Bacteria With Tandem GES Enzymes an Emerging Threat in Drug Resistance

The fight against drug-resistant bacteria may include new challenges on the horizon, according to a recent study that reported 2 clinical isolates of Pseudomonas aeruginosa that were resistant to all β-lactam antibiotics, including novel combinations.

“The introduction of newer therapeutics such as ceftolozane/tazobactam, which circumvents these common resistance mechanisms, has offered clinicians additional options for treating MDR strains,” the investigators on the study, published in the journal Open Forum Infectious Diseases, wrote. “However, the emergence of resistance to C/T associated with mutations in the intrinsic AmpC cephalosporinase is increasingly reported. In addition, the acquisition of β-lactam resistance arising from exogenous β-lactamase enzymes is another growing concern, especially in the high-risk clones.”

The research team, with the University of Texas Health Science Center, examined multidrug-resistant (MDR) sequence type 309 P aeruginosa that infected 2 unrelated patients in Texas. The bacteria carried 2 Guiana extended-spectrum (GES) β-lactamase enzymes—GES-19 and GES-26—in tandem, which are associated with higher drug resistance. One of the patients recovered after receiving ceftazidime/avibactam plus aztreonam. The other patient died.

Isolates of the bacteria were used to reconstruct a phylogenetic tree and clone β-lactamase enzymes GES-19 and GES-26, which were then expressed into Escherichia coli to examine the effect of the enzymes on drug resistance. The study found that E coli that included both enzymes had higher minimum inhibitory concentrations (MICs) to β-lactam antibiotics and combinations than those that included only 1 enzyme.

“This article is a sobering reminder that even our newest antibiotics will be inactive against some extensively drug-resistant isolates and the introduction of new mechanisms of resistance is possible,” said Ryan K. Shields, PharmD, MS, associate professor of medicine at the University of Pittsburgh and Contagion^®'s Multidrug-Resistant Infections Section Editor. “Clinicians should continue to use these agents judiciously, and request susceptibility testing when they are considered for treatment of P aeruginosa infections.”

The study, funded by the National Institutes of Health, also determined that the ST309 P aeruginosa bacteria are closely related to strains from Mexico that also carry both enzymes and are resistant to multiple drugs: aztreonam, cefepime, meropenem, ceftazidime/avibactam, and ceftolozane/tazobactam. However, the patients did not have a history of traveling to Mexico, suggesting that the bacteria may be widespread.

“The cases reported here offer several important insights into the evolving landscape of MDR P aeruginosa,” the study noted. “Both were serious infections due to ST309 P aeruginosa with an extensive antibiotic resistance phenotype. By phylogenetic analysis, these isolates were linked to strains reported from several clusters of ST309 P aeruginosa infections in Mexico City, which also displayed an MDR phenotype. Indeed, GES enzymes seem to be an important contributor to carbapenem resistance in P aeruginosa from Mexico, with a prevalence of 30.6%. Further, these enzymes are also present as plasmid borne resistance determinants among Enterobacteriaceae from this region, suggesting a potential for spread across species.”

Drug combinations have been a go-to strategy in fighting drug-resistant bacteria. A study released last year found that combinations of up to 4 or 5 antibiotics may be effective in fighting drug-resistant E coli.

Ceftolozane/tazobactam, first approved in 2014, recently was approved for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP).