IDCM Issue 8: Antibiotic Resistance

Post Date: 
2016-09-08
Author: 
Natasha Chida, MD, MSPH

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Why is Antimicrobial Resistance (AMR) of Such Great Concern? AMR is one of the greatest health threats facing the world today. It is possible that in the coming decades we will face a “post-antibiotic” era, where common infections cannot be treated.1 While resistance is  a concern for all types of pathogens—fungi, viruses, bacteria, etc.—bacteria are of particular concern given high rates of resistance to therapeutics used to treat common infections (such as urinary tract infections and pneumonia) in both the healthcare and community settings.1,2  While global estimates are unknown, each year in the United States at least 2 million people become infected with resistant bacteria, and at least 23,000 of those persons die as a direct result of their infections.3

Gram-negative bacteria are among the pathogens that top the list for resistance to the most therapeutic options. Infections with these pathogens are associated with high mortality and increased healthcare costs; in the United States alone resistant gram-negative infections cost 55 billion dollars annually.2, 4-7 This ID Clinical Minute reviews a few key mechanisms of resistance that occur among certain gram-negative bacteria that healthcare providers are most likely to encounter in clinical practice. Of note, there are many more bacteria that are exhibiting significant antibiotic resistance that are not discussed here.

Enterobacteriaceae and Beta-lactam Antibiotics. The Enterobacteriaceae are a family of gram-negative bacteria that are found in the gastrointestinal tract and are a common cause of human infection.4,8 A few examples include Escherichia coli, and the Klebsiella, Proteus, Enterobacter, Serratia, and Citrobacter genera.

For most of these pathogens Beta-lactam (β-L) antibiotics are the preferred treatment. β-L are named after the β-L ring that they contain as part of their structure. Examples are the pencillins (including β-L/ β-lactamase inhibitors [β-L β-LI] such as piperacillin-tazobactam), cephalosporins, cefamiycins (cefoxitin and cefotetan, which are often grouped into the cephalosporin category), the monobactam aztreonam, and the carbapenems. All of these antibiotics work by inhibiting the creation of the peptidoglycan layer of the bacterial cell wall, which is needed for structural integrity.9 As such, β-L are bactericidal and are highly effective. Unfortunately, resistance to β-L antibiotics is becoming more common; in some countries resistant pathogens have been found in the drinking water and environment.4

Beta-lactamases Undermining Antibiotics. Beta lactamases (β-lactamases) are enzymes that hydrolyze the β-L ring of β-L antibiotics and render them ineffective.9 The ability of bacteria to generate β-lactamases an important resistant mechanism for many of the Enterobacteriaceae. Multiple β-lactamases exist, each with their own spectrum of resistance. These enzymes may be acquired through the spread of mobile genetic elements (such as plasmids), both between patients and from the environment. Some pathogens also intrinsically carry genes for these B-lactamases, but they are not “turned on” until the pathogen is exposed to β-L antibiotics.

β-lactamases are organized by the Ambler Classification Scheme based on structural homology. Notable members of the various classes are as follows:10

Class A β-lactamases include the extended-spectrum β-Lactamases (ESBLs) andKlebsiella pneumoniae carbapenemases (KPCs)

o   ESBLs are spread by plasmids, clonal expansion, and mutations.

o   KPCs are generally spread by plasmids and are found in multiple(despite the name), as well as glucose non-fermenting organisms such as
and Acinetobacter

Class B β-lactamases include the metallo-β-lactamases

o   An example is the New Delhi metallo-β-lactamase (NDM)

o   These β-lactamases are generally spread by plasmids

Class C β-lactamases include the Amp C cephalosporinases

o   These β-lactamases are mainly spread by 2 mechanisms:

  • Plasmids
  • “Derepression” of part of the bacteria’s chromosome that codes for cephalosporinases, which occurs after exposure to certain antibiotics, most notably the third-generation cephalosporins  (such as ceftriaxon)
  • These β-lactamases are most commonly observed in Enterobacter  spp.
        

Class D β-lactamases include the Oxacillinase (OXA)-type carbapenemases

o   OXAs are generally spread by plasmids

Each of these enzymes confers a different antibiotic resistance pattern, as described in Table 1.

