Introduction
Gram-negative bacteria cause two-thirds of infections in intensive care units (ICUs), and antibiotic resistance among these bacteria is a serious issue. Several multidrug-resistant Gram-negative bacteria, including carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacterales, have been added to the World Health Organization’s latest list of high-priority pathogens. Beta-lactam antibiotics—penicillins, cephalosporins, carbapenems, and to a lesser extent monobactams—are often the antibiotics of choice in the ICU, but they can be inactivated by beta-lactamase enzymes.
These beta-lactamases can be classified into four molecular classes:
Class A (for example, KPCs that confer resistance to cephalosporins and to all carbapenems, and extended-spectrum beta-lactamases (ESBLs) that confer resistance to cephalosporins)
Class B (metallo-beta-lactamases (MBLs), such as NDM, VIM, and IMP, which can lead to resistance to all carbapenems except monobactam)
Class C (for example, AmpC (mostly chromosomal but can also be plasmidal), which confer resistance to cephalosporins)
Class D (for example, OXAs that confer resistance mostly to carbapenems)
Plazomicin, eravacycline, cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/va are examples of new antibiotics with predominant activity against Gram-negative bacteria that have been approved by the US Food and Drug Administration (FDA) and the European Medical Agency (EMA). Temiacillin, a beta-lactam antibiotic effective against Gram-negative bacteria that is only licenced in Belgium and the United Kingdom, is also worth mentioning alongside these novel medicines.
The goal of this narrative review is to look at the antibiotics’ spectrum (especially against ESBL and CPE microorganisms), potential side effects, and clinical studies. The review also focuses on infections in critically ill patients with complicated urinary tract infections (cUTI), intra-abdominal infections (cIAI), or hospital-acquired pneumonia/ventilator-associated pneumonia (HAP/VAP).
Methods
Newly approved (between 2015 and 2020) antibiotics with predominant activity against Gram-negative pathogens were identified from the FDA and EMA website. A subsequent search was performed in MEDLINE up to 1 December 2020, to search for information regarding surveillance studies on the activity of these antibiotics against Enterobacterales, Pseudomonas, and Acinetobacter isolates, including those that are ESBL producers or carbapenem-nonsusceptible.
Results
Plazomicin
Plazomicin is a synthetic aminoglycoside, and like other aminoglycosides, it inhibits bacterial protein synthesis and has dose-dependent bactericidal activity in vitro. The FDA approved plazomicin (brand name Zemdri) in 2018 for use in cUTI and pyelonephritis at a dose of 15 mg/kg IV, QD. The plazomicin FDA package insert includes nephrotoxicity and ototoxicity as possible side effects. However, a pooled analysis of three studies on plazomicin showed that nephrotoxicity in patients receiving plazomicin was comparable to nephrotoxicity in comparator drugs (4.8% vs. 4.1%) Two clinical studies have been conducted in patients with complicated urinary tract infection (cUTI) comparing plazomicin 15 mg/kg IV, QD with meropenem 1 g IV, TID and levofloxacin 750 mg IV, QD for up to 10 days . Both studies showed noninferiority of plazomicin. In these studies, only a limited number of patients were included with carbapenem resistant Enterobacterales (CRE) or P. aeruginosa.
Eravacycline
Eravacycline is a fluorocycline of the tetracycline class. Like other tetracyclines, it inhibits bacterial protein synthesis. The FDA approved eravacycline (brand name Xerava) in 2018 for the treatment of cIAI at a dose of 1 mg/kg IV, BD for a total duration of 4 to 14 days. It may cause the same adverse events as other tetracyclines, such as hypersensitivity reactions and permanent tooth discoloration. Further, the most common adverse events are infusion-site reactions (7.7%), nausea (6.5%), vomiting (3.7%), and diarrhea (2.3%).
In two separate RCTs, eravacycline 1.5 mg/kg IV, BD was shown to be noninferior to meropenem 1 g IV, TD or ertapenem 1 g IV, QD in treating cIAI patients (>80% of the patients also underwent surgery). In patients with ESBL-producing Enterobacterales, clinical cure rates were 87.5% (14/16) and 84.6% (11/13) in the eravacycline and meropenem groups, respectively. However, the cure rate in those patients was also > 90%, emphasizing the importance of surgery. Eravacycline has also been investigated in cUTI. Studies showed lower cure rates (84.8% vs. 94.8%) and (60.4% vs. 66.9%) than the comparators, respectively.
