Anthony M. Nicasio

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

Although much of todays 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 β‐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‐β‐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.

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

ABSTRACT 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 Kslope pharmacokinetic model relating the elimination rate constant (K10) to renal function, as defined by creatinine clearance (CLCR), and central distribution volume (V1) to total body weight (TBW). The final model was described by the following equations: K10 = 0.0027 × CLCR + 0.071 h−1 and V1 = TBW × 0.21 liter/kg. The median intercompartmental transfer constants K12 and K21 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 μg/ml, 24.0 μg/ml, and 26%, respectively. The independent validation group displayed a bias, precision, and coefficient of determination of −1.64 μg/ml, 17.1 μg/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 μg/ml, respectively. This study provides a pharmacokinetic model capable of predicting cefepime concentrations in critically ill patients with VAP.

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.

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

ABSTRACT Despite β-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 blaCTX-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 blaCTX-M-15 transcription levels were confirmed by relative quantitative real-time PCR (qRT-PCR) and β-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 (r2 = 0.938). The threshold concentrations identified were 0.05 μg/ml for low and moderate and 0.25 μg/ml for the high-β-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.

Bronchopulmonary Disposition of Micafungin in Healthy Adult Volunteers

ABSTRACT 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.

In Vitro Pharmacodynamics of Simulated Pulmonary Exposures of Tigecycline Alone and in Combination against Klebsiella pneumoniae Isolates Producing a KPC Carbapenemase

ABSTRACT 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.

In Vivo Pharmacodynamic Profile of Tigecycline against Phenotypically Diverse Escherichia coli and Klebsiella pneumoniae Isolates

ABSTRACT 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 μg/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 (EI80 and EI50) 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 EI80 and EI50 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.

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.

Treatment of Serratia marcescens Meningitis with Prolonged Infusion of Meropenem

OBJECTIVE: To describe the use of and cerebral spinal fluid (CSF) penetration o a prolonged infusion meropenem regimen in a patient with Serratia marcescen meningitis. CASE SUMMARY: A 54-year-old female was diagnosed with S. marcescen 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 patients 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) o 0.047 μg/mL for 100% of the dosing interval. After 6 days of therapy, the patien 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 o poor antibiotic penetration coupled with increasing antibiotic resistance. Although there are 2 other case reports that describe the use of prolonged infusion o 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. marcescensmenin gitis, the use of a high-dose prolonged infusion of meropenem resulted in adequate exposure at the site of infection and a successful clinical response.

Defining clinical exposures of cefepime for Gram negative bloodstream infections that are associated with improved survival

ABSTRACT 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.