The Threat of Gram-Negative Antimicrobial Resistance

Antimicrobial resistance of Gram-negative bacteria continues to persist as a global crisis that threatens the pharmacotherapeutic options available to treat these infections. Carbapenem-resistant Enterobacterales (CRE), extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P aeruginosa) have been designated as urgent or serious threats by the Centers for Disease Control and Prevention.¹

These 3 groups of pathogens present therapeutic challenges to patients nationwide. In the United States, more than 13,000 nosocomial CRE infections lead to more than 1000 deaths annually, most commonly caused by Klebsiella pneumoniae carbapenemases (KPC). From 2012 through 2017, the incidence of ESBLE-E infection has increased by 53% in the United States. The most prevalent Gram-negative pathogens displaying this resistance are Escherichia coli, Proteus mirabilis, and Klebsiella oxytoca. In 2017, 32,600 patients experienced DTR-P aeruginosa infection that resulted in 2700 deaths in the United States.¹

The following charts outline current antibiotic treatment for specific infection sources recommended by a panel of infectious disease specialists from the Infectious Diseases Society of America in 2020.¹

Current Antibiotic Treatment for CRE Infections

Infection Source	Recommended Treatment
Uncomplicated cystitis	Ciprofloxacin, levofloxacin, trimethoprim-sulfamethoxazole, nitrofurantoin, aminoglycoside (single dose)   Meropenem (ertapenem-resistant, meropenem-susceptible, and carbapenemase testing results not available or negative)
Pyelonephritis and complicated urinary tract infection	Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, cefiderocol   Meropenem (ertapenem-resistant, meropenem-susceptible, and carbapenemase testing results not available or negative)
Infection outside of urinary tract   (Ertapenem-resistant, meropenem-susceptible, and carbapenemase testing results not available or negative)	Meropenem
Infection outside of urinary tract   (Ertapenem-resistant, meropenem-resistant, and carbapenemase testing results not available or negative)	Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam
Klebsiella pneumoniae carbapenemase	Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam
Metallo-β-lactamase carbapenemase	Ceftazidime-avibactam plus aztreonam, cefiderocol
OXA-48-like carbapenemase	Ceftazidime-avibactam

Current Antibiotic Treatment for ESBLE-E Infections

Infection Source	Recommended Treatment
Uncomplicated cystitis	Nitrofurantoin, trimethoprim-sulfamethoxazole
Pyelonephritis and complicated urinary tract infection	Ertapenem, meropenem, imipenem-cilastatin, ciprofloxacin, levofloxacin, trimethoprim-sulfamethoxazole
Infection outside of urinary tract	Ertapenem, meropenem, imipenem-cilastatin

Current Antibiotic Treatment for DTR-P aeruginosa Infections

Infection Source	Recommended Treatment
Uncomplicated cystitis	Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, cefiderocol, aminoglycoside (single dose)
Pyelonephritis and complicated urinary tract infection	Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, cefiderocol
Infection outside of urinary tract	Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam

A Closer Look at CRE Treatment Recommendations

In patients with pyelonephritis or complicated urinary tract infections, a full treatment course of plazomicin once daily can be used for those without the potential for nephrotoxicity. In a clinical trial that included patients with these infections, once-daily plazomicin demonstrated noninferiority to meropenem.¹ Additionally, a study found higher percentages of clinical CRE isolates susceptible to plazomicin and amikacin than to other aminoglycosides.²

Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam are recommended for CRE infections outside of the urinary tract that are resistant to both ertapenem and meropenem due to the associated improved clinical outcomes and reduced toxicities compared with other CRE antimicrobial agents. A few limited studies compared the efficacy of these drugs to determine the preferred treatment; an observational study revealed no difference in clinical outcomes between ceftazidime-avibactam and meropenem-vaborbactam therapy. Other data have shown ceftazidime-avibactam resistance developing more frequently than meropenem-vaborbactam resistance following antibiotic exposure.^1,3

An alternative agent for CRE infections regardless of resistance mechanism is cefiderocol. This option should be reserved for use after treatment failure of preferred antibiotics due to a trial indicating 28-day mortality to be higher in the cefiderocol arm, specifically in patients with pneumonia and bloodstream infections.⁴

When treating infections caused by CRE, combination therapy is not routinely recommended. There is a lack of data supporting additional benefit of combination therapy once the β-lactam agent has exhibited activity against the pathogen. On the other hand, continuing the use of a second antibiotic increases the risk of antibiotic-associated adverse events and the potential for resistance to emerge.¹

Additionally, polymyxin B and colistin should be avoided due to increased nephrotoxicity and mortality. However, if necessary, colistin can be used as a last resort option for uncomplicated cystitis.¹

