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% 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% 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% 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% 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.

A eficácia antimicrobiana in vivo não pode ser definida exclusivamente pela atividade de um antibiótico determinada por um teste de sensibilidade in vitro. O conhecimento da farmacocinética e farmacodinâmica dos antimicrobianos, assim como de todos os fenômenos que ocorrem entre agentes antimicrobianos e microrganismos é fundamental na interpretação de alguns resultados. Os parâmetros farmacodinâmicos (PD) mais frequentemente usados nos estudos do efeito dos antibióticos incluem os seguintes relacionamentos: a concentração livre máxima (fCmax) com relação à concentração inibitória mínima (CIM), a área livre sob a curva (fAUC/CIM) e a duração do tempo em que a concentração livre excede a CIM (fT> CIM). A utilização dos dados conhecidos de farmacocinética/farmacodinâmica devem ajudar a otimizar o resultado dos tratamentos adotados, especialmente com relação à resistência emergente entre as bactérias Gram-positivas e Gram-negativas. Os estudos clínicos no campo da farmacodinâmica dos antimicrobianos ainda são relativamente escassos, e muita informação é necessária para permitir estratégias de dosagem relevantes para todos os tipos de antibióticos contra a todas as infecções e microorganismos comuns. Nesta revisão, os padrões distintos da atividade antimicrobianabaseado em parâmetros de farmacodinâmica são discutidos. Vários antibióticose patógenos bacterianos podem ser usados como modelos para demonstrar a utilidadede parâmetros de farmacodinâmica em predizer a eficácia in vivo da terapia antimicrobiana. E finalmente, o uso da modelagem computadorizada utilizando a simulação de Monte Carlo em determinadas populações podem realçar ainda mais o valor preditivo e a eficácia antimicrobiana quando se utilizam parâmetros de farmacodinâmica nas interpretações.

Antimicrobial efficacy in vivo is not exclusively defined by the activity of an antibiotic as determined in the in vitro susceptibility test. Knowledge of the pharmacokinetics and pharmacodynamics of antimicrobials and all phenomena occurring between antimicrobial agents and microorganisms is imperative. The pharmacodynamic (PD) parameters most often used in studies of antibiotic effect include the following relationships: the maximum free concentration (fCmax) to minimum inhibitory concentration (MIC) ratio, the free area under the curve (fAUC/MIC) ratio and the duration of time the free concentration exceeds the MIC (fT>MIC). Utilization of known pharmacokinetic/ pharmacodynamic surrogate relationships should help to optimize treatment outcome, especially in the face of emerging resistance among Gram-positive and Gram-negative bacteria. Clinical studies in the field of antibacterial PD are still relatively scarce, and much information is needed to enable relevant dosing strategies for all types of antibiotics against all common infections and microorganisms. In this review, the distinctive patterns of antimicrobial activitybased on PD parameters are discussed. Various antibioticsand bacterial pathogens can be used as models to demonstrate the utilityof PD parameters in predicting the in vivo efficacy of antimicrobialtherapy. And finally, the use of computer modeling with Monte Carlo populationsimulations can further enhance the predictability of antimicrobial efficacywhen using PD parameters.

Pharmacodynamic analyses were proposed to determine optimal empirical antibiotic therapy against Gram-negative bacteria isolated in a Brazilian ICU. Due to high resistance rates, standard regimens of cefepime, ciprofloxacin, meropenem, and piperacillin/tazobactam were not able to attain significant bactericidal CFR. Prolonged infusion of meropenem achieved 88% CFR, making it a possible empirical regimen in this ICU until susceptibilities become available. Still, even through administration of high dose prolonged infusions, 12.0% of simulated subjects did not achieve bactericidal exposure, suggesting that combination therapy would frequently be required in this setting. In conclusion, we recommend that in the presence of identified resistance problems among Gram-negative bacteria in a unit or hospital, MIC testing of formulary agents should be conducted along with pharmacodynamic simulation to assist in choosing an optimal antibiotic and dosage regimen for empirical use of severe infections until cultures and susceptibilities become available.