Pharmacokinetics, Safety, and Tolerability of Imipenem/Cilastatin/Relebactam in Children with Confirmed or Suspected Gram-Negative Bacterial Infections: A Phase 1b, Open-Label, Single-Dose Clinical Trial.

Imipenem/cilastatin/relebactam is approved for the treatment of serious gram-negative bacterial infections in adults. This study assessed the pharmacokinetics (PK), safety, and tolerability of a single dose of imipenem/cilastatin/relebactam (with a fixed 2:1 ratio of imipenem/cilastatin to relebactam, and with a maximum dose of 15 mg/kg imipenem and 15 mg/kg cilastatin [≤500 mg imipenem and ≤500 mg cilastatin] and 7.5 mg/kg relebactam [≤250 mg relebactam]) in children with confirmed/suspected gram-negative bacterial infections receiving standard-of-care antibacterial therapy. In this phase 1, noncomparative study (ClinicalTrials.gov identifier, NCT03230916), PK parameters from 46 children were analyzed using both population modeling and noncompartmental analysis. The PK/pharmacodynamic (PD) target for imipenem was percent time of the dosing interval that unbound plasma concentration exceeded the minimum inhibitory concentration (%fT>MIC) of ≥30% (MIC = 2 mcg/mL). For relebactam, the PK/PD target was a free drug area under the plasma concentration-time curve (AUC) normalized to MIC (at 2 mcg/mL) of ≥8.0 (equivalent to an AUC from time zero extrapolated to infinity of ≥20.52 mcg·h/mL). Safety was assessed up to 14 days after drug infusion. For imipenem, the ranges for the geometric mean %fT>MIC and maximum concentration (Cmax ) across age cohorts were 56.5%-93.7% and 32.2-38.2 mcg/mL, respectively. For relebactam, the ranges of the geometric mean Cmax and AUC from 0 to 6 hours across age cohorts were 16.9-21.3 mcg/mL and 26.1-55.3 mcg·h/mL, respectively. In total, 8/46 (17%) children experienced ≥1 adverse events (AEs) and 2/46 (4%) children experienced nonserious AEs that were deemed drug related by the investigator. Imipenem and relebactam exceeded plasma PK/PD targets; single doses of imipenem/cilastatin/relebactam were well tolerated with no significant safety concerns identified. These results informed imipenem/cilastatin/relebactam dose selection for further pediatric clinical evaluation.

Beneficial herb-drug interaction of rhein in Jinhongtang and Imipenem/Cilastatin mediated by organic anion transporters.

ETHNOPHARMACOLOGICAL RELEVANCE: Jinhongtang as a traditional Chinese medicine (TCM) formula, has been widely used as a clinical adjuvant in the treatment of acute abdominal diseases and sepsis. Clinical benefits of the concurrent use of Jinhongtang and antibiotics have been observed, however, the mechanism has not been fully understood. AIM OF THE STUDY: The present study aimed to explore the effect of Jinhongtang on the antibacterial activity of Imipenem/Cilastatin and to clarify the underlying mechanism of herb-drug interaction (HDI). MATERIALS AND METHODS: A mouse model of sepsis induced by Staphylococcus aureus (S. aureus) was used to evaluate the pharmacodynamic interaction in vivo. In vitro antibacterial activity of Imipenem/Cilastatin was studied by determining minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC). Pharmacokinetic interaction was investigated by pharmacokinetic studies in rats and uptake assays using OAT1/3-HEK293 cells. The main constituents ingested into blood of rats were qualitatively identified by UHPLC-Q-TOF-MS. RESULTS: Mice treated by Imipenem/Cilastatin and Jinhongtang exhibited higher survival rate, lower bacteria load and less inflammation in blood and lung tissues, compared with those treated by Imipenem/Cilastatin alone after injection of S. aureus. However, MIC and MBC of Imipenem/Cilastatin against S. aureus in vitro were not significantly changed in the presence of Jinhongtang. On the contrary, Jinhongtang increased the plasma concentration of Imipenem and decreased its urinary excretion in rats. CLr of Imipenem was reduced by 58.5%, while its half-life (t1/2) was prolonged for approximate 1.2 times after coadministered Jinhongtang. Furthermore, the extracts of Jinhongtang, single herb in the prescription, and main absorbable constituents inhibited cellular uptake of probe substrates and Imipenem by OAT1/3-HEK293 cells to different extents. Among them, rhein exhibited the strongest inhibition capacity with IC50 values of 0.08 ± 0.01 µM (OAT1) and 2.86 ± 0.28 µM (OAT3). Moreover, coadministration of rhein also significantly enhanced the antibacterial activity of Imipenem/Cilastatin in sepsis mice. CONCLUSION: Concomitant administration of Jinhongtang enhanced antibacterial activity of Imipenem/Cilastatin in sepsis mice induced by S. aureus through reducing renal elimination of Imipenem via inhibition of OATs. Our investigation provided the insight of Jinhongtang as an effective supplement to enhance the antibacterial activity of Imipenem/Cilastatin and can be useful for future clinical studies.

