We examined nosocomial isolates collected from ICUs in the United States during a multi-year surveillance study in order to assess the performance of antibiotics commonly used to treat infections in this setting, and to identify any trends in antimicrobial performance over time. Four broad-spectrum agents were studied: cefepime, ceftriaxone, imipenem and piperacillin-tazobactam. We used PK/PD principles to predict the likelihood that each compound and dose would achieve its maximum bactericidal effect against the tested population of organisms, as measured by cumulative fraction of response. The Monte Carlo simulation technique enables us to predict the microbiological performance of different regimens while accounting for the variance in PK characteristics that such regimens are likely to encounter in critically ill patients. It should be noted that microbiological success is but one part of clinical success in treating infection, as many factors – co-morbidities, immunocompetence, etc. – contribute to the ultimate recovery of a patient. However, we have found that simulation-predicted microbiological response does indeed correlate with clinical response. As such, identifying trends in probable microbiological success can provide useful insight into the clinical implications of changing resistance. We found moderate to good predicted responses (80% CFR or better) to all species aggregated as a group for three of the four compounds examined, with low response rates predicted for ceftriaxone. Response rates were dose-dependent, with more aggressive doses yielding greater predicted response. As to trend, imipenem's ability to achieve bactericidal effect showed a slight statistical improvement over time, whereas the effect of shifting MIC distributions on the other compounds was reflected in stable or worsening activity.
The examination of antibiotic performance against the entire cohort of isolates in the ISS Program is useful as a broad evaluation of continued efficacy to pathogens encountered in the ICU; however, clinically significant trends in any one species may be masked by the trend (or lack thereof) in the overall group. For this reason, the study also examined two species individually: P. aeruginosa and Acinetobacter species. Both species are implicated in a variety of nosocomial infections (including pneumonia, bacteremia, skin infections and others), and reports of multi-drug resistant strains have been increasing. P. aeruginosa was the most prevalent species in the ISS Program dataset, at 22% of tested isolates. This species is an important nosocomial pathogen not only because of its frequency, but also because it possesses intrinsic resistance to many antimicrobial agents, and has the ability to acquire both plasmid-mediated and chromosomal resistance genes. Acinetobacter spp. was the fifth most prevalent pathogen in the dataset (at 6%), but was modeled individually because high levels of resistance have been reported in Latin America and in some regions of the United States[1, 16]. Multi-drug resistance in these two species is associated with increased mortality, and has become sufficiently problematic in some locations that alternative therapy using older and more toxic agents such as polymyxins is sometimes considered the best option [17–19].
Against P. aeruginosa, cefepime, imipenem and piperacillin-tazobactam showed statistically significant declines in CFR over time for all regimens except cefepime 2 g q8h. This regimen also was clearly the most potent, with predicted CFRs >90%, where every other regimen had predicted CFRs <80% by the last time period. This suggests that, while more aggressive dosing may enable a compound to kill more reliably (i.e., with a greater probability of success), this effect no longer holds once the potency of the agent has sufficiently eroded. Overall, the magnitude of the CFR declines for all the regimens over the 12-year period of the study remains small, reflecting a steady, although moderate, upward shift in the distribution of MICs.
Against Acinetobacter spp., statistically significant declines in CFR were observed for all regimens of cefepime, imipenem and piperacillin-tazobactam. Further, the magnitude of the decline across periods is much greater than that observed against P. aeruginosa – on the order of 10%–15% decline in CFR against the former species versus 2–3% versus the latter. While both declines show statistically significant trends, whether or not the low single digit declines against P. aeruginosa are clinically significant is debatable – that is, these declines in effectiveness are probably noticed in some institutions more than others, to the extent that the higher MICs observed here are not evenly distributed among hospitals. However, the larger declines in predicted efficacy against Acinetobacter are of great enough magnitude that a clinical effect may commonly be seen. Indeed, cefepime and piperacillin-tazobactam were predicted to have such low CFRs (<50% for all regimens except cefepime 2 g q8h, with a predicted CFR of 65%) as to be of little use clinically. Imipenem, while showing declines in CFR over the four time periods, is the only modeled agent with a high enough probability of achieving its best bactericidal effect to be relied upon clinically. These results reflect a species with rapidly increasing MICs to the modeled compounds.