Effect of ceftazidime/avibactam plus fosfomycin combination on 30 day mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae: results from a multicentre retrospective study

Abstract

Introduction The primary outcome of the study was to evaluate the effect on 30 day mortality of the combination ceftazidime/avibactam + fosfomycin in the treatment of bloodstream infections (BSIs) caused by KPC-producing Klebsiella pneumoniae (KPC-Kp). Materials and methods From October 2018 to March 2021, a retrospective, two-centre study was performed on patients with KPC-Kp BSI hospitalized at Sapienza University (Rome) and ISMETT-IRCCS (Palermo) and treated with ceftazidime/avibactam-containing regimens. A matched cohort (1:1) analysis was performed. Cases were patients receiving ceftazidime/avibactam + fosfomycin and controls were patients receiving ceftazidime/avibactam alone or in combination with in vitro non-active drugs different from fosfomycin (ceftazidime/avibactam ± other). Patients were matched for age, Charlson comorbidity index, ward of isolation (ICU or non-ICU), source of infection and severity of BSI, expressed as INCREMENT carbapenemase-producing Enterobacteriaceae (CPE) score. Results Overall, 221 patients were included in the study. Following the 1:1 match, 122 subjects were retrieved: 61 cases (ceftazidime/avibactam + fosfomycin) and 61 controls (ceftazidime/avibactam ± other). No difference in overall mortality emerged between cases and controls, whereas controls had more non-BSI KPC-Kp infections and a higher number of deaths attributable to secondary infections. Almost half of ceftazidime/avibactam + fosfomycin patients were prescribed fosfomycin without MIC fosfomycin availability. No difference in the outcome emerged after stratification for fosfomycin susceptibility availability and dosage. SARS-CoV-2 infection and ICS ≥ 8 independently predicted 30 day mortality, whereas an appropriate definitive therapy was protective. Conclusions Our data show that fosfomycin was used in the treatment of KPC-Kp BSI independently from having its susceptibility testing available. Although no difference was found in 30 day overall mortality, ceftazidime/avibactam + fosfomycin was associated with a lower rate of subsequent KPC-Kp infections and secondary infections than other ceftazidime/avibactam-based regimens.

In vitro, in vivo and clinical studies comparing the efficacy of ceftazidime-avibactam monotherapy with ceftazidime-avibactam-containing combination regimens against carbapenem-resistant Enterobacterales and multidrug-resistant Pseudomonas aeruginosa isolates or infections: a scoping review

“…Similarly, CZA susceptibility rate was not documented in three studies ( 49 , 50 , 55 ), as well as it was found as 89.5% and 79% in two studies, respectively ( 57 , 61 ). More than half of the studies had CRE infections, while six included CRKP infections ( 15 , 52 – 54 , 56 , 60 ). MDR/XDR-PA infections were assessed only in one study ( 57 ) and two studies included mixed types of infections caused by CRE or carbapenem-resistant P. aeruginosa (CRPA) and CRE or MDR-PA, respectively ( 49 , 51 ).…”

Mutations in ompK36 differentially impact in vitro synergy of meropenem/vaborbactam and ceftazidime/avibactam in combination with other antibiotics against KPC-producing Klebsiella pneumoniae

“… 39 Ceftazidime/avibactam in combination with fosfomycin has been used successfully in patients with KPC- Kp bloodstream infections and is associated with reduced recurrence and secondary infection rates compared with treatment with ceftazidime/avibactam alone. 40 …”

Evaluation of the combination treatments with intravenous fosfomycin for carbapenem-resistant Klebsiella pneumoniae

“…Perdigao Neto et al, described a prospective series of 13 patients (treated with fosfomycin) who had infections (BSI, n=11) due to β-lactams and colistin-resistant gram-negative bacteria ( K. pneumoniae , n=9), and they showed that meropenem (82% synergism via time-kill assay) was the most commonly used antibiotic in combination with fosfomycin (n=10), with a cure rate of 70% 10 . Oliva et al, evaluated the effect of the ceftazidime/avibactam plus fosfomycin combination in the treatment of BSIs caused by CRKP, and although there was no difference in 30-day overall mortality, they showed a lower rate of subsequent CRKP or secondary infections than other ceftazidime/avibactam-based regimens in fosfomycin combination group 11 . In our study, we also found no statistically significant difference in 14- and 30-day mortality among different types of combination regimens such as one or two antibiotic combinations, meropenem-containing regimens, colistin/polymyxin B-containing regimens, and aminoglycoside-containing regimens.…”