Kidney-Protector Lipidic Cilastatin Derivatives as Structure-Directing Agents for the Synthesis of Mesoporous Silica Nanoparticles for Drug Delivery.

Mesoporous silica nanomaterials have emerged as promising vehicles in controlled drug delivery systems due to their ability to selectively transport, protect, and release pharmaceuticals in a controlled and sustained manner. One drawback of these drug delivery systems is their preparation procedure that usually requires several steps including the removal of the structure-directing agent (surfactant) and the later loading of the drug into the porous structure. Herein, we describe the preparation of mesoporous silica nanoparticles, as drug delivery systems from structure-directing agents based on the kidney-protector drug cilastatin in a simple, fast, and one-step process. The concept of drug-structure-directing agent (DSDA) allows the use of lipidic derivatives of cilastatin to direct the successful formation of mesoporous silica nanoparticles (MSNs). The inherent pharmacological activity of the surfactant DSDA cilastatin-based template permits that the MSNs can be directly employed as drug delivery nanocarriers, without the need of extra steps. MSNs thus synthesized have shown good sphericity and remarkable textural properties. The size of the nanoparticles can be adjusted by simply selecting the stirring speed, time, and aging temperature during the synthesis procedure. Moreover, the release experiments performed on these materials afforded a slow and sustained drug release over several days, which illustrates the MSNs potential utility as drug delivery system for the cilastatin cargo kidney protector. While most nanotechnology strategies focused on combating the different illnesses this methodology emphasizes on reducing the kidney toxicity associated to cancer chemotherapy.

Evaluating imipenem + cilastatin + relebactam for the treatment of complicated urinary tract infections.

INTRODUCTION: The addition of the ß-lactamase inhibitor relebactam to imipenem restores the antibacterial activity against the majority of multidrug resistant Gram-negative bacteria. Complicated urinary tract infections (UTIs) are predominantly caused by Gram-negative uropathogens. The rise in antibiotic resistance, including to carbapenems, is an increasing challenge in daily practice. AREAS COVERED: In the current review, the use of imipenem/relebactam in complicated UTI is evaluated by discussing its chemistry, pharmacokinetics/dynamics, microbiology, safety, and clinical efficacy. The authors also provide their expert perspectives onto its use and its future place in the treatment armamentarium. EXPERT OPINION: With respect to complicated UTI, it should be noted that, to our knowledge, there are no data yet upon the clinical efficacy of imipenem/relebactam in patients with severe urosepsis or men with suspected prostatitis. Further studies upon these specific groups of UTI patients are needed including additional pharmacokinetic studies upon its tissue penetration of the prostate which is currently unknown. However, in our opinion, imipenem/relebactam can be used in complicated UTI when other treatment options are limited.

