By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

Dr. Deresinski reports no financial relationships relevant to this field of study.

SYNOPSIS: No significant difference in the mortality of patients with Pseudomonas aeruginosa bacteremia was seen regardless of treatment with a carbapenem, ceftazidime, or piperacillin-tazobactam. However, the emergence of resistance occurred significantly more frequently in those treated with a carbapenem — largely related to imipenem use.

SOURCE: Babich T, Naucler P, Valik JK, et al. Ceftazidime, carbapenems, or piperacillin-tazobactam as single definitive therapy for Pseudomonas aeruginosa bloodstream infection: A multisite retrospective study. Clin Infect Dis 2020;70:2270-2280.

Babich and colleagues retrospectively evaluated the outcomes of β-lactam monotherapy in 767 adults with monomicrobial Pseudomonas aeruginosa bacteremia at 25 centers in nine countries during 2009-2015. Patients treated with carbapenems (meropenem or imipenem), ceftazidime, or piperacillin-tazobactam (PT) were included in the analysis.

Of the 767 patients, 134 (17.5%) died from any cause within 30 days. The all-cause 30-day mortality did not differ significantly by treatment group: 37/213 (17.4%) for ceftazidime, 42/210 (20%) for carbapenems, and 55/344 (16%) for PT. Multivariate analyses of the entire cohort, as well as a propensity score-adjusted cohort of 542 patients, identified several significant risk factors, including functional capacity, being bedridden at baseline, high Charlson comorbidity index, higher sequential organ failure assessment (SOFA) score, and others. Having the urinary tract as the source of bacteremia was protective, while the choice of β-lactam for definitive monotherapy was not significantly associated with mortality.

There was no significant difference between treatment groups in secondary outcomes, including seven-day mortality and clinical or microbiological failure. The latter was defined as persistence or re-isolation of the same bacteria/phenotype (as determined by the antibiotic susceptibility profile if bacteria were not identified) in blood 48 hours or more after definitive treatment initiation and within 30 days of index infection. Microbiological failure occurred in 11.2%, 15.7%, and 11.4% of those treated with ceftazidime, carbapenems, and PT, respectively. There also was no significant difference in adverse events.

Despite the finding that there was not a significant difference in microbiological outcomes by treatment type, carbapenem use was associated with a significantly greater incidence of the emergence of resistance to any antipseudomonal. This largely was associated with imipenem rather than meropenem, occurring in 17.5% of carbapenem recipients overall, but in 12 of 44 (27.3%) of those who received imipenem and 24/162 (14.8%) of meropenem recipients. Resistance occurred in 12.4% of those given ceftazidime and 8.4% of those treated with PT (P = 0.007).

COMMENTARY

Although there are published exceptions, a number of retrospective studies have failed to demonstrate that combination therapy is superior to monotherapy in the treatment of P. aeruginosa bacteremia. Thus, now it is generally recommended that patients with monomicrobial P. aeruginosa bacteremia be treated with a single active β-lactam antibiotic. The study reviewed here asks the next logical question — which β-lactam antibiotic? This large, multicenter, international trial found no difference in mortality or in a number of secondary outcomes in a comparison of treatment with carbapenems, ceftazidime, or PT.

The emergence of resistance to carbapenems has been a matter of concern. Thus, a systematic review found an increased risk of the emergence of resistance in patients with Pseudomonas pneumonia who were treated with imipenem compared to various other agents.1 However, in a separate retrospective comparison of 88 patients with ventilator-associated pneumonia due to P. aeruginosa, investigators found no significant difference in such emergence in patients treated with imipenem, meropenem, or doripenem.2

Babich and colleagues found a greater incidence of the emergence of resistance to any antipseudomonal antibiotic in association with carbapenem treatment compared to treatment with ceftazidime or PT. They concluded that the latter two agents are preferred. However, the observed increased risk of resistance clearly was associated with imipenem use, not meropenem use. Also clouding the interpretation of the results is the fact that the investigators did not specify the antibiotics to which resistance emerged.

REFERENCES

  1. Zilberberg MD, Chen J, Mody SH, et al. Imipenem resistance of Pseudomonas in pneumonia: A systematic literature review. BMC Pulm Med 2010;10:45.
  2. Luyt CE, Aubry A, Lu Q, et al. Imipenem, meropenem, or doripenem to treat patients with Pseudomonas aeruginosa ventilator-associated pneumonia. Antimicrob Agents Chemother 2014;58:1372-1380.