Combination Therapy for Carbapenemase-Producing Klebsiella pneumoniae Bacteremia Reduces Mortality

Abstract & Commentary

Combination Therapy for Carbapenemase-Producing Klebsiella pneumoniae Bacteremia Reduces Mortality

By Richard R. Watkins, MD, MS, FACP

Division of Infectious Diseases, Akron General Medical Center, Akron, OH; Associate Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH

Dr. Watkins reports no financial relationships in this field of study

SYNOPSIS: In an observational study of 205 patients with bloodstream infections caused by strains of carbapenemase-producing Klebsiella pneumoniae, mortality was higher in patients who received monotherapy vs. those treated with combination therapy (44.4% vs 27.2%, P = 0.018). The greatest mortality reduction was observed with combinations that included a carbapenem.

SOURCE: Daikos GL, et al. Carbapenemase-Producing Klebsiella pneumoniae Bloodstream Infections: Lowering Mortality by Antibiotic Combination Schemes and the Role of Carbapenems. Antimicrob Agents Chemother 2014;58:2322-28.

The ongoing spread of carbapenemase-producing Klebsiella pneumoniae (CPKP) poses a serious threat to global public health. Infections from these strains are associated with high morbidity and mortality. Moreover, current therapy is limited by toxicities (e.g. colistin) and concerns about efficacy (e.g. tigecycline and fosfomycin). Daikos and colleagues sought to determine whether combination antibiotic therapy improves mortality from infections caused by CPKP compared to monotherapy alone.

The study was conducted at two hospitals in Athens, Greece between August 2009 and December 2010. It had a retrospective observational design that included patients with K. pneumoniae bloodstream infections (BSIs), defined as at least one positive blood culture, and symptoms of the systemic inflammatory response syndrome (SIRS). The main outcome measured was all-cause mortality within 28 days after the onset of bacteremia. Of the 338 patients with Klebsiella pneumoniae BSIs, 205 were infected with CPKP strains. The mean age of the patients was 63 years and all episodes of CPKP BSIs were either hospital acquired (93%) or health care associated (7%). The probable source of bacteremia was the lung in 43 patients, the abdomen in 29, an intravascular catheter in 22, the genitourinary tract in 19, the skin in 6, and the central nervous system in 3. No portal of entry could be ascertained in 83 patients. Of the 205 CPKP strains, 163 (79.5%) produced KPC-2 and the remaining 42 isolates produced VIM-1. The most active antimicrobials were tigecycline and colistin although 15% and 25% of isolates were resistant to these two drugs, respectively. Antibiotic therapy was at the direction of the attending physician and appropriate source control (e.g. line removal and debridement/drainage) was performed in all cases. Eighteen patients died before antibiotic susceptibility results became available. Of the 175 patients who were treated with at least one active drug, 103 were given combination therapy (31 received a carbapenem-containing regimen and 72 a carbapenem-sparing regimen). Monotherapy was used for the remaining 72 patients. Older patients were more likely to have received monotherapy than their younger counterparts.

The all-cause mortality at 28 days was high with 82 of 205 patients (40%) dying during that timeframe. Univariate analysis revealed a higher risk for an adverse outcome among females, those with advanced age, a higher Charlson index, neutropenia, polymicrobial bacteremia, and severe sepsis or septic shock. Characteristics of the infecting CPKP strain and the timing of effective antibiotic therapy did not affect outcome. Overall mortality was lower in those patients treated with combination therapy compared to monotherapy (27.2% vs 44.4%, P = 0.018). Among the combinations used, those that contained a carbapenem had the lowest mortality rate (19.3%). Notably, all 11 patients treated with a carbapenem plus tigecycline plus an aminoglycoside or colistin survived. However, when the carbapenem MIC increased from ≤8 μg/ml to ≥8 μg/ml, mortality increased from 19.3% to 35.5%. Among those who received a carbapenem with an elevated MIC and an inactive drug, mortality was 58.3%. Combination therapy also provided a significant therapeutic benefit over monotherapy in patients with septic shock (odds ratio [OR] of survival: 0.22; 95% confidence interval [CI], 0.05 to 1.0; P = 0.045) and for those with rapidly fatal underlying disease (OR of survival: 0.08; 95% CI, 0.01 to 0.52; P = 0.001). Finally, combination therapy was an independent predictor of survival (hazards ratio of death for monotherapy vs. combination therapy, 2.08; 95% CI, 1.23 to 3.51; P = 0.006).

COMMENTARY

The two most significant findings from this study were the impressive mortality benefit observed with combination therapy and that the mortality benefit was greatest when the regimen contained a carbapenem. This latter observation seems paradoxical and possible explanations include additive or synergistic effects from the carbapenem, although differences in MIC reporting i.e. Etest vs. automated systems may have played a role. It was interesting that the investigators did not find an association between the timing of effective therapy and outcomes. Indeed, one of the central principles of sepsis management is administration of effective antibiotic therapy in a timely manner.¹ Although Daikos and colleagues did not find a statistically significant difference between those who received timely active therapy and those who did not (P = 0.086), patients who received effective therapy ≤48 h into their BSI had better survival (65.8%) compared to those treated at ≥48 h (53.2%). It isn’t clear if additional evaluation of these data would have produced different results and further investigation is warranted.

As with all observational studies, unmeasured variables may have led to selection bias that influenced the results. Moreover, differences in colistin dosing that occurred over the course of the study could have led to delays in pharmacokinetic and pharmocodynamic targets. The safety and efficacy of combination therapy has been controversial, with some authors arguing the addition of a second antimicrobial agent to treat a Gram-negative organism that is susceptible to a single agent may actually lead to increased antimicrobial resistance, adverse effects, and costs.² Thus, concerns about drug-induced toxicities might have been the reason that most older patients received monotherapy. Another interesting finding was the high prevalence of CPKP strains to non-CPKP ones (205 vs. 133, respectively), a rate fortunately not seen at present in North American hospitals.

Despite the limitations of the study, the robust mortality benefit from combination therapy provides clinicians a potential approach for dealing with the difficult challenge of CPKP BSIs. Hopefully prospective, randomized clinical trials that compare monotherapy to combination therapy and evaluate the efficacy of different combination regimens for CPKP infections will be conducted in the near future.

References

1. Dellinger RP, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 2013;39:165-228.

2. Tamma PD, et al. Combination therapy for treatment of infections with gram-negative bacteria. Clin Microbiol Rev 2012;25:450-470.