A translational pharmacokinetic/pharmacodynamic model to characterize bacterial kill in the presence of imipenem-relebactam.

OBJECTIVES: Relebactam is a small molecule ß-lactamase inhibitor under clinical investigation for use as a fixed-dose combination with imipenem/cilastatin. Here we present a translational pharmacokinetic/pharmacodynamic mathematical model to support optimal dose selection of relebactam. METHODS: Data derived from in vitro checkerboard and hollow fiber infection studies of imipenem-resistant strains of Pseudomonas aeruginosa were incorporated into the model. The model integrates the effect of relebactam concentration on imipenem susceptibility in a semi-mechanistic manner using the checkerboard data and characterizes the bacterial time-kill profiles from the hollow fiber infection model data. RESULTS: Simulations demonstrated that the ratio of the area under the concentration-time curve for free drug to the minimum inhibitory concentration (fAUC/MIC) was the pharmacokinetic driver for relebactam, with a target fAUC/MIC=7.5 associated with 2-log kill. At a clinical dose of 250mg relebactam, greater than 2-log reductions in bacterial load are projected for imipenem-resistant strains with an imipenem/relebactam MIC≤4µg/mL. CONCLUSIONS: The study confirms that the pharmacokinetic/pharmacodynamic driver for relebactam is fAUC/MIC, that an fAUC/MIC ratio of 7.5 is associated with 2-log kill in vitro, and that a 250mg clinical dose of relebactam achieves this target value when delivered in combination with imipenem/cilastatin.

Nontherapeutic equivalence of a generic product of imipenem-cilastatin is caused more by chemical instability of the active pharmaceutical ingredient (imipenem) than by its substandard amount of cilastatin.

BACKGROUND: We demonstrated therapeutic nonequivalence of "bioequivalent" generics for meropenem, but there is no data with generics of other carbapenems. METHODS: One generic product of imipenem-cilastatin was compared with the innovator in terms of in vitro susceptibility testing, pharmaceutical equivalence, pharmacokinetic (PK) and pharmacodynamic (PD) equivalence in the neutropenic mouse thigh, lung and brain infection models. Both pharmaceutical forms were then subjected to analytical chemistry assays (LC/MS). RESULTS AND CONCLUSION: The generic product had 30% lower concentration of cilastatin compared with the innovator of imipenem-cilastatin. Regarding the active pharmaceutical ingredient (imipenem), we found no differences in MIC, MBC, concentration or potency or AUC, confirming equivalence in terms of in vitro activity. However, the generic failed therapeutic equivalence in all three animal models. Its Emax against S. aureus in the thigh model was consistently lower, killing from 0.1 to 7.3 million less microorganisms per gram in 24 hours than the innovator (P = 0.003). Against K. pneumoniae in the lung model, the generic exhibited a conspicuous Eagle effect fitting a Gaussian equation instead of the expected sigmoid curve of the Hill model. In the brain infection model with P. aeruginosa, the generic failed when bacterial growth was >4 log10 CFU/g in 24 hours, but not if it was less than 2.5 log10 CFU/g. These large differences in the PD profile cannot be explained by the lower concentration of cilastatin, and rather suggested a failure attributable to the imipenem constituent of the generic product. Analytical chemistry assays confirmed that, besides having 30% less cilastatin, the generic imipenem was more acidic, less stable, and exhibited four different degradation masses that were absent in the innovator.

Intrapulmonary Pharmacokinetics of Relebactam, a Novel ß-Lactamase Inhibitor, Dosed in Combination with Imipenem-Cilastatin in Healthy Subjects.