Temocillin
Temocillin is a derivative of ticarcillin, a penicillin antibiotic targeting PBP3 primarily, that was developed and marketed in the UK in the 1980s, but was immediately abandoned because of its lack of activity against Gram-positive microorganisms, nonfermenters (including A. baumannii and P. aeruginosa), and anaerobes. However, there has been a renewed interest in this antibiotic agent in the last decade as a carbapenem-sparing option, given the increasing incidence of infections with Enterobacterales resistant to third-generation cephalosporins.
One observational study in UTI and BSI caused by ESBL or derepressed AmpC beta-lactamase-producing Enterobacterales showed clinical cure of 86% and microbiological cure of 84%. In the clinical trial register, there are two ongoing studies (NCT03543436 and registry number NCT04478721) identified that compare temocillin to carbapenems for the treatment of treat cUTI due to Gram-negative bacteria resistant to third-generation cephalosporins.
Cefiderocol
Cefiderocol is a novel catechol substituted siderophore. It was approved by the FDA in 2019 at a dose of 2 g IV, TD for the treatment of cUTI, and this indication was extended to HAP/VAP in 2020. Due to a cause that has not been established yet, cefiderocol has an FDA label warning for higher all-cause mortality versus other antibiotics in critically ill patients with multidrug-resistant Gram-negative bacterial infections. A clinical trial comparing cefiderocol to imipenem-cilastatin in patients with cUTI for a median treatment duration of 9 days showed significantly higher clinical and microbiological response than in the group on imipenem (73 vs. 55%).
A fresh from the press RCT comparing cefiderocol 2 g IV, TID in 145 patients with meropenem 2 g IV, TID in 146 nosocomial pneumonia patients showed comparable mortality at day 14, i.e., 12.4% vs. 11.6%. A small observational study including 10 critically ill patients with bacteraemia and VAP caused by carbapenem-resistant (MIC ≥ 2 mg/L) A. baumannii, Stenotrophomonas maltophilia, or NDM-producing k. pneumoniae who experienced clinical failure on previous antibiotic (including colistin) showed 70% clinical success at 30 days.
Beta-Lactam/Beta-Lactamase Inhibitor
The following antibiotics are a combination of a cephalosporin or a carbapenem antibiotic with a beta-lactamase inhibitor (BLI). By inhibiting beta-lactamases, the partner beta-lactam antibiotic is allowed to reach its target, the penicillin-binding proteins (PBPs).
The BLIs that are partnered with new beta-lactam antibiotics reviewed here are tazobactam (partner to ceftolozane), avibactam (to ceftazidime), vaborbactam (to meropenem), and relebactam (to imipenem-cilastatin). Tazobactam was invented in the early 1990s, and it inhibits ESBL, but not AmpC, KPC, MBL, or OXA-48. Other BLIs were invented after 2010. Avibactam protects partner antibiotics against ESBL, AmpC, KPC, and OXA-48, but not MBL (Table 1) .
Relebactam is structurally related to avibactam and has the same spectrum as avibactam. Vaborbactam (boronate BLI) inhibits ESBL, AmpC, and KPC, but it does not inhibit OXAs or MBLs. The addition of BLI leads to a more active antibiotic.
Ceftazidime/Avibactam
The FDA approved ceftazidime avibactam in 2015 for treating cIAI (in combination with metronidazole) and cUTI, at a dose of 2.5 g IV, TD, and extended to HAP/VAP in 2018. According to the FDA package insert, ceftazidime/avibactam had comparable possible adverse events to those of ceftazidime alone; the most commonly reported adverse reactions (in ≥5% of patients) were nausea and diarrhea, and positive direct Coombs test. Among the “new” antibiotics in this manuscript, the most clinical data are available for ceftazidime/avibactam. In treating cUTI due to ceftazidime-resistant Enterobacterales and Pseudomonas aeruginosa, it was shown to be noninferior against the best-available therapy.
This study also included < 10% patients with cIAI. In treating cIAI, ceftazidime/avibactam 2 g/0.5 g IV, TD, together with metronidazole showed slightly lower clinical cure at 28 to 35 days after randomization in comparison with meropenem 1 g, IV, TD: 81.6% vs. 85.1%, but the difference fell under the noninferiority margin. Ceftazidime/avibactam 2 g/0.5 g IV, TD has also been shown to be noninferior to meropenem 1 g IV, TD, in treating nosocomial pneumonia, including VAP , where clinical cure at 21 to 25 days after randomization was 68.8% vs. 73.0%.
Ceftolozane/Tazobactam
Ceftolozane/tazobactam is an antipseudomonal cephalosporin partnered with BLI tazobactam. This antibiotic combination was approved by the FDA in 2014 for cUTI and cIAI indications at a dose of 1.5 g IV, TD. The indication was extended to HAP/VAP in 2019. Like ceftazidime/avibactam, possible adverse events that are most commonly reported (in ≥5% of patients) were nausea and diarrhea, according to the FDA package insert. Two RCTs, one in cIAI , and one in nosocomial pneumonia patients, showed noninferiority of ceftolozane/tazobactam in comparison with comparator antibiotics.
