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Cited by 33Antibiotic Resistance in BacteriaAntibiotic Use and ResistanceInfections and bacterial resistance

The real crisis in antimicrobial resistance: failure to anticipate and respond

Open access
Bonomo, Robert A, Perez, Federico, Hujer, Andrea M, Hujer, Kristine M, Vila, Alejandro J·2024·Clinical Infectious Diseases
DOI 10.1093/cid/ciad758
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Abstract

Encountering multidrug-resistant (MDR) Gram-negative infections in critically ill patients has become an all-too-common occurrence in healthcare settings. Increasingly, clinicians are faced with pathogens that are “untreatable,” forcing them to design or implement novel or unproven combinations of antibiotics to address treatment dilemmas. In most cases, these untreatable pathogens possess a wide variety of resistance determinants that when combined create an “antimicrobial resistance nightmare”. Notably, the most problematic phenotypes include carbapenem resistance mediated by the expression of metallo-β-lactamases (eg, NDM, IMP, VIM, or L1) and/or serine carbapenemases (eg, KPC, OXA-23, OXA-24, or OXA-48). Oxyimino-cephalosporin resistance can be manifested in Gram-negative bacteria by inducible chromosomal cephalosporinases (eg, AmpCs like P99 and CMY-2) and extended-spectrum β-lactamases (eg, CTX-M-15 ESBLs). In the company of numerous aminoglycoside modifying enzymes, altered penicillin binding proteins, upregulated efflux pumps, target site modifications, membrane changes, and porin deletions, some bacteria are resistant to all known antibiotics. This is not a new story; it is just becoming more and more frequent. The Infectious Diseases Societies of Europe (European Society of Microbiology and Infectious Diseases [ESCMID]) and the United States (Infectious Diseases Society of America [IDSA]) recognize this crisis and have wisely created Guidelines and Guidance to assist clinicians [1, 2]. The pharmaceutical industry is also trying to assist and meet this challenge with the promise and intense development of new broad-spectrum therapeutic agents that will overcome these MDR pathogens. The most aggressive and forceful therapeutic development so far has been in the area of β-lactam and β-lactam/β-lactamase inhibitor combinations. Fortunately, some have been approved (eg, ceftazidime/avibactam, imipenem/relebactam, meropenem/vaborbactam, ceftolozane/tazobactam, and sulbactam/durlobactam), and many are in or completed Phase III trials (eg, cefepime/taniborbactam, cefepime/zidebactam) and will soon be ready for regulatory agencies to evaluate and hopefully for clinicians to use. Other promising therapeutics are on the horizon as well (eg, cefiderocol/xeruborbactam and cefepime/enmetazobactam). Agents that are improvements of the existing aminoglycoside and tetracycline classes, such as eravacycline, omadacycline, and plazomicin, could also potentially play a role. We will anxiously await the progress of Zosurabalpin as it makes its way to clinical trials [3]. As is widely recognized, getting a new antibiotic to market is not easy, guaranteed, or profitable in our current economic climate [4]. It is also very difficult to find an appropriate role for some of these agents. Most concerning is the accelerated development of resistance to novel agents that may not follow previously established patterns (Figure 1). We are now observing that resistance to more recent antibiotics introduced into the clinic is present before their commercial release [5–14]. A, The previous paradigm in the development of antibiotic resistance. Antibiotics are developed and then resistance is reported. B, The current paradigm in antibiotic resistance. Drug resistance is discovered and detected while the antibiotics are in the preclinical development phase. Abbreviations: PDR, pan drug resistance; XDR, extreme drug resistance. In this issue of Clinical Infectious Diseases, we encounter a tragic case report that challenges even our best efforts. In brief, Dr Senchyna and coauthors from the clinical microbiology laboratory of Dr Niaz Banaei at Stanford Hospital recount a fatal case of relapsing NDM-producing Escherichia coli bacteremia in a severely immunocompromised 12-year-old child. Blood cultures were positive on initial evaluation and on hospital days 26 and 36. A venous catheter for hemodialysis access was implicated, and a PICC was placed while the patient was bacteremic; both were eventually removed on hospital day 26. The initial bacteremia responded to the combination aztreonam plus ceftazidime/avibactam at recommended doses, as suggested by expert guidance from both IDSA and ESCMID as a treatment option for MBL producing Enterobacteria [1, 2]. Careful microbiological testing was also performed demonstrating activity of aztreonam and ceftazidime/avibactam. Fortunately, new microbiological testing guidance have just been approved by the Clinical and Laboratory Standards Institute (CLSI) so that clinicians can determine if this is a potentially appropriate choice for their patients [14]. In choosing this therapy, the treating team rightly considered that although observational studies report almost 80%–90% treatment response with this combination [15, 16], a prospective randomized clinical trial to confirm that this combination is the optimal choice for the treatment of MBL-producing Enterobacteria does not yet exist. Moreover,

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  • The rising mortality due to carbapenem-resistant Gram-negative bacteria is cause for concern, with problematic phenotypes becoming increasingly common.

    “The rising mortality due to carbapenem-resistant Gram-negative bacteria is cause for concern,69 with problematic phenotypes becoming increasingly common.”

    From Global burden of bacterial antimicrobial resistance 1990–2021: a systematic analysis with forecasts to 2050 (2024) · cites this paper as [69]

    The citation follows the mortality clause. The paper describes a fatal case of resistant E. coli bacteremia (Abstract, page unavailable) and calls multidrug-resistant pathogens a crisis (What Can we do About it?, page unavailable), but it does not report that mortality from carbapenem-resistant Gram-negative bacteria is rising. Its statement that resistance is becoming more frequent does not establish a mortality trend. (LLM, conf=0.80)

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Authors
Bonomo, R. A., Perez, F., Hujer, A. M., Hujer, K. M., & Vila, A. J.
Affiliations
  • Louis Stokes Cleveland VA Medical Center (US)
  • Louis Stokes Cleveland Department of Veterans Affairs Medical Center , Cleveland, Ohio , USA
  • Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
Corresponding author
Bonomo, Robert A
ORCID
Venue
Clinical Infectious Diseases
Publisher
Oxford University Press (OUP)
Published
2024-01-30
Volume
78
Issue
6
Pages
1429-1433
ISSN
  • 1058-4838 (ISSN-L)
  • 1537-6591
DOI
10.1093/cid/ciad758
OpenAlex
W4391345061
Cited by
33
References
30
Citations by year
2026: 10 · 2025: 19 · 2024: 4
FWCI
2.82
Type
journal article
Language
en
Open access
Licence
public-domain
Locations
  • Clinical Infectious Diseases (publishedVersion, public-domain)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
  • Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Antibiotic Use and Resistance
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Infections and bacterial resistance
Keywords
antimicrobial resistance, multidrug-resistant Gram-negative bacteria, carbapenem resistance, metallo-beta-lactamase, serine carbapenemases, extended-spectrum beta-lactamase, aminoglycoside-modifying enzymes, efflux pumps, beta-lactamase inhibitors, ceftazidime-avibactam, meropenem-vaborbactam, combination antibiotic therapy
MeSH terms
Anti-Bacterial Agents, Bacterial Infections, Humans, Drug Resistance, Bacterial

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