Following the discovery of penicillin in 1928, and its widespread use in clinical practice from the 1940s, several new antibiotic classes were introduced. Vancomycin was introduced in 1958, followed by the cephalosporins, beta-lactamase inhibitors, and quinolones. However, since the introduction of carbapenems in the 1980s, no new class of antibiotic has been added to our therapeutic armamentarium. Multidrug-resistant bacteria have, in the meantime, multiplied across the globe by several fold. There has been an ever-increasing problem with multidrug-resistant gram-negative bacteria (MDR-GNB) in critically ill patients. Different types of beta-lactamases are produced by GNB rendering them resistant to commonly available antibiotics (Table 1). Considering the lack of new agents to combat these organisms, several older antibiotics, including colistin, and fosfomycin, have found renewed utility in critically ill patients across the globe. Combination of drugs with reduced sensitivity have also been resorted to in the face of lack of availability of more effective therapy. However, infection with carbapenem-resistant Enterobacteriaceae, Ps. aeruginosa, and A.baumanni continue to wreak havoc among the critically ill. Several newer antibiotics have undergone clinical evaluation and introduced into clinical practice recently, with increased potency against MDR-GNB. Let us consider some of the newer drugs and their clinical efficacy based on the best available evidence.
Table 1. The Ambler classification of beta-lactamases
|Class A||Penicllinases, narrow and extended- spectrum beta-lactamases, carbapenemases including Klebsiella pneumoniae carbapenemase (KPC)|
|Class D||Oxa-type enzymes|
Ceftolozane is a third-generation cephalosporin with a distinctive side-chain that confers it with enhanced efficacy against penicillin-binding proteins. Ceftolozane has a much lower minimum inhibitory concentration (MIC) against Ps. aeruginosa compared to ceftazidime, imipenem, and ciprofloxacin. The addition of tazobactam enables inhibition of Amp C and extended-spectrum beta-lactamases (ESBLs). Following the ASPECT-cIAI1 and ASPECT-cUTI2trials, ceftolozane/tazobactam has been approved for clinical use in complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI). Ceftolozane/tazobactam may be efficacious against infections caused by carbapenem-resistant P. aeruginosa. It may also have a future role against ESBL producing Enterobacteriaceae. A recently completed randomized controlled trial compared 3 g cefotzolane/tazobactam with 1 g meropenem in patients with ventilator-associated pneumonia (VAP), for a period of 8–14 days. Clinical cure and microbiological eradication rates were comparable between the two agents in this non-inferiority trial. This combination may be a viable treatment option in VAP caused by gram-negative organisms.3
Avibactam is a non-beta-lactam type of beta-lactamase inhibitor that offers protection against class A and C beta-lactamases when used in combination with ceftazidime, a third-generation cephalosporin. Ceftazideme-avibactam is effective against most carbapenemase and OXA-48 producers, including Klebsiella pneumoniae carbapenemase (KPC). However, it is not effective against class B beta-lactamases, including metallo-lactamases. In a randomized, controlled study in patients with cUTI, the ceftazidime/avibactam combination was non-inferior to doripenem for the primary endpoints of clinical and microbiological cure.4 Ceftazidime/avibactam combined with metronidazole was non-inferior to meropenem in cIAI in another randomized controlled trial.5
Vaborbactam is a novel beta-lactamase inhibitor which has no intrinsic antibacterial activity; however, it inhibits beta-lactamases that neutralize meropenem. The meropenem/vaborbactam combination has a potent effect against type A beta-lactamases, including KPC. In the TANGO-I trial, meropenem/vaborbactam was shown to be superior to piperacillin/tazobactam in cUTI, including acute pyelonephritis. The meropenem/vaborbactam combination was also compared with the best available alternative therapy in carbapenem-resistant Enterobacteriaceae infections.6 The infections included cUTIs, hospital and community-acquired pneumonia, and bacteremia. The study was stopped early due to demonstrated superiority of meropenem/vaborbactam therapy. However, meropenem/vaborbactam may not be effective against OXA-type carbapenemase producing A. baumanni and P. aeruginosa that acquire resistance by porin changes and efflux mechanisms. The European Medical Agency has currently approved meropenem/vaborbactam in the treatment of cUTI, c-IAI, hospital-acquired pneumonia (HAP), VAP, and other infections due to aerobic gram-negative organisms.
