed in the foreseeable future, careful and conservative use of agents combined with good infection control practices is required.

Treatment of Serratia marcescens meningitis with prolonged infusion of meropenem.

OBJECTIVE: To describe the use of and cerebral spinal fluid (CSF) penetration of a prolonged infusion meropenem regimen in a patient with Serratia marcescens meningitis. CASE SUMMARY: A 54-year-old female was diagnosed with S. marcescens meningitis associated with an epidural abscess 57 days after surgery for a herniated spinal disk. Meropenem 2000 mg every 8 hours was administered as a prolonged (3 h) infusion for the purpose of optimizing pharmacodynamic exposure. Meropenem concentrations were measured from the patient's blood and CSF (via a lumbar drain). The prolonged infusion regimen resulted in concentrations in both serum and CSF above the meropenem minimum inhibitory concentration (MIC) of 0.047 microg/mL for 100% of the dosing interval. After 6 days of therapy, the patient showed no further signs of infection and was subsequently discharged to a rehabilitation facility. At follow-up, she had completed a 4 week course of the prolonged infused therapy without relapse or adverse events. DISCUSSION: Gram-negative infections of the central nervous system result in high morbidity and mortality. These infections are often difficult to treat because of poor antibiotic penetration coupled with increasing antibiotic resistance. Although there are 2 other case reports that describe the use of prolonged infusion of meropenem, our patient had a lumbar drain in place, thereby allowing us to collect multiple CSF samples and more accurately assess meropenem exposure at the site of infection. CSF penetration was 6.4% in this patient, resulting in 100% time above the MIC throughout the dosing interval. CONCLUSIONS: In this patient with meropenem-susceptible S. marcescens meningitis, the use of a high-dose prolonged infusion of meropenem resulted in adequate exposure at the site of infection and a successful clinical response.