This phase I study assessed the intrapulmonary pharmacokinetic profiles of relebactam (MK-7655), a novel ß-lactamase inhibitor, and imipenem. Sixteen healthy subjects received 250 mg relebactam with 500 mg imipenem-cilastatin, given intravenously every 6 h for 5 doses, and were randomized to bronchoscopy/bronchoalveolar lavage at 0.5, 1, 1.5, or 3 h after the last dose (4 subjects per time point). Both drugs penetrated the epithelial lining fluid (ELF) to a similar degree, with the profiles being similar in shape to the corresponding plasma profiles and with the apparent terminal half-lives in plasma and ELF being 1.2 and 1.3 h, respectively, for relebactam and 1.0 h in both compartments for imipenem. The exposure (area under the concentration-time curve from time zero to infinity) in ELF relative to that in plasma was 54% for relebactam and 55% for imipenem, after adjusting for protein binding. ELF penetration for relebactam was further analyzed by fitting the data to a two-compartment pharmacokinetic model to capture its behavior in plasma, with a partitioning coefficient capturing its behavior in the lung compartment. In this model, the time-invariant partition coefficient for relebactam was found to be 55%, based on free drug levels. These results support the clinical evaluation of relebactam with imipenem-cilastatin for the treatment of bacterial pneumonia.

Pharmacokinetics of Imipenem/Cilastatin Burn Intensive Care Unit Patients Undergoing High-Dose Continuous Venovenous Hemofiltration.

STUDY OBJECTIVE: High-dose continuous venovenous hemofiltration (CVVH) is a continuous renal replacement therapy (CRRT) used frequently in patients with burns. However, antibiotic dosing is based on inference from studies assessing substantially different methods of CRRT. To address this knowledge gap for imipenem/cilastatin (I/C), we evaluated the systemic and extracorporeal clearances (CLs) of I/C in patients with burns undergoing high-dose CVVH. DESIGN: Prospective clinical pharmacokinetic study. PATIENTS: Ten adult patients with burns receiving I/C for a documented infection and requiring high-dose CVVH were studied. METHODS: Blood and effluent samples for analysis of I/C concentrations were collected for up to 6 hours after the I/C infusion for calculation of I/C total CL (CLTotal ), CL by CVVH (CLHF ), half-life during CVVH, volume of distribution at steady state (Vdss ), and the percentage of drug eliminated by CVVH. RESULTS: In this patient sample, the mean age was 50 ± 17 years, total body surface area burns was 23 ± 27%, and 80% were male. Nine patients were treated with high-dose CVVH for acute kidney injury and one patient for sepsis. The mean delivered CVVH dose was 52 ± 14 ml/kg/hour (range 32-74 ml/kg/hr). The imipenem CLHF was 3.27 ± 0.48 L/hour, which accounted for 23 ± 4% of the CLTotal (14.74 ± 4.75 L/hr). Cilastatin CLHF was 1.98 ± 0.56 L/hour, which accounted for 45 ± 19% of the CLTotal (5.16 + 2.44 L/hr). The imipenem and cilastatin half-lives were 1.77 ± 0.38 hours and 4.21 ± 2.31 hours, respectively. Imipenem and cilastatin Vdss were 35.1 ± 10.3 and 32.8 ± 13.8 L, respectively. CONCLUSION: Efficient removal of I/C by high-dose CVVH, a high overall clearance, and a high volume of distribution in burn intensive care unit patients undergoing this CRRT method warrant aggressive dosing to treat serious infections effectively depending on the infection site and/or pathogen.

Phase 2, Dose-Ranging Study of Relebactam with Imipenem-Cilastatin in Subjects with Complicated Intra-abdominal Infection.

