Diagnosis and Management of Gram-Negative Nosocomial Infections

ContagionJune 2018
Volume 3
Issue 3

Patient and institutional history, as well as the individual niches of the new antibiotics, need to be considered when selecting a treatment for gram-negative infections.

Rapid diagnostic tests, distribution of local antibiograms, and cephalosporin/β-lactamase inhibitor antibiotics have improved the treatment of gram-negative nosocomial infections. However, patient and institutional history, as well as the individual niches of the new antibiotics, need to be considered when selecting a treatment, according to the participants of a Contagion® Peer Exchange panel.


Key considerations when choosing a treatment for gram-negative nosocomial infections include whether the patient was recently hospitalized or in a long-term acute care hospital as well as the level of susceptibility for certain pathogens based on institutional history, according to Sandy J. Estrada Lopez, PharmD. “If I’ve never seen a CRE [carbapenem-resistant Enterobacteriaceae] before, then, yes, I’m aware of it, but I’m not probably going to say, ‘Oh, I really think we should empirically cover for it until I do start seeing it,” she said.

Debra Goff, PharmD, noted that the threshold for selecting one of the new agents for gram-negative bacteria also depends on the patient characteristics and will likely be different for a 23-year-old with a bone marrow transplant than a 90-year-old from a nursing home, even if they have an equal risk of multidrug-resistant gram-negative infection.

Clinicians also need to consider the clinical evidence supporting the drug in certain disease states or syndromes, according to Andrew Shorr, MD. “The history of drug development is littered with pneumonia failures,” he said. “It looked great in the urine or looked great in skin, and [then] they studied it in pneumonia, and it didn’t work because it was inactivated by surfactant [or] underdosed because of lung penetration.”

Jason Pogue, PharmD, BCPS-AQID, countered that finding robust clinical trial data is impractical when considering some of the new agents for treating extremely drug-resistant infections, Pseudomonas, or CRE. “If the right preclinical work is done, you can predict…a pretty good likelihood of having a good outcome in that situation,” he said.

The patient’s renal function needs to be considered, Dr. Shorr said, because the nephrotoxicity of an antibiotic or antibiotic combination, which is often overlooked by clinicians, can lead to dangerous outcomes. For example, the combination of piperacillin/tazobactam and vancomycin demonstrated an increased incidence of nephrotoxicity over vancomycin alone.1 “The interaction might be something here that we never consider,” he said. “This might be dangerous because of what this kind of penicillin is doing with this kind of glycopeptide. I think all those things need to go into consideration.”


According to the panelists, rapid diagnostic tests and education of clinicians on the institution’s antibiogram have been instrumental for selecting the most appropriate treatment for gram-negative nosocomial infections within hours of presentation.

Rapid Diagnostic Tests

One of the first rapid diagnostic tests, an instrument by Cepheid that differentiates between MRSA (methicillin-resistant Staphylococcus aureus), MSSA (methicillin-sensitive S aureus), and coagulase-negative S aureus, was a game changer in the management of Staphylococcus infections at Ohio State University, according to Dr. Goff. “We could get patients on appropriate Staphylococcus therapy faster, and we actually had a trend toward a lower mortality,” she said.

She also noted that a new T2 test for Candida, which detects the specific species within 2 to 3 hours, helps identify the antifungal agent most likely to work, thus improving on the traditional paradigm of selecting an agent empirically and changing therapies, if necessary, when blood cultures come back in 3 or 4 days.

However, Dr. Pogue noted that many physicians may need education on how to interpret the results of the rapid diagnostic tests. “[The test] will tell you the bug, it will tell you certain resistance genes— there are 4 paragraphs of information that pop up,” he said. “It’s hard to even know what is positive when you’re looking at that.”


Knowing the antibiogram of the hospital—even of the specific department—is essential to ensure a high percentage of empiric coverage for gram-negative infections, according to Dr. Shorr. However, Dr. Goff noted, most hospital physicians are unaware of the most common pathogens at their hospital and how to access their antibiogram.

Drs. Shorr and Salgo said that measures taken by their respective institutions have helped educate clinicians. The unit directors at MedStar Washington Hospital Center are responsible for understanding and disseminating the local specific antibiogram to the clinicians; at NewYork-Presbyterian Hospital, physicians have been rounding in the intensive care unit with PharmDs who know the local antibiogram and appropriate antibiotics.


Meropenem/vaborbactam (Vabomere) was approved in 2017 based on the TANGO II study showing that the combination antibiotic had better efficacy, safety, and tolerability than best available therapy for CRE.2 “It’s the first real study that was trying to do a pathogen-directed study,” Dr. Pogue said. “They did a pragmatic study of patients who had either suspected or documented CRE infections. As you can imagine, that makes a mess of a clinical trial.”

The patients in TANGO II were notably sicker, with a higher mortality rate than those observed historically in randomized or nonblinded trials, Dr. Shorr noted. The signal suggesting improved outcomes with meropenem/vaborbactam was sufficient to terminate the trial early despite its small sample size. “I think we’re finally beginning to see data emerge where they’re actually taking the drugs that are designed for specific pathogens and doing studies in populations and disease states that prove the drug doesn’t kill anybody [and] does what it’s supposed to do,” he said.


The 3 new cephalosporin/β-lactamase inhibitors— meropenem/vaborbactam, ceftazidime/avibactam (Avycaz), and ceftolozane/tazobactam (Zerbaxa)—have a diverse spectrum of activity for treating gram-negative nosocomial infections; knowing where each is best utilized is critical for optimizing treatment, according to Dr. Goff. Meropenem/vaborbactam and ceftazidime/ avibactam are best targeted toward CRE, she said, whereas ceftolozane/ tazobactam is best targeted toward Pseudomonas: “They’re very targeted agents. They’re not the catchall.”

Dr. Pogue agreed that these combination antibiotics should be viewed as 3 individual agents, rather than a class of drug, and understanding each combination’s particular niche and how it performs as well as the local biology, are crucial for deciding which to use at a particular institution.

The activity of the 2 antibiotics in combination may also influence selection, Drs. Pogue and Shorr noted. For example, the extended infusion of meropenem optimizes its pharmacokinetics and may be effective against highly resistant Pseudomonas cases; ceftolozane/tazobactam has extended-spectrum β-lactamase activity, and ceftazidime/avibactam may be effective against cases that are resistant to ceftazidime alone. However, Dr. Shorr cautioned that these attributes should not be the primary deciding factor for selecting an agent: “We don’t want [the antibiotics] abused just because they can do something else.”

Despite their promise for gram-negative infections, Dr. Shorr warned about the risk of emergence of resistance to therapy and the need for judicious use of these new combination antibiotics. “If you use [Avycaz] over and over again in the same patient, you will create a clone that is causing an infection that is Avycaz-resistant,” he said. “The principles of stewardship become that much more important if you’re going to bring one of these drugs into your hospital.”


  1. Burgess LD, Drew RH. Comparison of the incidence of vancomycin-induced nephrotoxicity in hospitalized patients with and without concomitant piperacillin-tazobactam. Pharmacotherapy. 2014 Jul;34(7):670-676. doi:10.1002/phar.1442.
  2. Wunderink R, Giamarellos-Bourboulis E, Rahav G, et al. Meropenem-vaborbactam vs best available therapy for carbapenem-resistant Enterobacteriaceae infections in TANGO II: primary outcomes by site of infection. Open Forum Infect Dis. 2017 Oct;4(suppl 1):S536—S537. doi:10.1093/ofid/ofx163.1397.
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