Diving Deeper Into CRE Antimicrobial Resistance

To combat the threat of antimicrobial resistance to treatment and clinical outcomes of hospital-acquired infections, new agents must be researched and developed to demonstrate efficacy against Gram-negative bacteria. More importantly, these newer antibiotics must be used with utmost vigilance to avoid emergence of resistance and to ensure their longevity in clinical practice. Carbapenem resistance poses a serious threat to therapeutic options due to the inactivation of a potent antibiotic class and β-lactams, resulting in a lack of treatment alternatives and ultimately poor health outcomes.⁵

Ceftazidime-avibactam is a combination of a non-β-lactam β-lactamase inhibitor and a broad-spectrum cephalosporin that has potent activity against the majority of β-lactams and multidrug-resistant bacteria, includingKPC and OXA producers. Because of the wide range of antimicrobial coverage, this antibiotic is a significant part of empiric therapy in patients with related risk factors. It should be noted that this agent has an excellent safety profile with mild major adverse events that include headache, nausea, and diarrhea, among others.⁵

Meropenem-vaborbactam is a non-β-lactam β-lactamase inhibitor boronic acid with no antimicrobial activity combined with meropenem, which restores the activity of the carbapenem against KPC-producing bacteria because of the high affinity for serine proteases. The first carbapenem/β-lactamase inhibitor combination available for clinical use, this antibiotic has an excellent safety and tolerability profile. The potent in vitro activity against KPC producers and the low potential for emergence of resistance are 2 major advantages of this agent.⁵

Imipenem-cilastatin-relebactam inhibits class A carbapenemases and class C cephalosporinases as a non-β-lactam β-lactamase inhibitor and carbapenem combination. A study revealed that patients treated with this antibiotic had lower risk of 28-day mortality and lower rates of drug-related nephrotoxicity compared with those treated with imipenem-cilastatin.⁶

Despite the development of these newer agents to treat infections caused by CRE and other Gram-negative multidrug-resistant pathogens, antimicrobial stewardship is essential to avoid inappropriate use of these antibiotic combinations to avoid the development of resistance.

Current Pipeline Drugs for CRE

Taniborbactam (VNRX-5133) is a novel, broad-spectrum bicyclic boronate β-lactamase inhibitor undergoing phase 3 clinical trials used in combination with cefepime. A study investigated taniborbactam’s in vitro activity against various enzyme mutations of metallo-β-lactamases. The inhibition of enzyme levels by taniborbactam was found to preserve cefepime’s antimicrobial activity.⁶ Other studies have showed taniborbactam to potentiate the activity of the combined β-lactam against a broad range of multidrug-resistant Gram-negative pathogens, including KPC, OXA-48, and NDM carbapenemases. However, there are conflicting data regarding β-lactam potentiation against P aeruginosa and Acinetobacter baumannii with metallo-β-lactamases as a study revealed little to no potentiation by taniborbactam possibly due to slower uptake or stronger efflux.^7,8

Another antibiotic in the pipeline undergoing phase 3 clinical trials is cefepime-zidebactam (WCK 5222), which has demonstrated higher potency of activity compared with current broad-spectrum β-lactam. Coverage provided by this drug was comparable to that of ceftolozane-tazobactam plus fosfomycin or amikacin and when administered concomitantly with aztreonam, cefepime-zidebactam may offer enhanced coverage over meropenem-vaborbactam plus aztreonam. These observations suggest this antimicrobial agent to be a promising therapy for empiric and definitive treatment of infections caused by multidrug-resistant and carbapenemase P aeruginosa.^9,10

Antibiotic Research and Development Challenges

Although there are quite a few drugs in the pipeline for multidrug-resistant Gram-negative bacteria, the antibiotic market itself is struggling. In April 2019, the biopharmaceutical company Achaogen filed for bankruptcy protection shortly after their drug was approved by the US Food and Drug Administration. This event paired with generally low sales of newly approved agents has caused a decline in interest of other companies in supporting antimicrobial research and development. The marketplace is struggling due to these drugs being priced relatively lower compared with others and because they are held in reserve in order to protect their efficacy and maintain good stewardship. Additionally, the mechanisms of action of most antibiotics are not truly new as most are modifications of existing agents.¹¹

What Do We Do Now?

