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Multi-Drug Resistant Gram-Negative Bacterial Infections and Novel Antibiotic Agents that Treat Them

26 Sep 2019 1:31 PM | Mandy Garion (Administrator)

Authors: Justice Oehlert, PharmD Candidate 2020 and
Kathryn Lincoln, PharmD, BCPS, BCIDP, Clinical Pharmacist – Infectious Diseases, Olathe Medical Center

Learning Objectives:

  1. Describe the magnitude of the problem of multi-drug resistant gram negative bacteria
  2. Identify the bacteria that pose the most risk in the United States and globally
  3. Describe mechanisms of resistance for selected bacteria against antibiotic agents
  4. Evaluate the use of novel antibiotic agents against multi-drug resistant bacteria

Background

The discovery of antibiotics in the 20th century ushered in a golden age of medicine. Before the discovery of penicillin in 1928 and its subsequent wide-spread use, bacterial infections were much more deadly. The introduction of antimicrobial therapies markedly increased the average life expectancy and drastically reduced the mortality rate of communicable diseases. Over the next several decades many new classes of antibiotics were discovered and marketed. As we entered the 21st century, the discovery of new antibiotic classes plateaued, and newly approved agents had been limited to classes that were already established. Bacterial resistance to antibiotics has steadily followed the introduction of new agents. As soon as an agent is used in clinical practice, populations of bacteria that are exposed begin selecting individuals that harbor genetic mechanisms of resistance. Furthermore, resistance mechanisms often render the pathogen resistant to multiple, if not all, agents in a given class of antibiotics. Due to the costly development process and low rate of return on investment, pharmaceutical companies have had little incentive to perform research and development on new antimicrobial agents. Thus, we are currently seeing higher rates of resistance to our commonly employed antibiotics. Agents that had typically been reserved due to toxicity or low resistance, such as colistin, tigecycline or carbapenems, are being forcibly employed. As a result, resistance to these agents is increasing at an alarming rate. Pairing this resistance with a lack of viable antibiotic treatment options leads to a global crisis. The 2014 study commissioned by the UK government used predictive modeling to demonstrate that, in a worst case scenario, by 2050, the death rate from resistant bacteria could be as high as 10 million individuals per year, surpassing the current death rate of cancer.1

Pathogenic bacteria in humans are acquiring resistance at an alarming rate, often to many different available antibiotics. Multi-drug resistant (MDR) bacteria are non-susceptible to at least one agent in three or more antimicrobial classes, extensively-drug resistant (XDR) are non-susceptible to at least one agent in all but two or fewer classes, and pandrug-resistant bacteria are non-susceptible to all available agents.2 Some of the most concerning organisms to consider are gram negative bacilli (GNB), which are responsible for 45-70% of ventilator-associated pneumonia cases (VAP), 20-30% of catheter-related bloodstream infections, and commonly cause sepsis related to urinary tract infections (UTI) or surgical site infections.3 Gram-negative bacteria are often intrinsically more resistant to common antibiotics due to their additional lipopolysaccharide membrane, which serves as a permeability barrier to many drugs.2 Additionally, gram-negative bacteria can acquire resistance through mutations as well as horizontally transfer resistance genes through transformation, transduction, and conjugation both within and between species. Bacteria introduced into humans via consumption of livestock is potentially able to transfer resistance, having been demonstrated with extended spectrum beta-lactamase (ESBL) and the colistin resistance gene mcr-1 in GNR.2

The most relevant MDR gram-negative pathogens in humans are members of Enterobacteriaceae, such as Escherichia coli, Citrobacter spp., Enterobacter spp., Klebsiella spp., Pseudomonas aeruginosa, and Acinetobacter spp. In the latest antibiotic resistance report released by the CDC in 2013, carbapenem-resistant Enterobacteriaceae (CRE) account for approximately 9,000 infections and 600 deaths per year.10

Several studies have been performed to evaluate resistance rates of GNB in institutional settings. The INICC, SENTRY, ANSRPRG, and EARS-NET analyzed data in a multitude of countries and in both ICU and non-ICU settings. Results demonstrated Enterobacteriaceae resistance to fluoroquinolones from 0-70%, 3rd generation cephalosporins 0-72%, and carbapenems 0-59%, depending on the study. Pseudomonas aeruginosa was 0-53% resistant to fluoroquinolones, 0-51% resistant to aminoglycosides, 0-55% resistant to piperacillin/tazobactam, 0-44% resistant to ceftazidime, and 3-60% resistant to carbapenems. The resistance variability between study sites reiterates the importance of generating local antibiograms to help guide empiric therapy for bacterial infections.