 

Table 1.  Resistance Patterns Associated with Key β-lactamase Enzymes.2,4,10,11

Antibiotic

β-lactamase

ESBL

KPC

Amp-C

MβL

(eg: NDM-1)

OXA-type

(eg: OXA-48-type)

Ampicillin

R

R

R

R

R

β-L/β-LI*

V

R

R

R

R

Cefamycins

S

R

R

R

V

3rd generation Cephalosporins

R

R

R

R

V

4th generation Cephalosporins

V

R

S

R

V

Aztreonam

R

R

R

V

R

Carbapenems

S

V**

S

R**

R**

Ceftolozane/tazobactam+

S

R

V

R

V

Ceftazidime/avibactam+

S

S

S

R

V

ESBL=Extended-spectrum β-lactamase; KPC= Klebsiella pneumoniae carbapenemase; MβL=metallo-β-lactamases; NDM=New Delhi metallo-β-lactamase; R=Resistant; V=Variable resistance; S=Sensitive
*Examples include piperacillin-tazobactam and ampicillin-sulbactam
**The carbapenemases—the KPCs, MBLs, and OXAs—are by definition resistant to at least one carbapenem, but may not be resistant to all of them. For example, they may be resistant to ertapenem but susceptible to meropenem
+New B-L/B-LI with a wider spectrum of activity compared to older β-L/β-LI

 

What Antibiotics Can Be Used to Treat these Resistant Infections? In some cases β-lactamases that the pathogen is “resistant” to can still be used if their minimum inhibitory concentration is below a certain level; in these cases high and extended-infusion of the drug (eg, administering meropenem over 3 hours instead of 30 minutes) may be used, often in combination with other antibiotics. Decisions to employ such antibiotic regimens should be made in conjunction with infectious diseases specialists. Non-β-L antibiotic options include the polymixins (ie, colistin or polymixin B), tigecycline, ceftazidime-avibactam, fosfomycin, fluoroquinolones, and aminoglycosides. Some of these agents (eg, polymixins or tigecycline) have been associated with poorer outcomes in comparison with more traditionally prescribed agents like β-lactamases, and should only be used as a “last resort”.12,13 In addition, plasmids that encode for β-lactamases also encode for resistance to these antibiotics, rendering them ineffective.4 An example are plasmids that carry both β-lacatamases and efflux pumps that render fluroquinolones inactive.4,9,10

Will New Antibiotics Be Available? Two new β-L/β-LI combinations were approved in the United States by the Food and Drug Administration: ceftolazone/tazobactam and ceftazidime/avibactam (in 2014 and 2015, respectively). As noted in Table 1, while these drugs have an extended spectrum of activity compared to other β-L antibiotics, they are not effective against all β-lactamases. New antibiotics must therefore be developed to allow for effective treatment of patients with certain resistant gram-negative infections. We must also keep in mind that most effective way to combat resistance at the population level is through strategies such as limiting unnecessary antibiotic use, employing antimicrobial stewardship programs, and addressing the use of antibiotics in agriculture.18

Bottom line:  Antimicrobial resistance is an urgent public health problem that may lead to a “post-antibiotic era.” The Enterobacteriaceae are an example of a group of bacteria that are exhibiting dangerous resistance patterns through the production of β-lactamases.

 

We gratefully acknowledge Dr. Pranita Tamma, Assistant Professor of Pediatrics at The Johns Hopkins University School of Medicine, for her thoughtful review of this work.

 

