Sarah L. Spitznogle, PharmD*

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.

Patients with cystic fibrosis (CF) are at an elevated risk for chronic infections and morbidity. According to the 2017 

, which provides comprehensive data on nearly 30,000 patients with CF, 

complex in a further 2.5%.5 Patients with cancer, specif&shy;ically those with a hematologic malignancy, are also at height&shy;ened risk for infections with these organisms.

can have devastating complications in patients with a hematologic malignancy, for which mortality approaches 100% in patients with hemorrhagic pneumonia.

These pathogens share many features, including their envi&shy;ronmental origins, ability to cause persistent infections due to biofilm formation, and intrinsic multidrug resistance, specifi&shy;cally 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 

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.

is an intrinsically carbapenem -resistant organism and is the leading carbapenem-resistant pathogen isolated from patients with hospital-acquired and ventilator-associated pneumonia.

 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 recip&shy;ients because of concerns for myelosuppression and nephro&shy;toxicity.

 The characteristic β-lactam resistance profile of 

is achieved through the production of 2 chro&shy;mosomal, inducible β-lactamase enzymes: L1, an Ambler class B metallo-β-lactamase, and L2, an Ambler class A serine β-lactamase.

 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 inhib&shy;ited 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.

When both enzymes are expressed in combination, most β-lactams are eliminated as therapeutic options for 

and commercially available β-lactam/β-lactamase inhibitors have no added activity.

 Results from surveillance studies indicate similar resistance profiles for ceftazidime and ceftazidime/avibactam, meropenem and meropenem/ vaborbactam, and imipenem and imipenem/relebactam (

). 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 

and found that the combination restored activity in 23 of 27 isolates.

 These findings have been confirmed by others.

 Because aztreonam/avibactam is not commercially available, the combination of ceftazidime/avibactam and aztre&shy;onam has been used clinically. This triple-drug combination was used to successfully treat a renal transplant recipient with refractory 

 Recent whole-genome sequencing evaluations of 

suggest that L1 and L2 are subject to a high degree of interstrain vari&shy;ability 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 recom&shy;mended, 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 intra&shy;venous formulation of clavulanate is available commercially in the United States, the thera&shy;peutic potential of this synergy is limited.

Although relebactam is structurally similar to avibactam, it appears to be a less potent inhib&shy;itor of L2 than avibactam, with a half-maximal inhibitory concentration of 470nM against L2 relative to 15nM for avibactam.

 No data have been published for the boronic acid inhib&shy;itor vaborbactam. Ceftolozane/tazobactam has activity similar to that of ceftazidime and lacks additional activity against ceftazidime-resistant strains of 

have been described as causing infections in humans, 

is intrinsically resistant to aztreonam and most cephalosporins, whereas piperacillin/ tazobactam and the carbapenems, including ertapenem, have activity.

 The molecular mechanisms of β-lactam resistance in 

are not fully characterized; however, both multidrug efflux pumps and a narrow-spectrum Ambler class D β-lactamase, OXA-114, contribute to resistance.

 OXA-114 is a chromosomally encoded, noninducible serine β-lactamase that hydrolyzes piperacillin but otherwise does not appear to contribute to β

 Two resistance-nodulation-division (RND)—type efflux pumps, AxyABM and AxyXY-OprZ, mediate resistance to aztreonam, cefepime, fluoroquinolones, and aminoglyco&shy;sides inherent to 

 Acquisition of exogenous β-lactamases, including extended -spectrum β-lactamases and metallo-β

lact&shy;amases, contributes to β-lactam resistance.

Because of the lack of clinically significant endogenous β-lactamases, β-lactam/β-lact&shy;amase inhibitor combinations are not expected to have any significant activity against 

. Surveillance data indicate that ceftazidime/avibactam and ceftolozane/ tazobactam are both essentially inactive against 

 No published data are available on the carbapenem-based combination agents imipenem/relebactam and meropenem/vaborbactam.

includes several clini&shy;cally relevant organisms, including the 

genus possess a large genome with multiple chromo&shy;somes, which leads to genetic plasticity and multiple antimicrobial resistance determinants.

, the causative agent of melioidosis, is not found in the United States, and 

, the cause of glanders, is largely of histor&shy;ical concern.

 Therefore, these organisms are not further discussed. The 

B cepacia, Burkholderia cenocepacia, Burkholderia multivorans, 

and others, are predom&shy;inantly pathogens in patients with CF but have been described in other patients, particularly those with chronic granulomatous disease.

 In addition to intrinsic resistance to penicillins and narrow-spectrum cephalosporins, 

spp are intrinsically resistant to the polymyxins through alterations in lipid A, which lead to changes in net lipopolysaccharide charge and decreased poly&shy;myxin binding affinity.

spp produce numerous efflux pumps, including at least 6 RND-type efflux pumps in the 

complex is medi&shy;ated predominantly through 2 chromosomal β-lact&shy;amase enzymes, a broad-spectrum, Ambler class A carbapenemase (either PenB in 

and AmpC-like enzymes that hydro&shy;lyze penicillins, extended-spectrum cephalosporins, and carbapenems.

