Evaluating the Role of New Beta-Lactam Agents for Uncommon Pathogens

Stenotrophomonas maltophilia, Achromo-bacter xylosoxidans, and Burkholderia spp are relatively uncommon pathogens that are increasingly seen as causes of clinically significant infections, particularly respiratory tract infections among immunocompromised hosts and other vulnerable populations.^1-4

Patients with cystic fibrosis (CF) are at an elevated risk for chronic infections and morbidity. According to the 2017 Cystic Fibrosis Patient Registry, which provides comprehensive data on nearly 30,000 patients with CF, S maltophilia was identified in 12.9% of patients, A xylosoxidans in 5.7%, and Burkholderia cepacia complex in a further 2.5%.5 Patients with cancer, specif­ically those with a hematologic malignancy, are also at height­ened risk for infections with these organisms.^6-8 Infection with S maltophilia can have devastating complications in patients with a hematologic malignancy, for which mortality approaches 100% in patients with hemorrhagic pneumonia.⁹

These pathogens share many features, including their envi­ronmental origins, ability to cause persistent infections due to biofilm formation, and intrinsic multidrug resistance, specifi­cally to most β-lactam agents. Although other antimicrobials, particularly trimethoprim/sulfamethoxazole, later-generation tetracyclines, and fluoroquinolones, may be active in vitro and have clinical utility, emerging resistance and concerns over toxicity and efficacy in serious infections highlight a potential role for the newly available β-lactam/β-lactamase inhibitor combinations ceftazidime/avibactam, imipenem/relebactam, meropenem/vaborbactam, and ceftolozane/tazobactam. In this short review, we describe the mechanisms of β-lactam resistance for S maltophilia, A xylosoxidans, and Burkholderia spp and demonstrate how understanding the mechanistic basis of resistance is necessary to define the role of β-lactam /β-lactamase inhibitor combinations against these organisms. We additionally summarize clinical data on their use.

STENOTROPHOMONAS MALTOPHILIA

Stenotrophomonas maltophilia is an intrinsically carbapenem -resistant organism and is the leading carbapenem-resistant pathogen isolated from patients with hospital-acquired and ventilator-associated pneumonia.^3,10 Trimethoprim/ sulfamethoxazole is the current drug of choice; however, resistance is increasingly described, and its utility is limited in patients with hematologic malignancy and transplant recip­ients because of concerns for myelosuppression and nephro­toxicity.^11,12 The characteristic β-lactam resistance profile of S maltophilia is achieved through the production of 2 chro­mosomal, inducible β-lactamase enzymes: L1, an Ambler class B metallo-β-lactamase, and L2, an Ambler class A serine β-lactamase.^3,13 L1 has a substrate profile similar to that of other metallo-β-lactamases and hydrolyzes all commercially available β-lactamases, with the exception of aztreonam, and is not inhib­ited by commercially available β-lactamase inhibitors. L2 is a relatively narrow-spectrum cephalosporinase that hydrolyzes most cephalosporins and aztreonam but has no activity against carbapenems. L2 is inhibited by clavulanate but is generally not inhibited by the sulfone β-lactamase inhibitors sulbactam and tazobactam.¹⁴

When both enzymes are expressed in combination, most β-lactams are eliminated as therapeutic options for S malto­philia, and commercially available β-lactam/β-lactamase inhibitors have no added activity.¹⁵ Results from surveillance studies indicate similar resistance profiles for ceftazidime and ceftazidime/avibactam, meropenem and meropenem/ vaborbactam, and imipenem and imipenem/relebactam (Table^16-22). One approach to overcoming β-lactam— mediated resistance is to employ a combination of aztreonam, which is not hydrolyzed by L1, and avibactam, which inhibits L2. Mojica et al evaluated the combination of aztreonam and avibactam against 27 clinical isolates of aztreonam-resistant S maltophilia and found that the combination restored activity in 23 of 27 isolates.²³ These findings have been confirmed by others.²⁴ Because aztreonam/avibactam is not commercially available, the combination of ceftazidime/avibactam and aztre­onam has been used clinically. This triple-drug combination was used to successfully treat a renal transplant recipient with refractory S maltophilia bacteremia.²⁵ Recent whole-genome sequencing evaluations of S maltophilia suggest that L1 and L2 are subject to a high degree of interstrain vari­ability with implications for β-lactam substrate specificity and inhibitor profile.13 Additional in vitro surveillance and clinical data are needed before this combination can be broadly recom­mended, though the ability of most clinical microbiology laboratories to test for activity of this combination is limited. The combination of aztreonam and clavulanate has similar activity to aztreonam and avibactam, but as no intra­venous formulation of clavulanate is available commercially in the United States, the thera­peutic potential of this synergy is limited.^26,27

