Pharmacokinetics, efficacy and tolerance of cefoxitin in the treatment of cefoxitin-susceptible extended-spectrum beta-lactamase producing Enterobacterales infections in critically ill patients: a retrospective single-center study

Abstract

Background: Cefoxitin is active against some extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-PE), but has not been evaluated so far in the intensive care unit (ICU) settings. Data upon its pharmacokinetics (PK), tolerance and efficacy in critical conditions are scanty. We performed a retrospective single-center study in a university hospital medical ICU, in subjects presenting with cefoxitin-susceptible ESBL-PE infection and treated with cefoxitin. The primary aim was to determine cefoxitin PK. Secondary endpoints were efficacy, tolerance, and emergence of cephamycin-resistance.

Results: Forty-one patients were included in this study, mainly with ESBL-PE pneumonia (35 patients, 85%). Cefoxitin was administered during a median [interquartile range (IQR)] duration of 5 [4-7] days. Cefoxitin serum concentrations strongly depended on renal function. Target serum concentration (> 5 × minimum inhibitory concentration (MIC) 24 h after cefoxitin onset was obtained in 34 patients (83%), using a median [IQR] daily dose of 6 [6-6] g with continuous administration. The standard dosage of 6 g/24 h was not sufficient to achieve the PK/PD target serum concentration for MIC up to 4-8 mg/L, except in patients with severe renal impairment and those treated with renal replacement therapy. Treatment failure occurred in 26 cases (63%), among whom 12 patients (29%) died, 13 patients (32%) were switched to alternative antibiotic therapy and 11 patients (27%) presented with relapse of infection with the same ESBL-PE. Serious adverse events attributed to cefoxitin occurred in 7 patients (17%). Acquisition of cephamycin-resistance with the same Enterobacterales was identified in 13 patients (32%), and was associated with underdosage.

Conclusion: Continuous administration of large doses of cefoxitin appears necessary to achieve the PK/PD target in patients with normal renal function. Renal status, MIC determination and therapeutic drug monitoring may be useful for treatment individualization in this setting. The treatment failure rate was 63%. The cefoxitin safety profile was favorable, but we observed a high rate of cephamycin-resistance emergence.

Keywords: Antibacterial chemotherapy; Carbapenem-sparing agents; Cefoxitin; Extended-spectrum beta-lactamase; Healthcare-associated pneumonia; Intensive care; Population pharmacokinetics.

Fig. 1

Flowchart of the study. ^*Multiple sites could be positive for ESBL-PE per patients. C3G 3rd generation cephalosporin, ESBL extended-spectrum beta-lactamase, ESBL-PE ESBL producing Enterobacterales, ICU intensive care unit

Fig. 2

Proposed decision and posologic algorithm for cefoxitin use in ICU patients with ESBL-PE infection. ^*Proposed loading dose and consider measuring the MIC with E-test in this situation. ^¤Cefoxitin dosages required for achieving PTA ≥ 90% for target 100% fT_>MIC at 48 h, considering the maximal possible value for MIC in this interval of estimation (i.e., 4 mg/L (left) and 8 mg/L (right)). ^£Considering a continuous RRT and using standard parameters (blood flow rate 250 mL/min, ultrafiltration rate 2000 mL/h). ^#The computed PTA for CCR_IBW = 120 mL/min and a dose of 12 g/24 h was 89.5%, which was rounded to 90% and considered as acceptable. ^§The use of a dosage of cefoxitin above 12 g/24 h has not been reported so far. The absence of data concerning toxicity and uncertainty considering the possible non-linear PK over such dosage should be kept in mind. CCR_IBW creatinine clearance based on ideal body weight, ICU intensive care unit, ESBL-PE extended-spectrum beta-lactamase producing Enterobacterales, fT_>MIC proportion of time with free cefoxitin serum concentration over the minimum inhibitory concentration, MIC minimum inhibitory concentration, PK pharmacokinetics, PTA probability of target attainment, TDM therapeutic drug monitoring, RRT renal replacement therapy, ICU intensive care unit