Relebactam (REL [MK-7655]) is a novel class A/C ß-lactamase inhibitor intended for use with imipenem for the treatment of Gram-negative bacterial infections. REL restores imipenem activity against some resistant strains of Klebsiella and Pseudomonas In this multicenter, double-blind, controlled trial (NCT01506271), subjects who were ≥18 years of age with complicated intra-abdominal infection were randomly assigned (1:1:1) to receive 250 mg REL, 125 mg REL, or placebo, each given intravenously (i.v.) with 500 mg imipenem-cilastatin (IMI) every 6 h (q6h) for 4 to 14 days. The primary efficacy endpoint was the proportion of microbiologically evaluable (ME) subjects with a favorable clinical response at discontinuation of i.v. therapy (DCIV). A total of 351 subjects were randomized, 347 (99%) were treated, and 255 (73%) were ME at DCIV (55% male; mean age, 49 years). The most common diagnoses were complicated appendicitis (53%) and complicated cholecystitis (17%). Thirty-six subjects (13%) had imipenem-resistant Gram-negative infections at baseline. Both REL doses plus IMI were generally well tolerated and demonstrated safety profiles similar to that of IMI alone. Clinical response rates at DCIV were similar in subjects who received 250 mg REL plus IMI (96.3%) or 125 mg REL plus IMI (98.8%), and both were noninferior to IMI alone (95.2%; one-sided P < 0.001). The treatment groups were also similar with respect to clinical response at early and late follow-up and microbiological response at all visits. Pharmacokinetic/pharmacodynamic simulations show that imipenem exposure at the proposed dose of 500 mg IMI with 250 mg REL q6h provides coverage of >90% of carbapenem-resistant bacterial strains.

Comparative evaluation of intratracheal colistimethate sodium, imipenem, and meropenem in BALB/c mice with carbapenem-resistant Acinetobacter baumannii pneumonia.

OBJECTIVE: The identification of the optimal agent for administration via the respiratory tract when treating pneumonia caused by carbapenem-resistant Acinetobacter baumannii (CRAB). METHODS: A murine model of acute CRAB pneumonia was established by intratracheal (i.t.) inoculation with 2.5 × 107 colony-forming units (CFU) of A. baumannii strain Ab396 plus 10% porcine mucin. After 4h the infected BALB/c mice were treated intratracheally with 25µl of either 0.85% saline (control group), colistimethate sodium (CMS) (166 666 U/kg, CMS group), imipenem/cilastatin (30/30 mg/kg, imipenem group), or meropenem (20mg/kg, meropenem group), every 8h. The therapeutic efficacy of these agents was examined. RESULTS: A. baumannii strain Ab396 was susceptible to CMS only. However, meropenem treatment did give a significantly superior survival rate (100%) compared to treatment with imipenem (50%), CMS (33%), or saline (0%) (p<0.001 vs. the control and CMS groups, p=0.006 vs. the imipenem group, by log-rank test). Furthermore, compared to the other groups, the meropenem group demonstrated significantly more favorable results in terms of tissue penetration of the antibiotic, bacterial clearance, normalization of the wet lung-to-body weight ratio, and down-regulation of pro-inflammatory cytokine levels in the lungs. CONCLUSIONS: Administration of meropenem via the respiratory tract proved to have the best therapeutic efficacy among the antibiotics tested when treating advanced murine CRAB pneumonia.

Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia.

To compare efficacy and safety of a tigecycline regimen with an imipenem/cilastatin regimen in hospital-acquired pneumonia patients, a phase 3, multicenter, randomized, double-blind, study evaluated 945 patients. Coprimary end points were clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure. Cure rates were 67.9% for tigecycline and 78.2% for imipenem (CE patients) and 62.7% and 67.6% (c-mITT patients), respectively. A statistical interaction occurred between ventilator-associated pneumonia (VAP) and non-VAP subgroups, with significantly lower cure rates in tigecycline VAP patients compared to imipenem; in non-VAP patients, tigecycline was noninferior to imipenem. Overall mortality did not differ between the tigecycline (14.1%) and imipenem regimens (12.2%), although more deaths occurred in VAP patients treated with tigecycline than imipenem. Overall, the tigecycline regimen was noninferior to the imipenem/cilastatin regimen for the c-mITT but not the CE population; this difference appears to have been driven by results in VAP patients.

