June 22, 2017
5 min read

Code red for MDR bacteria: Resistance to carbapenems doubles in ICUs

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Four years ago, the CDC’s Antibiotic Resistance Threats in the United States report warned that inaction could have “potentially catastrophic consequences.” Today, these threats are even more prevalent, particularly regarding multidrug-resistant, or MDR, bacteria. Consider:

Thomas P. Lodise
  • A new study suggests that nonsusceptibility to carbapenem antibiotics — considered by many as a last resort treatment for patients with serious gram-negative infections — is almost twice as high in bacteria isolated from ICUs than from those isolated from non-ICU treatment settings (9.6% vs. 5.1%; P < .0001). This was true for patients who presented with a gram-negative infection at admission (6.4% vs. 3.5%; P < .001) as well as those with hospital-onset gram-negative infections (13.9% vs. 7%; P < .001).
  • In this study, rates of carbapenem nonsusceptible P. aeruginosa were 30% among patients in the ICU and 19% among patients in non-ICU settings. Carbapenem nonsusceptibility also exceeded 5% for patients with infections due to Morganella morganii, Enterobacter cloacae, E. aerogenes, Citrobacter freundii and Klebsiella pneumoniae.
  • In addition to rising rates of carbapenem resistance among patients with gram-negative infections, a report published in The Lancet identified a new mcr-1 gene in Escherichia coli singularly resistant to colistin, a last-line antibiotic that some microbiologists have called “the Holy Grail of resistance.” Moreover, mcr-1 is easily transferred to other bacteria; within a year of its discovery on a pig farm in China, it has been found in infected patients around the world. If a bacterium with genes that make it resistant to every other drug picks up mcr-1, a nightmare scenario — panresistant bacteria — becomes all too real.

Need for real-world, patient-level data

Infections due to MDR gram-negative bacteria typically affect the most vulnerable patients — a rapidly growing segment of the population due to demographics, longer lifespans and the fact that more people have multiple chronic diseases that weaken their immune systems. CDC data show that at least 2 million people annually acquire serious infections with bacteria that are resistant to one or more of the antibiotics designed to treat those infections. At least 23,000 people die each year as a direct result of these antibiotic-resistant infections, and many more die from other conditions that were complicated by these infections. More alarming, there are increasing reports of MDR gram-negative infections in the community setting among patients without any of the traditional “antibiotic resistance” risk factors (ie, prior antibiotic exposure, residence in a health care facility, etc.).

Hospitals and health care professionals must be acutely aware that infections due to MDR gram-negative bacteria can appear without warning anytime, anywhere. For example, the incidence of carbapenem-resistant K. pneumoniae pathogens rose from less than 0.1% to 4.5% from 2002 to 2010. Nationwide, more than 14% of P. aeruginosa, which the CDC specifically identifies as a serious threat, are resistant to antibiotics in at least three categories.


These developments and the continuing spread of the mcr-1 gene (which has been found in bacteria in humans in 10 states) elevate the importance of hospitals’ vigilance in using antibiograms, the periodic summaries of antimicrobial susceptibilities of local bacterial isolates. The CDC includes two functions of cumulative antibiograms as “core” elements of hospital antimicrobial stewardship programs: (1) tracking antimicrobial resistance, and (2) regular reporting of information on antibiotic resistance to relevant hospital staff.

Growing rates of patients with infections due to MDR gram-negative bacteria are concerning for two primary reasons. First, there are limited treatment options for patients with these infections, and clinicians often must rely on antibiotics and combinations of antibiotics that have not been vetted in randomized clinical trials to treat patients with MDR gram-negative infections. Second, patients with MDR gram-negative infections are at an increased risk for delayed administration of a microbiologically active antibiotic, and numerous investigators in various practice settings across various infection types and pathogens have correlated the risk of a poor outcome to treatment delays.

Clinicians can use antibiograms to assess local susceptibility rates, determine empiric antibiotic therapy and monitor resistance trends over time within an institution or treatment setting. They also can be used by infection control practitioners to design, implement and adjust institutional antimicrobial stewardship practices.

Real-world data, ideally at the patient level, will lead to a better understanding of the full burden of infections due to MDR gram-negative bacteria on both patients and health care systems. An analysis presented at the recent European Congress of Clinical Microbiology and Infectious Diseases, or ECCMID, found that although various sources for real-world, patient-level data relating to carbapenem resistance are available in the U.S. and Europe, economic outcomes data are scant.

An expanding role for manufacturers

The pharmaceutical industry will play a key role in helping hospitals and health care professionals combat this threat. Manufacturers should take the lead in advancing technology and research for both molecular characterization and surveillance techniques and practices. The latter will provide invaluable empirical data on not only epidemiology but also prescribing patterns relating to both the treatment setting and targeted bacteria. This knowledge can provide an evidence-based foundation for antimicrobial stewardship programs and guide practitioners in determining which new drugs are most appropriate for patients.

As bacteria strengthen their resistance to standard therapies, hospital pharmacies clearly need more than one or two drugs on their shelves to effectively treat all the different types of patients with MDR gram-negative infections. The CDC recommended the development of new antibiotics as a core action, and the Pew Trust’s Scientific Roadmap for Antibiotic Discovery notes that a “sustained and robust pipeline of new antibacterial drugs and therapies is critical to preserve public health.”

Although no new classes of antibiotics have been registered with the FDA in more than 30 years, drug manufacturers have been able to restore susceptibility to gram-negative bacteria by combining different drug classes. For example, Zerbaxa (Cubist), a combination of ceftolozane, a novel cephalosporin, and tazobactam, a beta-lactamase inhibitor, is indicated in adult patients with complicated urinary tract infections caused by E. coli, K. pneumoniae, Proteus mirabilis and P. aeruginosa. Avycaz (Allergan) is another relatively new agent for the treatement of MDR gram-negative bacteria that combines ceftazidime, a third-generation antipseudomonal cephalosporin, and avibactam, a non–beta-lactam beta-lactamase inhibitor.

The actions of hospitals and health care professionals are our last line of defense against the assault of MDR gram-negative bacteria. According to a MMWR report, “If best infection control practices and antibiotic stewardship were nationally adopted, more than 600,000 infections and 37,000 deaths could be prevented over 5 years.”

Disclosure: Lodise is a consultant for Allergan, Merck, Zavante, and Achaogen.