Although relebactam is structurally similar to avibactam, it appears to be a less potent inhib­itor of L2 than avibactam, with a half-maximal inhibitory concentration of 470nM against L2 relative to 15nM for avibactam.²⁸ No data have been published for the boronic acid inhib­itor vaborbactam. Ceftolozane/tazobactam has activity similar to that of ceftazidime and lacks additional activity against ceftazidime-resistant strains of S maltophilia.²⁹

ACHROMOBACTER XYLOSOXIDANS

Although several members of the genus Achromobacter have been described as causing infections in humans, A xylosoxidans is the most common and well described. A xylosox­idans is intrinsically resistant to aztreonam and most cephalosporins, whereas piperacillin/ tazobactam and the carbapenems, including ertapenem, have activity.^30-32 The molecular mechanisms of β-lactam resistance in A xylosox­idans are not fully characterized; however, both multidrug efflux pumps and a narrow-spectrum Ambler class D β-lactamase, OXA-114, contribute to resistance.^33,34 OXA-114 is a chromosomally encoded, noninducible serine β-lactamase that hydrolyzes piperacillin but otherwise does not appear to contribute to β-lactam resistance in A xylosoxidans.^33-35 Two resistance-nodulation-division (RND)—type efflux pumps, AxyABM and AxyXY-OprZ, mediate resistance to aztreonam, cefepime, fluoroquinolones, and aminoglyco­sides inherent to A xylosoxidans.^36-38 Acquisition of exogenous β-lactamases, including extended -spectrum β-lactamases and metallo-β-lact­amases, contributes to β-lactam resistance.^39,40

Because of the lack of clinically significant endogenous β-lactamases, β-lactam/β-lact­amase inhibitor combinations are not expected to have any significant activity against A xylosoxidans. Surveillance data indicate that ceftazidime/avibactam and ceftolozane/ tazobactam are both essentially inactive against A xylosoxidans.^17,20,41-43 No published data are available on the carbapenem-based combination agents imipenem/relebactam and meropenem/vaborbactam.

BURKHOLDERIA SPECIES

The genus Burkholderia includes several clini­cally relevant organisms, including the B cepacia complex, Burkholderia mallei, and Burkholderia pseudomallei. Members of the Burkholderia genus possess a large genome with multiple chromo­somes, which leads to genetic plasticity and multiple antimicrobial resistance determinants.⁴⁴ Burkholderia pseudomallei, the causative agent of melioidosis, is not found in the United States, and B mallei, the cause of glanders, is largely of histor­ical concern.⁴⁵ Therefore, these organisms are not further discussed. The B cepacia complex species, consisting of B cepacia, Burkholderia cenocepacia, Burkholderia multivorans, and others, are predom­inantly pathogens in patients with CF but have been described in other patients, particularly those with chronic granulomatous disease.⁴⁶ In addition to intrinsic resistance to penicillins and narrow-spectrum cephalosporins, Burkholderia spp are intrinsically resistant to the polymyxins through alterations in lipid A, which lead to changes in net lipopolysaccharide charge and decreased poly­myxin binding affinity.⁴⁷ Burkholderia spp produce numerous efflux pumps, including at least 6 RND-type efflux pumps in the B cepacia complex.^47,48

