Antibiotic Innovation Is Losing Ground to Gram-Negative Bacteria

Gram-negative pathogens are gaining ground against antibiotics as fewer new agents are being developed to combat antimicrobial resistance (AMR).¹ Antibiotics are one of medicine’s greatest achievements, yet their misuse has led to a public health threat.

What’s in development?

Of the more than 30 antimicrobials in development in the United States and Europe, most are from existing antibiotic classes.¹ When new agents are approved, many pivotal trials are based on the drug’s noninferiority in complicated urinary tract infections (cUTI) and complicated  intra-abdominal infections (cIAI), but not in more serious blood stream infections (BSI), which have higher mortality rates than cUTIs and cIAIs.¹ In the near term, the most promising agents to fight resistance are combinations of agents from different classes.¹

There are many antibiotic combinations in development or undergoing trials, including the β-lactam/β-lactamase inhibitors such as ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, meropenem/vaborbactam, and aztreonam/avibactam. Single agents include cefiderocol, plazomicin, and eravacycline. The pipeline is lacking in oral agents and agents that target Acinetobacter baumannii.¹

Which Agents Hold the Most Promise?

Before the emergence of new agents to eradicate multidrug-resistant pathogens, clinicians had been turning to older antibiotics such as colistin.¹ The novel aminoglycoside plazomicin was compared with colistin (polymyxin E) in a study (N=69) to treat carbapenem-resistant Enterobacteriaceae (CRE) infections in bloodstream infection (BSI) (ClinicalTrials.gov identifier: NCT01970371).²

At day 5, 85.7% of patients treated with plazomicin had CRE bacteremia clearance vs 46.7% of patients in the colistin group.² Moreover, at day 28, 40% of patients in the plazomicin group were alive vs 7.1% of patients in the colistin group (90% CI –60.1 to –4.0).² There was a lower incidence of drug-related adverse events in the plazomicin group vs the colistin group, which consisted of mostly serum creatinine elevations.²

In some cases, combining agents may prove to be more effective than using a single agent. One such combination is ceftazidime-avibactam (CEF/AVI), a cephalosporin-β-lactamase inhibitor, for CRE infections.¹ In 60 severely ill hospitalized patients, CEF/AVI demonstrated its effectiveness: 65% of patients had clinical success, 53% had a microbiological cure, and 32% died in the hospital.³

“We collected evidence that supports ceftazidime-avibactam for CRE infections,” says Jason C. Gallagher, PharmD, FCCP, FIDSA, BCPS, clinical professor and director of

PGY2 residency in infectious diseases pharmacy at Temple University in Philadelphia, Pennsylvania. “That coupled with evidence from other investigators supports that this should be a first-line drug for infections caused by these resistant organisms.”

Of all the agents in development, cefiderocol, a siderophore cephalosporin, holds the most promise because it has the broadest coverage against class A, B, C, and D β-lactamase organisms, carbapenem-resistant A baumannii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia.¹

In a phase 3 trial, cefiderocol was compared with imipenem/cilastatin in 452 hospitalized patients with cUTI.⁴ The test-of-cure rate was 72.6% in the cefiderocol group vs 54.6% in the imipenem/cilastatin group (P =.0002). The primary pathogens were Escherichia coli and Klebsiella pneumoniae.⁴

What Can Clinicians and Patients Do to Prevent Further Antibiotic Resistance?

“The prevention of Gram-negative resistance will hinge on how responsibly physicians wield the power of antibiotics,” says James A. McKinnell, MD, assistant professor of medicine, David Geffen School of Medicine, University of California, Los Angeles. “The irresponsible physician who treats a viral infection with antibiotics, treats asymptomatic urinary colonization, or extends treatment beyond current recommendations (eg, 5 days for community-associated pneumonia, 7 days for healthcare-associated pneumonia) simply creates a legacy problem of antibiotic resistance that will increase their patient’s risk of death from a subsequent infection and increase work for their colleagues who must manage these patients.” 

As part of antibiotic stewardship, many clinicians are turning to point-of-care diagnostics to identify the pathogen.¹ Such tests may prevent empiric prescribing and thus preserve the newer agents.¹

“The most important things are to minimize modifiable risk factors, including antibiotic use,” says Dr Gallagher. “These patients often have multiple comorbid conditions and their infections are often a marker of their illness as much as a cause. Minimizing antibiotic use where possible and giving shortest possible durations of therapy for proven infections is key.”

Recognizing that antibiotic resistance is a critical global problem, the World Health Organization (WHO) has urged clinicians to slow antibiotic resistance by:⁵

• Ensuring that hands, instruments, and the environment are clean
• Hewing to updated guidelines and prescribing antibiotics only when they are essential
• Reporting AMR infections to surveillance teams
• Instructing patients how to take antibiotics correctly and explaining the dangers of AMR
• Encouraging patients to prevent infections (eg, vaccination, hand hygiene, safer sex, and covering nose and mouth when sneezing).

In addition to WHO sounding the global AMR alarm, individual governments are working on regional efforts to inform clinicians and the public about the urgent need for antimicrobial stewardship.⁵ To speed new agents to market, the US government has provided financial incentives and an expedited review process through the Generating Antibiotic Incentives Now program.⁶ In Europe, the Innovative Medicines Initiative’s program New Drugs 4 Bad Bugs is encouraging private-public partnerships to generate pharmaceutical innovations where they are most needed.⁷                                                             

Meanwhile, Dr McKinnell cautions, “Patients and patient’s families need to consider the risk of side effects for antibiotics. In all circumstances, antibiotics should be considered a last-line approach to the management of infections, not our first short-cut solution.”

Summary & Clinical Applicability

The introduction of new antibiotics to eradicate Gram-negative pathogens has not kept pace with antibiotic resistance. Clinicians must use existing and newer antibiotics judiciously to prevent further antibiotic resistance.

References

1. Wright H, Bonomo RA, Paterson DL. New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn? Clin Microbiol Infect. 2017;23:704-712.
2. McKinnell JA, Connolly LE, Pushkin R, et al. Improved outcomes with plazomicin compared with colistin in patients with bloodstream infections caused by carbapenem-resistant Enterobacteriaceae (CRE): results from the CARE study. Poster presented at IDWeek, October 4-8, 2017, San Diego, California. Poster 1853.
3. King M, Heil E, Kuriakose S, et al. Multicenter study of outcomes with ceftazidime-avibactam in patients with carbapenem-resistant Enterobacteriaceae infections. Antimicrob Agents Chemother. 2017;61:e00449-7.  doi:10.1128/AAC.00449-17
4. Portsmouth S, Vennhuyzen D, Echols R, et al. Cefiderocol compared with imipenem/cilastatin in the treatment of adults with complicated urinary tract infections with or without pyelonephritis or acute uncomplicated pyelonephritis: results from a multicentre, doubleblind, randomized study. Paper presented at: 27th European Congress of Clinical Microbiology and Infectious Diseases; April 22-25, 2017; Vienna, Austria. Poster OS0250D.
5. World Health Organization (WHO). Antibiotic resistance fact sheet. Updated November 2017.  www.who.int/mediacentre/factsheets/antibiotic-resistance/en/. Accessed November 29, 2017.
6. US Food and Drug Administration. FDA approves new antibacterial drug. August 29, 2017. Accessed November 29, 2017.
7. Innovative Medicines Initiative. New Drugs for Bad Bugs: The Innovative Medicines Initiative response to antimicrobial resistance. Accessed November 29, 2017.