Resistance Mechanisms

For Enterobacteriaceae, the primary mechanism of resistance to beta-lactams is the production of beta-lactamases, which are enzymes that hydrolyze the beta-lactam ring of these agents and render them unable to bind to penicillin-binding protein (PBP). Additionally, AmpC, an inducible beta-lactamase, can confer further resistance to 2nd and 3rd generation cephalosporins in Enterobacter spp., Citrobacter freundii, Serratia marcescens, Morganella morganii, and others. Exposure to penicillins and 1st-3rd generation cephalosporins can cause the AmpC gene to become de-repressed and resistance can evolve quickly. Additionally, plasmid-borne beta-lactamases of the ESBL variety confer resistance to all cephalosporins. Finally, strains which carry plasmid-borne carbapenemases that inactivate carbapenems have rapidly spread.3

While all Enterobacteriaceae are naturally susceptible to fluoroquinolones, chromosomal mutations in DNA gyrase and topoisomerase IV genes modify the binding affinity and raise the MIC for specific agents. Additionally, mutations may lead to decreased permeability into the cytoplasm or increased drug efflux. Plasmid-borne mechanisms of resistance have also been observed, and are frequently associated with ESBL producing strains.3

Pseudomonas aeruginosa, like the Enterobacteriaceae, also carry an inducible AmpC cephalosporinase that confer resistance to 3rd generation cephalosporins. Wild-type strains are intrinsically resistant to amoxicillin, amoxicillin/clavulanate, 1st and 2nd generation cephalosporins, cefotaxime, ceftriaxone, and ertapenem. They are susceptible to piperacillin, ceftazidime, cefepime, imipenem, meropenem, and doripenem. Mutations in efflux transporters rendering them overexpressed confers resistance to aztreonam, cefepime, and meropenem. Fluoroquinolone resistance results from mutations in topoisomerase-encoding genes and/or hyperactive efflux systems. Finally, colistin resistance has been well documented in regards to selection of mutants. More recently, transferable resistance has been described in Pseudomonas harboring mcr-5, a variant of the gene discussed previously.3,11

The newest advancement in the bacterial arms race is the emergence of resistance to colistin. Certain species are intrinsically resistant, such as Proteus spp., Providencia spp., Serratia spp., and Morganella spp. Naturally, MDR strains of these organisms are concerning due to the lack of susceptibility to colistin, which is currently the last resort agent for CRE. Until recently, transferable resistance to colistin had not been observed. The plasmid-borne mcr-1 gene confers resistance to colistin and was described in farm animals in several countries, including the U.S. In China, the mcr-1 gene has been found in humans, livestock, and food products.2,3

Novel Agents

Ceftolozane/tazobactam (TOL/TAZ) is a cephalosporin/beta-lactamase inhibitor combination FDA approved for the treatment of complicated intra-abdominal infections (cIAIs), in combination with metronidazole, and complicated urinary tract infections (cUTIs), including pyelonephritis. TOL/TAZ demonstrated superiority to levofloxacin in the outcomes of composite cure and microbiological eradication in cUTI. It was non-inferior to meropenem in the outcome of clinical cure of cIAI.5 It is highly potent against P. aeruginosa, most Enterobacteriaceae and also ESBL-producing GNB, but provides little activity against Acinetobacter baumannii.5,7 Common mechanisms of resistance in P. aeruginosa are ineffective against ceftolozane/tazobactam. TOL/TAZ provides most of its utility in practice towards treating Pseudomonas and ESBL producing GNB infections while sparing carbapenems. It has been referred to as the most potent antibiotic against Pseudomonas.7