-controlled mechanism similar to other gram-negative organisms with chromosomal, inducible AmpC β-lactamases.

 As these enzymes are not constitutively expressed, β-lactams, partic&shy;ularly ceftazidime and meropenem, are frequently active against 

 However, when PenA or PenB is expressed, 

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.

 Similar to other class A enzymes, avibactam is a potent inhibitor of PenA in 

and can restore in vitro activity against ceftazidime-resistant strains.

 Ceftazidime/avibactam has been used successfully in the treatment of a 2-month-old child with refractory 

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-re&shy;sistant 

Despite promising in vitro activity and successful use in a small number of patients, the activity of ceftazidime/avibactam against 

 Against extensively drug-resistant isolates, a novel quadruple-drug combi&shy;nation of ceftazidime/avibactam and piperacillin/ tazobactam has shown promising activity.

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 combina&shy;tion is currently available. No published data are available on the potential utility of other novel β-lactamase inhibitors against 

complex infections. Ceftolozane/tazobactam activity has variable activity against 

complex members and does not add appreciable activity in ceftazidime-resistant strains.

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.

 Against a collection of North American and European gram-negative organisms, cefiderocol demonstrated potent in vitro activity against 

, 0.5 μg/mL; 100% sensitive at a provi&shy;sional breakpoint of 

1 μg/mL, with a single isolate having a MIC of 16 μg/mL.

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 

 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.

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 

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 

, 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, 

, 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.

1.         Abbott IJ, Peleg AY. Stenotrophomonas, Achromobacter, and nonmelioid Burkholderia species: antimicrobial resistance and therapeutic strategies. 

2.         Swenson CE, Sadikot RT. Achromobacter respiratory infections. 

3.         Brooke JS. Stenotrophomonas maltophilia: an emerging global opportunistic pathogen. 

4.         Sfeir MM. Burkholderia cepacia complex infections: More complex than the bacterium name suggest. 

5.         Cystic Fibrosis Foundation. Patient Registry 2017 Annual Data Report. CFF.org. 

https://www.cff.org/Research/Researcher-Resources/Patient-Registry/2017-Patient-Registry-Annual-Data-Report.pdf

. Published August 2018. Accessed August 1, 2019.

6.         Aisenberg G, Rolston KV, Dickey BF, Kontoyiannis DP, Raad, II, Safdar A. Stenotrophomonas maltophilia pneumonia in cancer patients without traditional risk factors for infection, 1997-2004. 

7.         Aisenberg G, Rolston KV, Safdar A. Bacteremia caused by Achromobacter and Alcaligenes species in 46 patients with cancer (1989-2003). 

8.         Vardi A, Sirigou A, Lalayanni C, et al. An outbreak of Burkholderia cepacia bacteremia in hospitalized hematology patients selectively affecting those with acute myeloid leukemia. 

9.         Kim SH, Cha MK, Kang CI, et al. Pathogenic significance of hemorrhagic pneumonia in hematologic malignancy patients with Stenotrophomonas maltophilia bacteremia: clinical and microbiological analysis. 

10.       Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. A Novel Algorithm to Analyze Epidemiology and Outcomes of Carbapenem Resistance Among Patients With Hospital-Acquired and Ventilator-Associated Pneumonia: A Retrospective Cohort Study. 

11.       Schey SA, Kay HE. Myelosuppression complicating cotrimoxazole prophylaxis after bone marrow transplantation. 

12.       Fraser TN, Avellaneda AA, Graviss EA, Musher DM. Acute kidney injury associated with trimethoprim/sulfamethoxazole. 

13.       Mojica MF, Rutter JD, Taracila M, et al. Population Structure, Molecular Epidemiology, and beta-Lactamase Diversity among Stenotrophomonas maltophilia Isolates in the United States. 

14.       Lecso-Bornet M, Bergogne-Berezin E. Susceptibility of 100 strains of Stenotrophomonas maltophilia to three beta-lactams and five beta-lactam-beta-lactamase inhibitor combinations. 

15.       Calvopina K, Hinchliffe P, Brem J, et al. Structural/mechanistic insights into the efficacy of nonclassical beta-lactamase inhibitors against extensively drug resistant Stenotrophomonas maltophilia clinical isolates. 

16.       Castanheira M, Huband MD, Mendes RE, Flamm RK. Meropenem-Vaborbactam Tested against Contemporary Gram-Negative Isolates Collected Worldwide during 2014, Including Carbapenem-Resistant, KPC-Producing, Multidrug-Resistant, and Extensively Drug-Resistant Enterobacteriaceae. 