Comparison of 30-min and 3-h infusion regimens for imipenem/cilastatin and for meropenem evaluated by Monte Carlo simulation.

Imipenem/cilastatin and meropenem are carbapenem antibiotics that are infused intravenously (IV) over 30 to 45 min. We evaluated probability of target attainment and cumulative probability of target attainment of 30-min and 3-h infusions for imipenem/cilastatin and meropenem. Eighteen healthy adults in a randomized, 4-phase, crossover study received 1000 mg of imipenem/cilastatin or meropenem as a single-dose IV over 30 min or 3 h. A population pharmacokinetics analysis using a 2-compartment IV infusion model was performed. Monte Carlo simulations using various dosage regimens at steady-state and 30-min and 3-h infusion rates were performed to evaluate the probabilities of attaining 20% (bacteriostatic), 30%, and 40% (maximum kill) time above the MIC. Three-hour infusions of imipenem/cilastatin and meropenem improved the cumulative probability of target attainment for a variety of populations of microorganisms compared to 30-min infusions. Prolonged infusions have the potential to optimize efficacy of imipenem/cilastatin and meropenem.

Pharmacokinetic-pharmacodynamic modeling and simulation for in vivo bactericidal effect in murine infection model.

A pharmacokinetic (PK)/pharmacodynamic (PD) modeling strategy to simulate in vivo bactericidal effects for three carbapenem antibiotics, doripenem (DRPM), meropenem (MEPM)/cilastatin (CS), and imipenem (IPM)/CS, against a Pseudomonas aeruginosa (P. aeruginosa) strain is proposed. The PD model we have already developed to explain in vitro time-kill profiles was modified to incorporate the growth rate, bactericidal activities, and PK profiles in murine lung infection models. Plasma concentration data and bacterial time-kill data for each antibiotic consist of six and eight time points, respectively, at one dose regimen (four or five mouse/point). In vivo time-kill curves could be well simulated for each antibiotic by the PK/PD model. Simulated bacterial counts at 24 h and PK/PD indices derived from total drug concentrations (time above the minimum inhibitory concentration (MIC) (T > MIC), C(max)/MIC, and AUC/MIC) for various dose regimens were examined for MEPM/CS and IPM/CS. Simulated bacterial counts correlated only with T > MIC (correlation coefficient: 0.951 for MEPM/CS, 0.982 for IPM/CS) and T > MIC values to achieve a bacteriostatic effect and a 2-log killing effect for both antibiotics were estimated to be approximately 15 and 20%, respectively, which are similar to previously reported results. These findings suggested that the proposed PK/PD model is a good tool for predicting in vivo bactericidal effects.

Population pharmacokinetics and pharmacodynamics of continuous versus short-term infusion of imipenem-cilastatin in critically ill patients in a randomized, controlled trial.

Beta-lactams are regularly administered in intermittent short-term infusions. The percentage of the dosing interval during which free drug concentrations exceed the MIC (fT(>MIC)) is the measure of drug exposure that best correlates with clinical outcome for beta-lactams. Therefore, administration by continuous infusion has gained increasing interest recently. We studied 20 critically ill patients with nosocomial pneumonia and investigated whether continuous infusion with a reduced total dose, compared to the standard regimen of intermittent short-term infusion, results in a superior probability of target attainment as assessed by the fT(>MIC) value of imipenem. In this prospective, randomized, controlled clinical study, patients received either a loading dose of 1 g/1 g imipenem and cilastatin (as a short-term infusion) at time zero, followed by 2 g/2 g imipenem-cilastatin per 24 h as a continuous infusion for 3 days (n = 10), or 1 g/1 g imipenem-cilastatin three times per day as a short-term infusion for 3 days (total daily dose, 3 g/3 g; n = 10). Imipenem concentrations in plasma were determined by using a validated liquid chromatography-tandem mass spectrometry assay. A two-compartment open model was employed for population pharmacokinetic modeling. We simulated 10,000 intensive-care-unit patients via Monte Carlo simulations for pharmacodynamic evaluation using the target 40% fT(>MIC). The probability of target attainment by MIC for intermittent infusion was robust (>90%) up to MICs of 1 to 2 mg/liter. The corresponding value for continuous infusion was 2 to 4 mg/liter. Although all 20 patients had an fT(>MIC) of 100%, 3 patients died. Patient survival was best described by employing a sepsis-related organ failure assessment score as a covariate in a logistic regression analysis. Larger clinical trials are warranted for evaluation of continuous infusions at a reduced dose of imipenem for critically ill patients.

