Superbugs vs. superdrugs: are we waging a losing battle?

 

Intensive care units (ICUs) are the breeding grounds for resistant microorganisms. The use of invasive devices that breach physiological defensive barriers predispose to nosocomial infections in ICUs. A state of “immunoparalysis” often accompanies critical illness, including sepsis, trauma, and major surgery. Furthermore, therapy with powerful, broad-spectrum antibiotics, appropriate or otherwise, is common in the ICU, contributing to the preponderance of drug-resistant microorganisms.

The most frequently encountered resistant pathogens in the ICU include:

  • Carbapenem-resistant Enterobacteriaceae
  • Multidrug-resistant Pseudomonas aeruginosa, Acinetobacter spp, and Stenotrophomonas maltophilia
  • Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE)

In this review, we shall focus on resistant gram-negative pathogens that are commonly encountered in ICUs.

Carbapenemase-producing Enterobacteriaceae

The family of Enterobacteriaceae includes Escherichia coli, Klebsiella pneumoniae, and Enterobacter species, and commonly cause gram-negative bacteremia, intra-abdominal, and urinary tract infections. Infection with resistant Enterobacteriaceae results in poor clinical outcomes, including high mortality, in addition to the increased cost of care. Carbapenem resistance is conferred by the production of the hydrolyzing enzyme carbapenemase, an extended-spectrum beta-lactamase (ESBL). Carbapenemases are carried on genetic material including transposons and plasmids and transmitted extensively to other bacterial genera. Pseudomonas aeruginosa and Acinetobacter baumanni can also acquire carbapenem resistance through mechanisms other than carbapenemase production.

Beta-lactamases are classified based on the amino acid sequence into 4 types (Ambler classification).

  • Class A: Penicillinases, including Klebsiella pneumoniae carbapenemase (KPC). KPC confers resistance to most beta-lactams; besides, KPC can be transmitted from Klebsiella to other Enterobacteriaceae and Pseudomonas aeruginosa.
  • Class B: Metallo-beta-lactamases (MBL), including the New Delhi metallo-beta-lactamase (NDM-1). NDM-1-producing bacteria have been isolated from tap water and sewage effluents from New Delhi (1). Metallolactamases mediate resistance to all beta-lactamase inhibitors
  • Class C: Cephalosporinases
  • Class D: Oxacillinases, which hydrolyze oxacllin and hence referred to as OXA-type; some beta-lactamase inhibitors can neutralize them. Enterobacteriaceae and Acinetobacer baumanni are known to produce OXA-type carbapenemases.

Carbapenems are generally considered as the most effective therapy against resistant pathogens; however, there is an ever-increasing proliferation of carbapenem-resistant pathogens in ICUs all over the world. The mortality rate associated with carbapenem resistance may be 24–70% (2).

Faced with a daunting milieu of highly resistant, potentially lethal pathogens, what are our therapeutic options?  Several new antimicrobials have been added to our therapeutic armamentarium; besides some older antibiotics that have re-emerged as possible treatment options.

A common mechanism of resistance to carbapenem is through the production of Klebsiella pneumoniae carbapenemases (KPC). KPC is produced by several enterobacterial species; besides carbapenems, they confer resistance against penicillins, cephalosporins, and monobactams. Polymyxins, generally colistimethate (polymyxin E) is the preferred treatment for KPC-producing organisms if the isolate is sensitive. Polymyxins are often used in combination, usually with meropenem, if the minimum inhibitory concentration (MIC) for meropenem is less than 8–12 mcg/ml. Combination therapy with meropenem may not be superior to monotherapy with polymyxin if the MIC for meropenem is more than 16 mcg/ml (3). An emerging therapeutic option is the combination of ceftazidime, a third-generation cephalosporin with the novel beta-lactamase inhibitor, avibactam. Avibactam is more potent and active against a wider range of beta-lactamases including Amber class A, C, and D. The ceftazidime-avibactam combination was non-inferior to imipenem-cilastatin in complicated urinary tract infections, including acute pyelonephritis (4). In another study, a combination of ceftazidime-avibactam and metronidazole was shown to be equivalent to meropenem in the treatment of complicated intra-abdominal infections (5). This combination is an emerging therapeutic option for infections caused by carbapenemase-producing Enterobacteriaceae and has been approved by the FDA for the treatment of complicated urinary tract and intra-abdominal infections. The combination of meropenem with vaborbactam, another novel beta-lactamase inhibitor, may also be effective in the treatment of infection with KPC-producing organisms, although it requires further studies to establish clinical efficacy.

A polymyxin-based combination as described previously is generally preferred for metallo-lactamase producers. If the isolate is colistin resistant, the options are limited, as beta-lactamase inhibitors are ineffective against metallo-lactamases. However, ceftazidime-avibactam combined with aztreonam has been successfully used in this situation (6). This combination may have a synergistic effect as avibactam may inhibit beta-lactamases other than metallo-lactamases and enhance the effectiveness of aztreonam.

The new aminoglycoside antibiotic, plazomycin is another new antibiotic that may be useful in the treatment of carbapenemase-producing Enterobacteriaceae. Unaffected by carbapenemase, it is effective against beta-lactamase producing K. pneumoniae, E. coli, and Enterobacter species. However, it may be less effective against NDM-1 producers. Plazomycin was shown to be equally effective compared to levofloxacin in the treatment of complicated urinary tract infections (7). Besides, the nephrotoxic and ototoxic effects may be less compared to other aminoglycosides.