17.       Grohs P, Taieb G, Morand P, et al. In Vitro Activity of Ceftolozane-Tazobactam against Multidrug-Resistant Nonfermenting Gram-Negative Bacilli Isolated from Patients with Cystic Fibrosis. 

18.       Hsueh SC, Lee YJ, Huang YT, Liao CH, Tsuji M, Hsueh PR. In vitro activities of cefiderocol, ceftolozane/tazobactam, ceftazidime/avibactam and other comparative drugs against imipenem-resistant Pseudomonas aeruginosa and Acinetobacter baumannii, and Stenotrophomonas maltophilia, all associated with bloodstream infections in Taiwan. 

19.       Massip C, Mathieu C, Gaudru C, et al. In vitro activity of seven beta-lactams including ceftolozane/tazobactam and ceftazidime/avibactam against Burkholderia cepacia complex, Burkholderia gladioli and other non-fermentative Gram-negative bacilli isolated from cystic fibrosis patients. 

20.       Mathy V, Grohs P, Compain F. In vitro activity of beta-lactams in combination with avibactam against multidrug-resistant Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Achromobacter xylosoxidans isolates from patients with cystic fibrosis. 

21.       Mazer DM, Young C, Kalikin LM, Spilker T, LiPuma JJ. In Vitro Activity of Ceftolozane-Tazobactam and Other Antimicrobial Agents against Burkholderia cepacia Complex and Burkholderia gladioli. 

22.       Zhanel GG, Lawrence CK, Adam H, et al. Imipenem-Relebactam and Meropenem-Vaborbactam: Two Novel Carbapenem-beta-Lactamase Inhibitor Combinations. 

23.       Mojica MF, Papp-Wallace KM, Taracila MA, et al. Avibactam Restores the Susceptibility of Clinical Isolates of Stenotrophomonas maltophilia to Aztreonam. 

24.       Emeraud C, Escaut L, Boucly A, et al. Aztreonam plus Clavulanate, Tazobactam, or Avibactam for Treatment of Infections Caused by Metallo-beta-Lactamase-Producing Gram-Negative Bacteria. 

25.       Mojica MF, Ouellette CP, Leber A, et al. Successful Treatment of Bloodstream Infection Due to Metallo-beta-Lactamase-Producing Stenotrophomonas maltophilia in a Renal Transplant Patient. 

26.       Milne KE, Gould IM. Combination antimicrobial susceptibility testing of multidrug-resistant Stenotrophomonas maltophilia from cystic fibrosis patients. 

27.       Garcia Sanchez JE, Vazquez Lopez ML, Blazquez de Castro AM, et al. Aztreonam/clavulanic acid in the treatment of serious infections caused by Stenotrophomonas maltophilia in neutropenic patients: case reports

28.       Tooke CL, Hinchliffe P, Lang PA, et al. Molecular Basis of Class A beta-lactamase Inhibition by Relebactam. 

29.       Farrell DJ, Sader HS, Flamm RK, Jones RN. Ceftolozane/tazobactam activity tested against Gram-negative bacterial isolates from hospitalised patients with pneumonia in US and European medical centres (2012). 

30.       Almuzara M, Limansky A, Ballerini V, Galanternik L, Famiglietti A, Vay C. In vitro susceptibility of Achromobacter spp. isolates: comparison of disk diffusion, Etest and agar dilution methods.

31.       Gales AC, Jones RN, Andrade SS, Sader HS. Antimicrobial susceptibility patterns of unusual nonfermentative gram-negative bacilli isolated from Latin America: report from the SENTRY Antimicrobial Surveillance Program (1997-2002). 

32.       Sader HS, Jones RN. Antimicrobial susceptibility of uncommonly isolated non-enteric Gram-negative bacilli. 

33.       Hu Y, Zhu Y, Ma Y, et al. Genomic insights into intrinsic and acquired drug resistance mechanisms in Achromobacter xylosoxidans. 

34.       Doi Y, Poirel L, Paterson DL, Nordmann P. Characterization of a naturally occurring class D beta-lactamase from Achromobacter xylosoxidans. 

35.       Turton JF, Mustafa N, Shah J, Hampton CV, Pike R, Kenna DT. Identification of Achromobacter xylosoxidans by detection of the bla(OXA-114-like) gene intrinsic in this species. 

36.       Bador J, Amoureux L, Duez JM, et al. First description of an RND-type multidrug efflux pump in Achromobacter xylosoxidans, AxyABM. 

37.       Bador J, Amoureux L, Blanc E, Neuwirth C. Innate aminoglycoside resistance of Achromobacter xylosoxidans is due to AxyXY-OprZ, an RND-type multidrug efflux pump. 