Plazomicin is a new aminoglycoside that shares a common mechanism of action by inhibition of bacterial protein synthesis. Similar to other aminoglycosides, lung penetration is poor and elimination is through the kidneys. It has good in vitro activity against carbapenem resistant Enterobacteriaceae; however, the efficacy is much less against carbapenem-resistant A. baumanni and P. aeruginosa. In the phase 3 EPIC trial, plazomicin was demonstrated to be superior to meropenem in c-UTI.7 Plazomicin and colistin were compared in combination with other drugs in the treatment of blood stream infections, HAP, and VAP. All-cause mortality with combination therapy, including plazomicin was lower compared to combination therapy with colistin.3 Plazomicin may be a therapeutic option in resistant gram-negative infections in combination with meropenem, colistin, or fosfomycin.
Eravacycline is a novel derivative of tigecycline with a broader spectrum of activity. It is not susceptible to beta-lactamases and efflux channel mechanisms that confer resistance to GNBs. In vitro studies have demonstrated a wide spectrum of activity against GNB, except Ps. aeruginosa and Burkholderia cenocepacia. Particularly noteworthy is the superior efficacy against carbapenem-resistant A. baumanni. In a randomized controlled trial, eravacycline was compared with ertapenem in cIAI. Clinical cure was comparable with both drugs, establishing non-inferiority compared to ertapenem.8 In cUTI, eravacycline did not achieve non-inferiority compared to levofloxacin and ertapenem.9 Eravacycline has a high bioavailability on oral administration, enabling switch from intravenous to oral therapy if appropriate.
The bottom line
- In the face of increasingly resistant GNB, the antibiotic cupboard appears relatively bare. The aforementioned drugs have been approved by the FDA for use against MDR-GNB.
- The newly available agents are derivatives of existing class of antibiotics; no new class of antibiotic has been introduced into clinical practice in more than three decades.
- It is of utmost importance to use these drugs only when there is no viable alternative; bacteria evolve over time and develop resistance following exposure to newer antibiotics.
1. Solomkin J, Hershberger E, Miller B, et al. Ceftolozane/Tazobactam Plus Metronidazole for Complicated Intra-abdominal Infections in an Era of Multidrug Resistance: Results From a Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI). Clin Infect Dis Off Publ Infect Dis Soc Am. 2015;60(10):1462-1471. doi:10.1093/cid/civ097
2. Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI). Lancet Lond Engl. 2015;385(9981):1949-1956. doi:10.1016/S0140-6736(14)62220-0
3. Koulenti D, Song A, Ellingboe A, et al. Infections by multidrug-resistant Gram-negative Bacteria: What’s new in our arsenal and what’s in the pipeline? Int J Antimicrob Agents. 2019;53(3):211-224. doi:10.1016/j.ijantimicag.2018.10.011
4. Wagenlehner FM, Sobel JD, Newell P, et al. Ceftazidime-avibactam Versus Doripenem for the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis: RECAPTURE, a Phase 3 Randomized Trial Program. Clin Infect Dis Off Publ Infect Dis Soc Am. 2016;63(6):754-762. doi:10.1093/cid/ciw378
5. Qin X, Tran BG, Kim MJ, et al. A randomised, double-blind, phase 3 study comparing the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem for complicated intra-abdominal infections in hospitalised adults in Asia. Int J Antimicrob Agents. 2017;49(5):579-588. doi:10.1016/j.ijantimicag.2017.01.010
6. Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G, et al. Effect and Safety of Meropenem-Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial. Infect Dis Ther. 2018;7(4):439-455. doi:10.1007/s40121-018-0214-1
7. Wagenlehner FME, Cloutier DJ, Komirenko AS, et al. Once-Daily Plazomicin for Complicated Urinary Tract Infections. N Engl J Med. 2019;380(8):729-740. doi:10.1056/NEJMoa1801467
8. Solomkin J, Evans D, Slepavicius A, et al. Assessing the Efficacy and Safety of Eravacycline vs Ertapenem in Complicated Intra-abdominal Infections in the Investigating Gram-Negative Infections Treated With Eravacycline (IGNITE 1) Trial: A Randomized Clinical Trial. JAMA Surg. 2017;152(3):224-232. doi:10.1001/jamasurg.2016.4237
9. Bassetti M, Peghin M, Vena A, Giacobbe DR. Treatment of Infections Due to MDR Gram-Negative Bacteria. Front Med. 2019;6:74. doi:10.3389/fmed.2019.00074