Carbapenem-sparing cephamycins effective in E coli-induced UTI

Cefmetazole and cefoxitin prove to be effective in the treatment of patients with urinary tract infections (UTIs) due to extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli, according to two separate studies presented at IDWeek 2022.

Both drugs are said to provide useful strategies to reduce the use of carbapenems, which has important clinical implications given that overuse of carbapenems may lead to an increase in carbapenem-resistant bacteria.

The first study evaluated the efficacy of cefmetazole against meropenem in 123 patients hospitalized for invasive UTI due to ESBL-producing E Coli. Treatment was initiated within 96 hours of culture submission as definitive therapy and used for at least 4 days.

Compared with patients in the meropenem group, those in the cefmetazole group were older (median 85 vs 78 years), had lower Quick Sequential Organ Failure Assessment (qSOFA) score (0 vs 1), and less likely to have and C-reactive protein of ≥10 mg/dL (40.9 percent vs 64.3 percent) at baseline.

Of note, cefmetazole compared favourably with meropenem. Outcomes such as clinical effectiveness (resolution of all clinical symptoms or improvement to preinfection status) between day 4–6 of treatment and between the final day of treatment and 2 days later, microbiological effectiveness (≤10^3 CFU/ml) between day 4–6, and 30-day mortality were similar in the two treatment groups. [IDWeek 2022, abstract 658]

Analysis adjusted for the inverse probability of propensity scores showed that cefmetazole remained as good as meropenem in terms of clinical effectiveness. However, cefmetazole was associated with lower 30-day mortality and similar recurrence risk, noted Dr Kayoko Hayakawa, the presenting study author and chief physician at the National Center for Global Health and Medicine in Shinjuku, Tokyo, Japan.

In the second study, 41 haemodynamically stable patients (median age 79 years, 70.7 percent female) with negative blood cultures who demonstrated signs and symptoms of a UTI with a urine culture showing ESBL-producing E coli were started on initial antimicrobial therapy at the discretion of the admitting physician.

If the urine culture showed ESBL-producing E coli with a minimum inhibitory concentration of <8, the patients were switched to cefoxitin 2 g intravenously every 6 hours via extended infusion.  The dose was renally adjusted as appropriate, and patients with beta-lactam allergies were excluded.

The patients received antibiotics for 2.6 days before the switch to cefoxitin, and the mean duration of therapy with cefoxitin was 4.5 days. Fever and dysuria were resolved in all patients. Six patients were readmitted within 30 days, but none were due to a UTI.  [IDWeek 2022, abstract 680]

All 30 patients who underwent a repeat urinalysis at 48 hours demonstrated reduction in pyuria. Meanwhile, 36 out of 39 patients who had a repeat urine culture following completion of therapy had converted to culture-negative status.

The optimal cefoxitin dose appeared to be 2 g, administered intravenously every 6 hours via extended infusion, in patients with normal creatinine clearance, according to Dr Ramesh Nathan, the presenting study investigator and a partner at Los Robles Health System, Thousand Oaks, California, US.

Carbapenem-sparing strategies

ESBL are enzymes that render E coli resistant to nearly all cephalosporins and penicillins. Meanwhile, carbapenems such as meropenem remain active and are considered the gold standard for treating bloodstream infections due to ESBL-producing organisms. [Antibiotics 2020;9:61]

“However, carbapenem overutilization stimulates various resistance pathways including outer membrane protein mutations and the selection of β-lactamases capable of hydrolysing carbapenems,” Nathan said.

Cephamycins such as cefoxitin and cefmetazole, on the other hand, belong to a subclass of second-generation cephalosporins that confer resistance to degradation by ESBL enzymes.

Taken together, the findings of the two studies provide evidence that cephamycins provide an attractive alternative to carbapenems for UTIs but should be administered at high dose and continuous infusion.