Case Commentary: An espresso, a free puppy, and multidrug-resistant Campylobacter

ABSTRACT

Campylobacter species infections in immunocompromised patients have the potential to progress to bacteremia and other extra-intestinal diseases. There is a sparsity of robust data, including antibiotic susceptibility data for contemporary agents, upon which to base treatment decisions. Moreover, intrinsic antimicrobial resistance in Campylobacter spp. further limits treatment options. The current publication by Bonilla-Moreno et al. elaborates on this clinical dilemma through the development, treatment, and molecular investigation of the putative mechanisms of carbapenem resistance in an immunocompromised patient with Campylobacter coli bacteremia.

COMMENTARY

The last publication I recall reading involving Campylobacter spp. was a report from the Ohio Department of Health and the Centers for Disease Control and Prevention (CDC) describing a multistate outbreak investigation of Campylobacter jejuni. The Morbidity and Mortality Weekly Report detailed the association with exposure to puppies and a multidrug-resistant (MDR) strain of C. jejuni in 118 people and 149 puppies (1). Admittedly, my interest (at the time) in this publication was driven more by the puppies than the MDR pathogen. But I digress.

In this issue of Antimicrobial Agents and Chemotherapy, Bonilla-Moreno and colleagues recount the case of a person with relapsed/refractory lymphoma with C. coli bacteremia and the emergence of meropenem resistance while on meropenem therapy (2). While also describing the treatment approach and clinical outcomes of this patient, the team from Barcelona expertly conducted whole-genome sequencing to identify and posit potential molecular mechanisms for their observations.

Although relatively infrequently encountered in hospital-based practice, campylobacteriosis is one of the top four causes of diarrheal illness globally (3) and, per the US CDC, is the primary cause of bacterial diarrheal illness in the US (4). While clinical manifestations can be severe (including bloody diarrhea, fever, and abdominal pain), the disease is fortunately largely self-limiting and rarely requires antibiotics or hospital admission.

However, when considering campylobacteriosis in the immunocompromised patient, disease progression can be significant and include extra-intestinal disease (5). Cases of campylobacter extra-intestinal disease typically involve non-jejuni species, such as Campylobacter fetus or Campylobacter coli (as in the current case). Antibiotic resistance in Campylobacter spp. is of international concern. The US CDC’s National Antimicrobial Resistance Monitoring System for Enteric Bacteria NARMS Now tool reports ciprofloxacin and azithromycin (the first-line treatment options) resistance in isolates from human cases at 33% (on the rise) and 1% (stable), respectively (6). Indeed, antibiotic-resistant Campylobacter is listed among the CDC’s Antibiotic Resistance Threats (7). Internationally, upward of 80% of Campylobacter spp. isolates have been reported as non-susceptible to either ciprofloxacin or azithromycin, with significant geographic variation (8 – 10). Public health antibiotic susceptibility surveillance and reporting is often limited in scope and rarely includes the newest agents used in the treatment of MDR bacteria (e.g., carbapenems, advanced tetracycline derivatives, and beta-lactam/inhibitor combinations). As such, public health surveillance data is informative but generally does not offer alternative solutions supported by a large sample size.

Campylobacter spp. are a worthy foe from an antimicrobial resistance perspective. Beyond their capacity for acquired resistance to fluoroquinolones and macrolides, Campylobacter exhibits intrinsic resistance to cephalosporins and folate inhibitors (11). Tetracycline and aminoglycoside resistance have been described (12). Further, multidrug efflux pumps have been well characterized (to export macrolides, tetracyclines, quinolones, beta-lactams, and bile salts) (13). In this milieu, we are increasingly only left with carbapenems and agents with limited availability and/or concerning adverse event profiles (i.e., polymyxins and chloramphenicol). Carbapenems have emerged as potential treatment options for patients with severe and/or extra-intestinal disease in the setting of drug-resistant Campylobacter infections (14, 15). Unfortunately, as demonstrated by Bonilla-Moreno et al., even carbapenems are not a panacea. A mutation in the promoter region of OXA-61 leading to over-expression combined with a multidrug efflux pump and a porin mutation may have increased the meropenem MIC to >64 mcg/mL. Fortunately, the cocktail of intravenous imipenem/cilastatin with oral decolonization containing gentamicin and fosfomycin (along with reversal of hypogammaglobulinemia) appeared to be successful for this patient.

Where does this leave us? Antibiotic-resistant Campylobacter is clearly on the rise, and the few remaining options often remain. On top of this, modern medicine is immunosuppressing more patients year-over-year (e.g., stem cell transplants and solid-organ transplants). It follows that we should expect to encounter more cases akin to the current report. What is the optimal treatment for azithromycin-resistant, ciprofloxacin-resistant, and carbapenem-resistant C. coli? Regrettably, we do not have sufficient data to address this question. However, expanded-scope surveillance data, including more contemporary antimicrobials, could at least provide in vitro drug activity from which to select potential therapeutic agents when needed. Larger, more robust in vitro data are clearly needed, and we are capable of doing so (16). The time for formal treatment recommendations beyond azithromycin and ciprofloxacin is now.

Commentary title from:

“Unattended children will be given an espresso and a free puppy.”

-Anonymous (sign in store window)