Strategies focusing on antimicrobial stewardship should be implemented as new antibiotics are being developed. Shorter treatment courses, use of narrow-spectrum agents, and use of step-down oral therapy are methods that will aid in preserving the efficacy of currently available agents. Rapid diagnostic tests should also be used to identify pathogens earlier, allowing patients to be treated with targeted therapy and avoiding unnecessary antibiotic use.¹¹

Recently, a coalition of organizations asked congressional leaders to increase national investments to combat the threat of multidrug antibiotic resistance via creating an armamentarium of new antibiotics. These infections affect at least 28 million people in the United States annually, adding at least $20 billion to US healthcare costs. These agents are integral to the success of other medical advancements such as organ transplantation, cancer chemotherapy, and cesarean section deliveries, among others. Additionally, due to the COVID-19 pandemic, there has been an overuse of antibiotics, which has increased the potential for resistance. It is therefore imperative that antimicrobial resistance be controlled and new agents identified to better equip ourselves for the future. “Without greatly increased investments in all of these areas, the letters say, antibiotic resistant infections will be the leading cause of death by 2050, at a global economic impact of $100 trillion.”¹²

References

1. Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America guidance on the treatment of extended-spectrum β-lactamase producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa). Clin Infect Dis. Published online October 27, 2020. doi:10.1093/cid/ciaa1478
2. Castanheira M, Davis AP, Mendes RE, Serio AW, Krause KM, Flamm RK. In vitro activity of plazomicin against Gram-negative and Gram-positive isolates collected from U.S. hospitals and comparative activities of aminoglycosides against carbapenem-resistant Enterobacteriaceae and isolates carrying carbapenemase genes. Antimicrob Agents Chemother. Published online July 27, 2018. doi:10.1128/AAC.00313-18
3. Ackley R, Roshdy D, Meredith J, et al. Meropenem-vaborbactam versus ceftazidime-avibactam for treatment of carbapenem-resistant Enterobacteriaceae infections. Antimicrob Agents Chemother. Published online April 21, 2020. doi:10.1128/AAC.02313-19
4. Shionogi, Inc. Antimicrobial Drugs Advisory Committee cefiderocol briefing document, NDA # 209445. Available at: www.fda.gov/media/131705/download. Accessed March 22, 2021.
5. Karaisko I, Lagou S, Pontikis K, Rapti V, Poulakou G. The “old” and the “new” antibiotics for MDR gram-negative pathogens: for whom, when, and how. Front Public Health. Published online June 11, 2019. doi:10.3389/fpubh.2019.00151
6. Piccirilli A, Segatore B, Brisdelli F, Amicosante G, Perilli M. Potent inhibitory activity of taniborbactam towards NDM-1 and NDM-1Q119X mutants, and in vitro activity of cefepime/taniborbactam against MBLs producing Enterobacterales. Int J Antimicrob Agents. 2021;57(1):106228. doi:10.1016/j.ijantimicag.2020.106228
7. Mushtaq S, Vickers A, Doumith M, Ellington MJ, Woodford N, Livermore DM. Activity of β-lactam/taniborbactam (VNRX-5133) combinations against carbapenem-resistant Gram-negative bacteria. J Antimicrob Chemother. 2021;76(1):160-170. doi:10.1093/jac/dkaa391
8. Wang X, Zhao C, Wang Q, et al. In vitro activity of the novel β-lactamase inhibitor taniborbactam (VNRX-5133), in combination with cefepime or meropenem, against MDR Gram-negative bacterial isolates from China [published correction appears in J Antimicrob Chemother. 2020;75(7):2019]. J Antimicrob Chemother. 2020;75(7):1850-1858. doi:10.1093/jac/dkaa053
9. Avery LM, Mullane EM, Nicolau DP. Evaluation of the in vitro activity of WCK 5222 (cefepime/zidebactam) and currently available combination therapies against single- and double-carbapenemase producing Enterobacteriaceae: Expanding the zone of hope. Int J Antimicrob Agents. 2020;55(2):105863. doi:10.1016/j.ijantimicag.2019.105863
10. Mullane EM, Avery LM, Nicolau DP. Comparative evaluation of the in vitro activities of WCK 5222 (cefepime-zidebactam) and combination antibiotic therapies against carbapenem-resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother. Published online February 21, 2020. doi:10.1128/AAC.01669-19
11. Moss S, Boucher HW. What’s hot in clinical infectious diseases? 2019 IDWeek summary. Open Forum Infectious Diseases. Published online March 23, 2020. https://doi.org/10.1093/ofid/ofaa104
12. Cross-sector coalition calls for significantly increased investments to combat AMR. Infectious Diseases Society of America website. https://www.idsociety.org/news–publications-new/articles/2021/cross-sector-coalition-calls-for-significantly-increased-investments-to-combat-amr/. Published March 18, 2021. Accessed March 24, 2021.

This article originally appeared on Infectious Disease Advisor