Lucasti and coworkers compared ceftolozane/tazobactam 1 g/0.5 g IV, TD (together with metronidazole 500 mg IV, TD in treating cIAI that included ICU patients. Kollef and coworkers compared ceftolozane/tazobactam 2 g/1 g IV, TD with meropenem 1 g IV, TD to treat nosocomial pneumonia patients (71% were ICU patients), of whom 25% were due to P. aeruginosa, but the susceptibility pattern was not specified. Pogue and coworkers compared 100 patients who received ceftolozane/tazobactam with 100 patients who received polymyxin (n = 56) or aminoglycoside-based therapy (n = 44) to treat various infections (VAP, UTI, and HAP) due to MDR or XDR P. aeruginosa. They showed higher clinical cure in patients treated with ceftolozane/tazobactam: 81% vs. 61% (OR of 2.7 (95% CI 1.4 to 5.2).
Meropenem/Vaborbactam
The FDA approved meropenem/vaborbactam to treat cUTI at a dose of 4 g (meropenem 2 g and vaborbactam 2 g) IV, TD. In treating cUTI, meropenem/vaborbactam 2 g/2 g IV, TD showed similar clinical success when it was compared with piperacillin/tazobactam 4 g/0.5 g IV, TD in a noninferiority study: 98.4% vs. 94.0%. An interesting comparison was made between meropenem/vaborbactam (n = 26) for the median duration of 12 days and ceftazidime/avibactam (n = 105) for a median duration of 11 days in treating mostly UTI and IAI patients due to CRE in an observational study.
The clinical success was higher in meropenem/vaborbactam than in ceftazidime/avibactam group: 69.2% vs. 61.9% (p = 0.49). In a study with various type of infections including cUTI, HAP/VAP, and bacteremia due to carbapenem-nonsusceptible pathogens, meropenem/vaborbactam showed higher clinical cure at day 28 in comparison with the best-available therapy of 65.6% vs. 33.3%.
Imipenem-Cilastatin/Relebactam
The FDA approved imipenem-cilastatin/relebactam in 2019 for cUTI and cIAI indications at a dose of 1.25 g, IV, QID. Like all beta-lactam/ beta-lactamase inhibitor (BL/ BLI) presented in the present manuscript, imipenem (+cilastatin)/relebactam, further referred to as imipenem/relebactam, shows activity against Enterobacterales and P. aeruginosa, but not against Acinetobacter spp.
It restores activity against K. pneumoniae isolates that harbour KPCs, and partnering relebactam with imipenem decreased the MIC values of imipenem in P. aeruginosa isolates fourfold. An RCT that compared imipenem-cilas-tatin/relebactam (500 mg–500 mg/250 mg IV, QID), for 7 to 14 days with piperacillin/tazobactam 4 g/500 mg IV, QID, in treating VAP patients showed apparently lower all-cause mortality at day 28 (15.9% vs. 21.3%).
Discussion
The eight antibiotics reviewed here add to the armamentarium of antibiotics against carbapenem-resistant Gram-negative microorganisms. Almost all of these new antibiotics are approved for cUTI and most of them for cIAI (eravacycline, ceftazidime/avibactam, ceftolozane/tazobactam, and imipenem/relebactam). Ceftazidime/avibactam was the first antibiotic approved for HAP/VAP by the FDA in 2018, and over the years, ceftolozane/tazobactam (2019), imipenem/relebactam (2020), and cefiderocol (2020) were also approved by the FDA for this indication.
Developing antibiotics active against Gram-negative microorganisms that harbor MBL remains a challenge. While several inhibitors for serine beta-lactamases (i.e., group A, C, and D) are available as reviewed above, not many MBL inhibitors are included. Avibactam is partnered with aztreonam to prevent aztreonam from being hydrolyzed by non-MBL beta-lactamases. While this antibiotic seemed to be active against Enterobacterales with MBL genes (NDM, VIM, IMP), it was less active against P. aeruginosa with MBL genes.
In conclusion, we have reviewed eight novel antibiotics that are predominantly active against Gram-negative bacteria, and all have potential in the treatment of infections due to carbapenem-nonsusceptible microorganisms.
Source: Erlangga Yusuf, Hannelore I. Bax, Nelianne J. Verkaik and Mireille van Westreenen, J. Clin. Med. 2021, 10(5), 1068; https://doi.org/10.3390/jcm10051068