β-lactam resistance in B cepacia complex is medi­ated predominantly through 2 chromosomal β-lact­amase enzymes, a broad-spectrum, Ambler class A carbapenemase (either PenB in B cepacia or PenA in B multivorans), and AmpC-like enzymes that hydro­lyze penicillins, extended-spectrum cephalosporins, and carbapenems.^47,49 Both enzymes are inducible through an ampD-controlled mechanism similar to other gram-negative organisms with chromosomal, inducible AmpC β-lactamases.⁵⁰ As these enzymes are not constitutively expressed, β-lactams, partic­ularly ceftazidime and meropenem, are frequently active against B cepacia complex.¹⁹ However, when PenA or PenB is expressed, B cepacia complex species become resistant to extended-spectrum cephalosporins and carbapenems. Efflux pumps, particularly RND-3 pumps, also appear to have a role in resistance to ceftazidime and meropenem.⁵¹ Similar to other class A enzymes, avibactam is a potent inhibitor of PenA in B multivorans and can restore in vitro activity against ceftazidime-resistant strains.^52,53 Ceftazidime/avibactam has been used successfully in the treatment of a 2-month-old child with refractory B cepacia complex bacteremia who had failed both ceftazidime and meropenem, as well as in a small case series of 4 patients with cystic fibrosis colonized with extensively drug-re­sistant Burkholderia spp.^54,55

Despite promising in vitro activity and successful use in a small number of patients, the activity of ceftazidime/avibactam against B cepacia complex is highly variable.⁴¹ Against extensively drug-resistant isolates, a novel quadruple-drug combi­nation of ceftazidime/avibactam and piperacillin/ tazobactam has shown promising activity.⁵⁶ The mechanism appears to be dependent on slow hydrolysis of piperacillin by AmpC and inhibition of PenA by avibactam, and therefore, ceftazidime and tazobactam are simply “bystanders” to the desired piperacillin/avibactam combination. No literature on the clinical utility of this combina­tion is currently available. No published data are available on the potential utility of other novel β-lactamase inhibitors against B cepacia complex infections. Ceftolozane/tazobactam activity has variable activity against B cepacia complex members and does not add appreciable activity in ceftazidime-resistant strains.^21,43,53

CEFIDEROCOL

Cefiderocol, a novel siderophore cephalosporin, is stable against hydrolysis by both serine and metallo-b-lactamases. Mechanistically, cefiderocol chelates ferric iron and is transported across the outer membrane and into the periplasmic space, where it binds to penicillin binding protein 3.⁵⁷ Against a collection of North American and European gram-negative organisms, cefiderocol demonstrated potent in vitro activity against S maltophilia (minimum inhibitory concentration [MIC]₉₀, 0.5 μg/mL; 100% sensitive at a provi&shy;sional breakpoint of <4 μg/mL) and was active against 11/12 Burkholderia isolates at MICs <1 μg/mL, with a single isolate having a MIC of 16 μg/mL.⁵⁸ Activity of cefiderocol against S malto&shy;philia and Burkholderia was again seen in a collection of gram-negative isolates from a Comprehensive Cancer Center in the southern United States, in addition to observed activity against Achromobacter spp.⁵⁹ To date, no published clinical data are available on the utility of cefid&shy;erocol against these organisms, and the compound is not by the US Food and Drug Administration. In vitro data suggest that cefiderocol is a potentially promising option against these problem pathogens.

SUMMARY

A knowledge of the molecular mechanisms of β-lactam resistance is crucial to understanding the potential utility, or lack thereof, of novel β-lactam/β-lactamase inhibitors against less common non—lactose-fermenting gram-negative organisms. These associations can be extended to Achromobacter spp, in which intrinsic resis&shy;tance to cephalosporins and carbapenems is due to efflux pumps, and accordingly novel β-lactam/β-lactamase inhibitors are inactive. In S maltophilia, an intrinsic cephalosporinase and metallo-β-lactamase confer resistance to novel β-lactam/β-lactamase inhibitors, although the addition of aztreonam to avibactam overcomes this resistance. Lastly, Burkholderia, which expresses a class A carbapenemase and AmpC-type enzyme, is generally sensitive to ceftazidime/avibactam and in combination with piperacillin/avibactam appears to restore activity against some resistant isolates. As these organisms are poorly studied, further in vitro and clinical data are needed to validate the potential clinical role of these novel agents.

Spitznogle is a PGY-2 infectious diseases pharmacy resident at The University of Texas MD Anderson Cancer Center in Houston. She graduated from the University at Buffalo School of Pharmacy and Pharmaceutical Sciences in New York. *She is an active member of the Society of Infectious Diseases Pharmacists.Aitken is a pharmacy clinical specialist in infectious diseases at The University of Texas MD Anderson Cancer Center and a faculty member of the Center for Antimicrobial Resistance and Microbial Genomics at UTHealth McGovern Medical School, both in Houston. *He is an active member of the Society of Infectious Diseases Pharmacists.

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