Using imipenem and cilastatin during continuous renal replacement therapy.

AIM: To identify and review studies which have sought to define the pharmacokinetics of imipenem and cilastatin in patients receiving continuous renal replacement therapy (CRRT). METHOD: Literature was primarily identified using Pharmline, Embase and Medline databases using the search terms "imipenem," "haemofiltration," "haemodialysis" and "pharmacokinetics." Papers that discussed only intermittent haemodialysis were excluded. RESULTS: Seven papers were identified which described the pharmacokinetics of imipenem in patients receiving CRRT. Four different modes of CRRT were used. The methods of sampling, dosages used and assumptions made during pharmacokinetic calculations varied widely between the studies. Total body clearance of imipenem during CRRT in patients suffering from acute renal failure was found to range between 89 and 149 ml/min. Total body clearance of cilastatin ranged between 9 and 32 ml/min. Total body clearance of both imipenem and cilastatin was reduced in patients with chronic renal failure. Total body clearance of cilastatin was also reduced by impaired liver function. Dose recommendations made ranged between 500 mg 6-hourly and 500 mg 12-hourly. CONCLUSIONS: The heterogeneity of the studies identified prevents them being analysed as a single group. For meaningful dosage recommendations to be made, further studies are required using larger populations and with more detail regarding liver dysfunction and duration of renal failure.

Pharmacodynamic modeling of beta-lactam antibiotics for the empiric treatment of secondary peritonitis: a report from the OPTAMA program.

BACKGROUND: In this report of the OPTAMA (Optimizing Pharmacodynamic Target Attainment using the MYSTIC Antibiogram) program, we utilized Monte Carlo simulation to compare the probabilities of achieving bactericidal time above the minimum inhibitory concentration (MIC) (%T > MIC) exposures for imipenem-cilastatin 500 mg q6h and 1000 mg q8h, meropenem 500 mg q6h and 1000 mg q8h and piperacillin/tazobactam 3.375 g q6h and 4.5 g q8h in the empiric treatment of secondary peritonitis. METHODS: The prevalence of pathogens causing secondary peritonitis was identified from the primary surgical and infectious diseases literature. Data for these pathogens with respect to MIC were obtained from the 2003 MYSTIC surveillance study and weighted by the prevalence of each pathogen. A sensitivity analysis varying the prevalence of P. aeruginosa was performed with two additional models to determine the robustness of the data. Pharmacokinetic parameters, obtained from previously published studies in healthy volunteers were used to simulate the %T > MIC for 10,000 patients receiving imipenem-cilastatin, meropenem, and piperacillin/tazobactam. The likelihood of obtaining bactericidal exposure is reported. RESULTS: Empiric utilization of imipenem-cilastatin and meropenem 500 mg q6h and 1000 mg q8h regimens achieved 99.6%-99.7% likelihood of bactericidal exposure. Piperacillin/ tazobactam 3.375 g q6h and 4.5 g q8h produced bactericidal target attainments of 92.9% and 85.2%, respectively. Models simulating higher prevalence of P. aeruginosa reduced the likelihood of bactericidal exposure for piperacillin/tazobactam regimens significantly and had little effect on the carbapenems. CONCLUSION: All of the beta-lactams used in the current analysis were predicted to achieve high target attainment consistently for the empiric treatment of secondary peritonitis. However, imipenem-cilastatin 500 mg q6h and 1000 mg q8h, meropenem 1000 mg q8h and 500 mg q6h, and piperacillin/tazobactam 3.375 g q6h achieved the highest likelihood. These, in particular, would be effective choices for the empiric treatment of secondary peritonitis.