References

  1. World Health Organization. Antimicrobial resistance: global report on surveillance. 2014. Available from: http://www.who.int/drugresistance/documents/surveillancereport/en/. Accessed 8/27/2016.
  2. Ben-Ami R, Rodríguez-Baño J, Arslan H, et al. A multinational survey of risk factors for infection with extended-spectrum beta-lactamase-producing enterobacteriaceae in nonhospitalized patients. Clin Infect Dis 2009; 49:682. PMID: 19622043
  3. Centers for Disease Control and Prevention. Antibiotic/Antimicrobial Resistance. 2016. Accessed 8/27/16. Avaialble at https://www.cdc.gov/drugresistance/
  4. Vasoo S1, Barreto JN2, Tosh PK3.  Emerging issues in gram-negative bacterial resistance: an update for the practicing clinician. Mayo Clin Proc. 2015;90(3):395-403. PMID 25744116
  5. Kang CI, Kim SH, Park WB, Lee KD, Kim HB, Kim EC, Oh MD, Choe KW.  Bloodstream infections caused by antibiotic-resistant gram-negative bacilli: risk factors for mortality and impact of inappropriate initial antimicrobial therapy on outcome. Antimicrob Agents Chemother. 2005;49(2):760. PMID: 15673761
  6. Micek ST, Welch EC, Khan J, Pervez M, Doherty JA, Reichley RM, Hoppe-Bauer J, Dunne WM, Kollef MH. Resistance to empiric antimicrobial treatment predicts outcome in severe sepsis associated with Gram-negative bacteremia. SOJ Hosp Med. 2011;6(7):405-10. PMID: 21916003
  7. Lye DC, Earnes Ling ML, Lee TE, Yong HC, Fisher DA, Krishnan P, Hsu LY. The impact of multidrug resistance in healthcare-associated and nosocomial Gram-negative bacteraemia on mortality and length of stay: cohort study. Clin Microbiol Infect. 2012;18(5):502-8. Epub 2011 Aug 18. PMID: 21851482
  8. Kaye KS1, Pogue JM2. Infections Caused by Resistant Gram-Negative Bacteria: Epidemiology and Management. Pharmacotherapy. 2015;35(10):949-62. PMID 26497481.
  9. Rahal JJ. Antimicrobial resistance among and therapeutic options against gram-negative pathogens. Clin Infect Dis. 2009;49 Suppl 1:S4-S10. PMID: 19619021
  10. Ruppé É1, Woerther PL, Barbier F. Mechanisms of antimicrobial resistance in Gram-negative bacilli. Ann Intensive Care. 2015;5(1):61. PMID 26261001.
  11. Bradford PA. Extended-Spectrum β-Lactamases in the 21st Century: Characterization, Epidemiology, and Detection of This Important Resistance Threat. Clin Microbiol Rev. 2001;14(4):933-51. PMID: 11585791
  12. Kelesidis T, Karageorgopoulos DE, Kelesidis I, Falagas ME. Tigecycline for the treatment of multidrug-resistant Enterobacteriaceae: a systematic review of the evidence from microbiological and clinical studies. J Antimicrob Chemother. 2008;62(5):895-904. PMID: 18676620
  13. Endimiani A, Luzzaro F, Perilli M, Lombardi G, ColìA, Tamborini A, Amicosante G, Toniolo A. Bacteremia due to Klebsiella pneumoniae isolates producing the TEM-52 extended-spectrum beta-lactamase: treatment outcome of patients receiving imipenem or ciprofloxacin. Clin Infect Dis. 2004;38(2):243. PMID: 14699457
  14. Solomkin J, Hershberger E, Miller B, Popejoy M, Friedland I, Steenbergen J, Yoon M, Collins S, Yuan G, Barie PS, Eckmann C. Solomkin  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. 2015 May;60(10):1462-71.  PMID: 25670823
  15. Harris PN, Tambyah PA, Paterson DL.  β-lactam andβ-lactamase inhibitor combinations in the treatment of extended-spectrumβ-lactamase producing Enterobacteriaceae: time for a reappraisal in the era of few antibiotic options? Lancet Infect Dis. 2015 Apr;15(4):475-85. PMID: 25716293
  16. Farrell DJ, Flamm RK, Sader HS, Jones RN. Antimicrobial activity of ceftolozane-tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa with various resistance patterns isolated in U.S. Hospitals (2011-2012). Antimicrob Agents Chemother. 2013 Dec;57(12):6305-10. PMID: 25716293
  17. Levasseur P, Girard AM, Miossec C, Pace J, Coleman K. In vitro antibacterial activity of the ceftazidime-avibactam combination against enterobacteriaceae, including strains with well-characterizedβ-lactamases. Antimicrob Agents Chemother. 2015 Apr;59(4):1931-4. PMID: 25583732
  18. Society for Healthcare Epidemiology of America; Infectious Diseases Society of America; Pediatric Infectious Diseases Society.  Policy statement on antimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS). Infect Control Hosp Epidemiol. 2012;33(4):322-7.

 

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