The IDSA 2024 Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections recommend avoiding the use of amoxicillin-clavulanate (AMC) for the treatment of cystitis or bloodstream infections due to Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca and Proteus mirabilis with extended-spectrum B-lactamase activity. The guidance also reminds us not to use AMC or ampicillin-sulbactam (SAM) to treat infections involving Enterobacter cloacae complex, Klebsiella aerogenes and Citrobacter freundii because of intrinsic resistance due to AmpC B-lactamase production.
A retrospective study conducted within the laboratory systems of New York-Presbyterian/Weill Cornell Medical Center between 2018 and 2022, published in JAC-Antimicrobial Resistance, reviewed AMC and SAM susceptibility patterns for 35,089 isolates that included E. coli (66.9%), Citrobacter amalonaticus complex (0.2%), Citrobacter koseri (1.8%), K. pneumoniae group (18.9%), K. oxytoca (2.5%), Proteus mirabilis (9.1%) and Proteus vulgaris (0.5%).
The CLSI M100 31st edition determined the MIC breakpoints for this study. Intermediate MICs were classified as resistant. ESBL-producing isolates were defined as those resistant to ceftriaxone and susceptible to cefoxitin. To avoid double counting isolates, if multiple isolates of the same species were recovered from the same patient in a single year, only one isolate was included in this study.
The study found 27,009 isolates (77.0%) tested against AMC and SAM had concordant susceptibilities, meaning if the isolate was sensitive to AMC, then the isolate was sensitive to SAM also (same for resistance). In addition, 8,080 isolates (23.0%) had discordant results, meaning if the isolate was resistant to SAM, then the isolate was sensitive to AMC or vice versa.
In the discordant group, 7,873 isolates (97.4%) were resistant to SAM but sensitive to AMC, and E.coli had the highest percentage of isolates in this subgroup (83.3%), followed by K. pneumoniae (10.5%), P. mirabilis (3.2%), K. oxytoca (2.5%), P. vulgaris (0.3%), C. amalonaticus (0.1%) and C. koseri (0.1%). In the discordant group, only 207 isolates (2.6%) were sensitive to SAM but resistant to AMC, with E. coli having the highest percentage of isolates in this subgroup (66.7%).
In subgroup analysis involving only ESBL-producing isolates, the study found that most of this subgroup comprised E. coli, K. pneumoniae and P. mirabilis discordant isolates that were resistant to SAM but sensitive to AMC.
This study suggests that up to 23% of E. coli, K. pneumoniae, P. mirabilis, K. oxytoca, C. amalonaticus, P. vulgaris and C. koseri could have discordant sensitivity results when testing against AMC and SAM, so clinicians may want to ask their local microbiology laboratories to test both drugs for these organisms.
This study also shows a higher proportion of E. coli, K. pneumoniae and P. mirabilis in the ESBL subgroup with AMC MICs in susceptible range when SAM is resistant. This supports IDSA’s guidance, which says that clavulanic acid has activity against ESBL organisms in vitro, but further in vivo research is needed to determine clinical applications.
Another recent study comparing an oral carbapenem with AMC in patients with uncomplicated urinary tract infections that included about 10% ESBL organisms in each group showed noninferiority between the two drugs, providing some clinical evidence for the efficacy of AMC in certain populations.