Pharmacokinetics of imipenem-cilastatin following intravenous administration in healthy adult horses.

In two studies, six healthy adult horses were given imipenem-cilastatin by slow intravenous (i.v.) infusion at an imipenem dosage of 10 mg/kg (study 1) and 20 mg/kg (study 2). The same horses were used in each dosage schedule, with a 2-week washout period between studies. In each dosage group, serial blood and synovial fluid samples were collected for 6 h after completion of the infusion. HPLC was used to determine the imipenem concentration in all samples. Imipenem was well tolerated by all horses at both dosages; no adverse effects were noted during the study period or during the 24-hour postinfusion observation period. The pharmacokinetic profiles of imipenem in the plasma and synovial fluid indicate that an imipenem dosage of 10-20 mg/kg by slow i.v. infusion q6h (every 6 h) is appropriate for most susceptible pathogens.

Pharmacodynamic modeling of imipenem-cilastatin, meropenem, and piperacillin-tazobactam for empiric therapy of skin and soft tissue infections: a report from the OPTAMA Program.

BACKGROUND: The bactericidal exposures necessary for positive clinical outcomes among skin and soft tissue infections are largely dependent on interpatient pharmacokinetic variability and pathogen drug susceptibility. By simulating the probability of achieving target bactericidal exposures, the pharmacodynamics of three beta-lactam agents were compared against a range of pathogens implicated commonly in complicated skin and soft tissue infections. METHODS: Using Monte Carlo simulation, pharmacodynamic target attainment expressed as the percentage of the time interval during which the antibiotic concentration exceeded the minimal inhibitory concentration (%T > MIC) in serum and blister fluid was calculated for 5,000 simulated patients receiving imipenem-cilastatin 0.5 g q8h, meropenem 0.5 g q8h, piperacillin-tazobactam 3.375 g q6h, and piperacillin-tazobactam 4.5 g q8h. The pharmacokinetics for each antibiotic were derived from previously published healthy volunteer studies. The MICs for Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Enterobacter sp., Klebsiella sp., coagulase-negative staphylococci, Proteus sp., beta-hemolytic streptococci, and Serratia sp. were taken from the MYSTIC 2003 surveillance study and weighted by the prevalence of each pathogen among 1,404 isolates collected from skin and soft tissue infections during the 2000 SENTRY study. The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) was added into the model at increasing resistance rates. RESULTS: Imipenem-cilastatin, meropenem, and piperacillin-tazobactam 3.375 g q6h achieved greater than 90% likelihood of achieving bactericidal exposure in serum and blister fluid until the prevalence of MRSA increased beyond 10%. Piperacillin-tazobactam 4.5 g q8h achieved a lower probability of achieving bactericidal exposure than the other regimens (88.7%, p < 0.001). CONCLUSIONS: When the incidence of MRSA is low, imipenem-cilastatin, meropenem and piperacillin-tazobactam 3.375 g q6h would be optimal choices for the empiric treatment of complicated skin and soft tissue infections among the regimens studied. When MRSA is suspected, a drug that retains activity against this pathogen should be considered.

Pharmacodynamic evaluation of extending the administration time of meropenem using a Monte Carlo simulation.

A Monte Carlo simulation demonstrated that 1 g of meropenem (MEM) every 8 h (q8h) (3-h infusion) has a higher target attainment rate against Pseudomonas aeruginosa than either 500 mg of MEM q8h (3-h infusion) or 0.5 g of imipenem-cilastatin (I-C) q6h (1-h infusion). For other pathogens, 500 mg of MEM q8h was equivalent or superior to I-C.