Amoxicillin/clavulate for ESBL UTI?

Everyone falls a little behind in life (although my hiatus from writing is almost a year!), but instead of making excuses, I need to get myself in gear and start posting again. Here goes:

As most of the adult healthcare providers are aware of (and there is growing knowledge in the general population), there is an increasing amount of extended-spectrum beta-lactamase (EBSL)-producing organisms in the community; however, it seems that some of us in the pediatric side are still a little naïve to this. However, our renal/urology patients are definitely blowing our innocence out of the water and I feel like I see a new patient colonized with ESBL-producing about every few weeks or so. Unfortunately, their isolates are often resistant to oral antibiotics and have to be admitted for intravenous antibiotics for urinary tract infections (UTIs); although, sometimes you will get lucky and one will actually be amoxicillin/clavulante susceptible.

Some of our practitioners feel a little leery about using amoxicillin/clavulante alone for UTIs, mostly due to limited experience as well as the idea of how such an everyday antibiotic can work the same wonders as a broad-spectrum carbapenem. But it kind of makes some sense that the addition of clavulante might do the trick: beta-lactamase inhibitors can inhibit Ambler Class A ESBLs, whereas AmpC beta-lactamases (Ambler Class C) are not affected.¹ Phenotypic confirmation of ESBLs can be performed through disk diffusion. The zone of inhibition is compared between ceftazidime and cefotaxime alone and in combination with clavulanic acid and an increase of >= 5 mm confirms the presence of an ESBL (see figure).^2,3 The Clinical Laboratory Standards Institute recommends that all other penicillins, cephalosporins, and aztreonam be reported as “resistant” but does not indicate whether or not amoxicillin/clavulanate should be defaulted as non-susceptible when the MIC <= 8 mcg/mL.

There appears to be very limited studies about the clinical usage of amoxicillin/clavulante in this setting. One study of community-acquired uncomplicated cystitis caused by ESBL-producing E. coli suggests that amoxicillin/clavulate can often be successful if the organism is susceptible (MIC <= 8 mcg/mL) and less so if less susceptible (MIC ³ 16 mcg/mL), 93% vs. 56%.⁴  Additionally, the pharmacokinetic/pharmacodynamics properties of amoxicillin/clavulanate are maximized for uncomplicated UTIs due to the concentration of the antibiotic in the bladder. The challenge, however, is finding an isolate that is susceptible to this beta-lactam/beta-lactamase inhibitor combination since the resistance can be upwards of 70% in E. coli isolates. Thus, empiric use of amoxicillin/clavulanate should be avoided and other agents, such as nitrofurantoin or fosfomycin, can be considered as initial treatment (although treatment spectrum is limited to cystitis).⁵

However, the other question would be whether or not clavulanate in combination with other oral cephalosporins would be adequate as an oral outpatient therapy for UTIs? Which, hopefully, will be explored in the next week or so.

Figure 1. ESBL detection by disk diffusion.

1.     Drawz SM, Bonomo RA. Three decades of beta-lactamase inhibitors. Clin Microbiol Rev. 2010;23:160-201. PMID:20065329

2.     Clinical and Laboratory Standards Institute. 2011. Performance standards for antimicrobial susceptibility testing. Supplement M100-S21.Clinical and Laboratory Standards Institute, Wayne, PA.

3.     Kumar V, Sen MR, Nigam C, Gahlot R, Kumari S. Burden of different beta-lactamase classes among clinical isolates of AmpC-producing Pseudomonas aeruginosa in burn patients: a prospective study. Indian J Crit Care Med. 2012;16:136-140. PMID: 23188953

4.     Rodríguez-Baño J, Alcalá JC, Cisneros JM, et al. Community infections caused by extended-spectrum beta-lactamase-producing Escherichia coli. Arch Intern Med. 2008;168:1897-902. PMID: 18809817

5.     Meier S, Weber R, Zbinden R, Hasse B. Extended-spectrum β-lactamase-producing Gram-negative pathogens in community-acquired urinary tract infections: an increasing challenge for antimicrobial therapy. Infection. 2011;39:333-40. PMID: 21706226