Fosfomycin

Intravenous fosfomycin has excellent penetration into tissues and body fluids including lungs, soft tissue, bone, urinary bladder, and the central nervous system. It has a broad spectrum of activity against gram-positive and gram-negative bacteria. The efficacy against carbapenemase-producing Enterobacteriaceae is variable. It is mainly used in urinary tract infections as it is excreted in the urine and works optimally in an acidic environment. There are anecdotal reports of its efficacy against NDM-1 producing Enterobacteriaceae (8). Fosfomycin is moderately effective against pseudomonas; however, Acinetobacter and anaerobic organisms are poorly susceptible. It is advisable to use fosfomycin as part of combination therapy as evidence for its efficacy as monotherapy is currently unclear.

Minocycline

Another re-emerging antibiotic, minocycline has evinced renewed interest in the treatment of multi-drug resistant infections. A tetracycline class of antibiotic, minocycline has been showed to be effective against infections caused by Acinetobacter baumanni. It has been successfully used in combination with colistin, meropenem, and aminoglycosides in carbapenem-resistant bloodstream infections caused by Klebsiella pneumoniae. It may result in higher serum levels compared to tigecycline; besides, it has relatively few side effects and carries the option of scaling down to oral therapy. The FDA has approved its use in urinary tract infections.

Pseudomonas aeruginosa and Acinetobacter baumanni resistant to carbapenems

Carbapenem-resistant A. baumannii and P. aeruginosa are usually resistant to all beta-lactams and fluoroquinolones. Polymyxins, usually colistimethate, are commonly used solely or in combination to treat multi-drug resistant infections due to these organisms. Besides, for ventilator-associated pneumonia and tracheobronchitis, aerosolized colistin may be administered. Aerosolized colistin has minimal systemic absorption and hence may be safely used in renal dysfunction. However, it is doubtful if aerosolized therapy alone is efficacious in lung infections.

Colistin resistance in A. baumanni and P. aeruginosa is bad news. Carbapenem-resistant A. baumanni may be susceptible to tigecycline; another option is eravacycline, the novel synthetic fluorocycline, which is 2–4 times more potent than tigecycline. Eravacycline was comparable to imipenem in the treatment of complicated intra-abdominal infections (9). Although sulbactam is another therapeutic option for multi-drug resistant A. baumanni, most isolates have reduced susceptibility. Ceftazidime-avibactam may not be effective against most isolates of carbapenem-resistant P. aeruginosa and A. baumanni. Aztreonam may be a potential therapeutic option against carbapenem-resistant P. aeruginosa; however, corroboratory clinical evidence regarding efficacy is lacking.

The bottom line

  • Carbapenemase-producing gram-negative pathogens pose an increasing threat worldwide and therapeutic options are limited. These organisms are resistant to most other classes of antibiotics. Among the most worrisome are KPC-producing pathogens.
  • The ceftazidime-avibactam combination is preferred for KPC-producing organisms.
  • Possible therapeutic options are re-emergent, older drugs, including colistin, fosfomycin, and minocycline; novel agents that may have an increasing role to play include ceftazidime-avibactam, plazomycin, and eravacycline.
  • The optimal dosing regimen is unclear with many of the newer drugs.
  • Metallo-lactamases, including NDM-1 have proliferated across ICUs in India.
  • Beta-lactamase inhibitors are largely ineffective against metallo-lactamase producing pathogens; colistin remains the preferred therapeutic option.
  • Although combination therapy is often preferred in resistant infections, there is no corroboratory clinical evidence.
  • Clinical studies are urgently required to adequately assess the efficacy of newer agents in the real world.

 

References

  1. Walsh TR, Weeks J, Livermore DM, Toleman MA. Dissemination of NDM-1 positive bacteria in the New Delhi environment and its implications for human health: an environmental point prevalence study. Lancet Infect Dis. 2011 May;11(5):355–62.
  2. Thaden JT, Pogue JM, Kaye KS. Role of newer and re-emerging older agents in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae. Virulence. 2017 May 19;8(4):403–16.
  3. Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis Off Publ Infect Dis Soc Am. 2012 Oct;55(7):943–50.
  4. Vazquez JA, González Patzán LD, Stricklin D, Duttaroy DD, Kreidly Z, Lipka J, et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study. Curr Med Res Opin. 2012 Dec;28(12):1921-31
  5. Mazuski JE, Gasink LB, Armstrong J, Broadhurst H, Stone GG, Rank D, et al. Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-abdominal Infection: Results From a Randomized, Controlled, Double-Blind, Phase 3 Program. Clin Infect Dis Off Publ Infect Dis Soc Am. 2016 01;62(11):1380–9.
  6. Shaw E, Rombauts A, Tubau F, Padullés A, Càmara J, Lozano T, et al. Clinical outcomes after combination treatment with ceftazidime/avibactam and aztreonam for NDM-1/OXA-48/CTX-M-15-producing Klebsiella pneumoniae infection. J Antimicrob Chemother. 2018 Apr 1;73(4):1104–6.
  7. Connolly LE, Riddle V, Cebrik D, Armstrong ES, Miller LG. A Multicenter, Randomized, Double-Blind, Phase 2 Study of the Efficacy and Safety of Plazomicin Compared with Levofloxacin in the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis. Antimicrob Agents Chemother. 2018;62(4).
  8. Denis C, Poirel L, Carricajo A, Grattard F, Fascia P, Verhoeven P, et al. Nosocomial transmission of NDM-1-producing Escherichia coli within a non-endemic area in France. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2012 May;18(5):E128-130.
  9. Solomkin J, Evans D, Slepavicius A, Lee P, Marsh A, Tsai L, 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 01;152(3):224–32.

 

 

 

 

 

 

 

  

 

 

 

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