Pharmacodynamic profiling of commonly prescribed antimicrobial drugs against Escherichia coli isolates from urinary tract

Since antimicrobial resistance among uropathogens against current first line agents has affected the management of severe urinary tract infection, we determined the likelihood that antibiotic regimens achieve bactericidal pharmacodynamic exposures using Monte Carlo simulation for five antimicrobials (ciprofloxacin, ceftriaxone, piperacillin/tazobactam, ertapenem, and meropenem) commonly prescribed as initial empirical treatment of inpatients with severe community acquired urinary tract infections. Minimum inhibitory concentration determination by Etest was performed for 205 Brazilian community urinary tract infection Escherichia coli strains from 2008 to 2012 and 74 E. coli bloodstream strains recovered from a surveillance study. Pharmacodynamic exposure was modeled via a 5000 subject Monte Carlo simulation. All isolates were susceptible to ertapenem and meropenem. Piperacillin/tazobactam, ceftriaxone and ciprofloxacin showed 100%, 97.5% and 83.3% susceptibility among outpatient isolates and 98.6%, 75.7% and 64.3% among inpatient isolates, respectively. Against outpatient isolates, all drugs except ciprofloxacin (82.7% in aggressive and 77.6% in conservative scenarios) achieved high cumulative fraction of response: car-bapenems and piperacillin/tazobactam cumulative fraction of responses were close to 100%, and ceftriaxone cumulative fraction of response was 97.5%. Similar results were observed against inpatients isolates for carbapenems (100%) and piperacillin/tazobactam (98.4%), whereas ceftriaxone achieved only 76.9% bactericidal cumulative fraction of response and ciprofloxacin 61.9% (aggressive scenario) and 56.7% (conservative scenario) respectively. Based on this model, standard doses of beta-lactams were predicted to deliver sufficient pharmacodynamic exposure for outpatients. However, ceftriaxone should be avoided for inpatients and ciprofloxacin empirical prescription should be avoided in both inpatients and outpatients with complicated urinary tract infection.

Assessing the pharmacodynamic profile of intravenous antibiotics against prevalent Gram-negative organisms collected in Colombia

OBJECTIVES: This study was designed to simulate standard and optimized dosing regimens for intravenous antibiotics against contemporary populations of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa using MIC distribution data to determine which of the tested carbapenem regimens provided the greatest opportunity for obtaining maximal pharmacodynamic (PD) activity. METHODS: The isolates studied were obtained from the COMPACT-COLOMBIA surveillance program conducted between February and November 2009. Antimicrobial susceptibility testing was conducted by broth microdilution method according to the CLSI guidelines. Doripenem, imipenem-cilastatin, and meropenem, were the modeled antibiotics. A 5,000 patient Monte Carlo simulation was performed for each regimen and PD targets were defined as free drug concentrations above the MIC for at least 40 percent of the dosing interval. RESULTS: All carbapenem regimens obtained optimal exposures against E. coli, unlike the other Enterobacteriaceae tested. Against P. aeruginosa, only a prolonged infusion of doripenem exceeded the 90 percent cumulative fraction of response (CFR) threshold. Worrisomely, no regimens for any of the drugs tested obtained optimal CFR against A. baumannii. For P. aeruginosa intensive care unit (ICU) isolates, CFR was approximately 20 percent lower for isolates collected in the respiratory tract compared with bloodstream or intra-abdominal for imipenem and meropenem. Noteworthy, all doripenem and meropenem regimens achieved greater than 90 percent CFR against bloodstream and respiratory isolates of K. pneumoniae. CONCLUSIONS: Our data suggests that higher dosing and prolonged infusion of doripenem or meropenem may be suitable for empirically treating ICU P. aeruginosa, while none of the carbapenems achieved optimal cumulative fraction of response against A. baumannii. Standard dosing regimens of all the carbapenems tested achieved optimal CFR against E. coli isolates, but higher carbapenem dosages might be required for empiric treatment of K. pneumoniae, particularly from an intra-abdominal source. Non-standard dosage regimens studied in this modeling should be proven effective in prospective clinical trials.

Bioequivalence, antibacterial activity and therapeutic outcome of a generic meropenem (Mapenem).

BACKGROUND: The authors aimed to compare the bioequivalence and antibacterial activity of a generic meropenem with the original meropenem and studied its preliminary therapeutic outcome. MATERIAL AND METHOD: A randomized, open-label, crossover study was employed to assess the bioequivalence and antibacterial activity. Twenty-six healthy males were recruited at Siriraj Hospital, Thailand and randomized to firstly receive either a single intravenous 30-minute infusion of a generic (Mapenem) or original meropenem (Meronem) and vice versa for the second period. The washout period was one week. Ten milliliters of blood samples were collected before meropenem infusion and at 0, 10, 15, 30, 45, 60, 90, 120, 150, 180, 240, 360, 470 and 480 minutes after the beginning of the drug infusion. Blood samples were coded and separated into plasma and serum samples. Plasma samples were used to determine drug concentrations by HPLC-UV detector and the data were analyzed for Cmax, AUC0-t and AUC0-inf. Serum samples were assayed in triplicate for measuring generic and original meropenems' inhibitory activities of a meropenem-susceptible E. coli ATCC 25922 in the same agar plate. An open-label design was used to preliminarily study of the therapeutic outcome and adverse effects of the generic meropenem in 30 patients. RESULTS: All enrolled twenty-six volunteers completed the whole study. The statistical analysis of 90% confidence interval of Cmax, A UC0-t, and AUC0-inf of the generic and original meropenems were 87.7 to 101.7%, 96.3 to 102.4% and 96.3 to 102.3%, respectively. The results were within the standard range of bioequivalence acceptance criteria (80-125%) and the powers of the test were greater than 80%. Using E. coli ATCC 25922 in the blind assay of serum inhibition activity, the inhibitory zone sizes (mm) of the generic compared to original meropenems were not statistically different with respect to every time points of blood collections (p < 0.05). Correlation of mean values of serum meropenem levels and the widths of inhibitory zone sizes of the same samples collected at the same intervals showed good linear relationship with r = 0.891; R2 = 0.794 (p < 0.01) for the generic meropenem and r = 0.885; R2 = 0.784 (p < 0.01) for the original meropenem. The therapeutic result with the generic meropenem for various indications was successful or improved in 24 cases from 30 cases (80%) and the bacterial cure rate was 23 in 30 clinical isolates (76.7%). Adverse reactions probably related to the study medication were rash and elevated liver enzymes in 1 and 3 patients, respectively, and all resolved spontaneously. CONCLUSION: In the present study, the generic meropenem exhibited indifferent bioequivalence and antibacterial activity compared to the original meropenem. There was also a good correlation between serum levels and inhibitory zone sizes produced by the same serum samples in every periods of blood collection. Clinical efficacy of the generic meropenem was shown to be satisfactory without notable severe adverse reaction.