38.       Bador J, Neuwirth C, Grangier N, et al. Role of AxyZ Transcriptional Regulator in Overproduction of AxyXY-OprZ Multidrug Efflux System in Achromobacter Species Mutants Selected by Tobramycin. 

39.       Yamamoto M, Nagao M, Hotta G, et al. Molecular characterization of IMP-type metallo-beta-lactamases among multidrug-resistant Achromobacter xylosoxidans. 

40.       Traglia GM, Almuzara M, Merkier AK, et al. Achromobacter xylosoxidans: an emerging pathogen carrying different elements involved in horizontal genetic transfer. 

41.       Farfour E, Trochu E, Devin C, et al. Trends in ceftazidime-avibactam activity against multidrug-resistant organisms recovered from respiratory samples of cystic fibrosis patients. 

42.       Forrester JB, Steed LL, Santevecchi BA, Flume P, Palmer-Long GE, Bosso JA. In Vitro Activity of Ceftolozane/Tazobactam vs Nonfermenting, Gram-Negative Cystic Fibrosis Isolates. 

43.       Gramegna A, Millar BC, Blasi F, Elborn JS, Downey DG, Moore JE. In vitro antimicrobial activity of ceftolozane/tazobactam against Pseudomonas aeruginosa and other non-fermenting Gram-negative bacteria in adults with cystic fibrosis.

44.       Mahenthiralingam E, Baldwin A, Dowson CG. Burkholderia cepacia complex bacteria: opportunistic pathogens with important natural biology.

45.       Galyov EE, Brett PJ, DeShazer D. Molecular insights into Burkholderia pseudomallei and Burkholderia mallei pathogenesis. 

46.       Sousa SA, Ramos CG, Leitao JH. Burkholderia cepacia Complex: Emerging Multihost Pathogens Equipped with a Wide Range of Virulence Factors and Determinants. 

47.       Rhodes KA, Schweizer HP. Antibiotic resistance in Burkholderia species. 

48.       Podnecky NL, Rhodes KA, Schweizer HP. E ffl ux pump-mediated drug resistance in Burkholderia. 

49.       Poirel L, Rodriguez-Martinez JM, Plesiat P, Nordmann P. Naturally occurring Class A ss-lactamases from the Burkholderia cepacia complex. 

50.       Hwang J, Kim HS. Cell Wall Recycling-Linked Coregulation of AmpC and PenB beta-Lactamases through ampD Mutations in Burkholderia cenocepacia. 

51.       Tseng SP, Tsai WC, Liang CY, et al. The contribution of antibiotic resistance mechanisms in clinical Burkholderia cepacia complex isolates: an emphasis on efflux pump activity. 

52.       Papp-Wallace KM, Becka SA, Zeiser ET, et al. Overcoming an Extremely Drug Resistant (XDR) Pathogen: Avibactam Restores Susceptibility to Ceftazidime for Burkholderia cepacia Complex Isolates from Cystic Fibrosis Patients. 

53.       Van Dalem A, Herpol M, Echahidi F, et al. In Vitro Susceptibility of Burkholderia cepacia Complex Isolated from Cystic Fibrosis Patients to Ceftazidime-Avibactam and Ceftolozane-Tazobactam. 

54.       Tamma PD, Fan Y, Bergman Y, et al. Successful Treatment of Persistent Burkholderia cepacia Complex Bacteremia with Ceftazidime-Avibactam. 

55.       Spoletini G, Etherington C, Shaw N, et al. Use of ceftazidime/avibactam for the treatment of MDR Pseudomonas aeruginosa and Burkholderia cepacia complex infections in cystic fibrosis: a case series. 

56.       Zeiser ET, Becka SA, Wilson BM, Barnes MD, LiPuma JJ, Papp-Wallace KM. "Switching Partners": Piperacillin-Avibactam Is a Highly Potent Combination against Multidrug-Resistant Burkholderia cepacia Complex and Burkholderia gladioli Cystic Fibrosis Isolates. 

57.       Jean SS, Hsueh SC, Lee WS, Hsueh PR. Cefiderocol: a promising antibiotic against multidrug-resistant Gram-negative bacteria.

58.       Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF. In Vitro Activity of the Siderophore Cephalosporin, Cefiderocol, against a Recent Collection of Clinically Relevant Gram-Negative Bacilli from North America and Europe, Including Carbapenem-Nonsusceptible Isolates (SIDERO-WT-2014 Study). 

59.       Rolston KVI, Gerges B, Raad I, Aitken SL, Reitzel R, Prince R. 1375. In vitro Activity of Cefiderocol and Comparator Agents against Gram-Negative Isolates from Cancer Patients. 

Articles

Novel β-lactam/β-lactamase inhibitor combinations and cefiderocol may play a part in the treatment of infections caused by Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Burkholderia cepacia complex. 

Sarah L. Spitznogle, PharmD*

Articles

Latest News