Ceftazidime/avibactam (TAZ/AVI) is a cephalosporin/beta-lactamase inhibitor combination FDA approved for cUTI, cIAI (in combination with metronidazole), healthcare-associated pneumonia (HAP) and VAP.7 The addition of avibactam restores activity of ceftazidime to a variety of organisms, including ESBL producing GNB and some, but not all, carbapenemase producing GNB, including Pseudomonas aeruginosa.4,5,7 In comparison to TOL/TAZ, the presence of avibactam leads to retention of activity against GNB that produce Klebsiella pneumoniae carbapenemases (KPC).6 In clinical trials, TAZ/AVI plus metronidazole was compared with meropenem in patients with cIAIs and nosocomial pneumonia, and proved non-inferiority. An open-label trial comparing TAZ/AVI to best available therapy in cUTI or cIAI caused by ceftazidime-resistant Enterobacteriaceae or P. aeruginosa showed utility as an alternative to carbapenems.7 The Consortium of Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE) database demonstrated that therapy for CRE infection with TAZ/AVI had significantly lower mortality than therapy with colistin. Current data does not support the use of TAZ/AVI as monotherapy when MDR GNB are suspected. Use of local antibiograms should be employed to pair its use with an aminoglycoside, fosfomycin, tigecycline, or colistin.7

Meropenem/vaborbactam is the first carbapenem/beta-lactamase inhibitor combination product available. Addition of vaborbactam restores activity of meropenem against some, but not all, carbapenemase producing GNB.7 It was FDA approved for cUTI, including acute pyelonephritis, after demonstrating non-inferiority to piperacillin/tazobactam.4,7 On a negative note, one study found that the addition of vaborbactam did not increase in vitro activity against P. aeruginosa or Acinetobacter spp. in comparison to meropenem alone.4 Real-life clinical data is lacking at this point, which will be necessary to define its place in clinical practice.7

Plazomicin is the newest agent in the aminoglycoside class and is active against MDR Enterobacteriaceae due to its stability against AMEs.4,7 Plazomicin spectrum of activity includes Enterobacteriaceae (including CRE, ESBL, and MDR isolates) as well as methicillin-resistant Staphylococcus aureus (MRSA) irrespective of resistance to currently available aminoglycosides. Moreover, plazomicin has demonstrated favorable in vitro activity against polymyxin-resistant Enterobacteriaceae, including mcr-1 producing isolates.4,9 FDA approval was achieved for cUTI based on comparisons of plazomicin with meropenem or colistin with concurrent tigecycline or meropenem, in which non-inferiority was demonstrated. Favorable lung penetration, in comparison to colistin, may hold some promise as to future adjunctive therapy for VAP. Plazomicin potentially has utility as part of combination therapy for XDR GNB along with novel beta-lactams.7

Eravacycline, a synthetic fluorocycline with similarities to tigecycline, has activity against GNB and gram positive cocci. It inhibits peptide elongation by binding to the 30s subunit of the bacterial ribosome and inhibiting addition of amino acids to the growing peptide chain. Many mechanisms of resistance, such as ESBL production, do not affect the activity of eravacycline. While it does not inhibit P. aeruginosa, it is active against MRSA and vancomycin-resistant enterococcus (VRE). Its advantages over tigecycline include more potent in vitro activity, excellent oral bioavailability, lower potential for drug interactions, and greater activity in biofilms. Of note, it extensively concentrates in alveolar macrophages, indicating potential utility in pneumonias caused by MDR bacteria. It is the most potent antibiotic against carbapenem resistant A. baumannii. Eravacycline is FDA approved for cIAI based on 2 clinical trials that demonstrated non-inferiority to ertapenem and meropenem.

Omadacycline is a semisynthetic derivative of minocycline within the tetracycline class. It is FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) as well as community-acquired pneumonia (CAP). Coverage includes gram-positive, including MRSA and VRE, gram-negative, anaerobic and atypical pathogens. FDA approval was obtained for ABSSSIs based on the results of 2 trials demonstrating non-inferiority to linezolid. Approval for CAP was obtained based on a trial comparing omadacycline to moxifloxacin, in which omadacycline demonstrated non-inferiority.8

Imipenem/cilastatin/relebactam (IMI/REL) is a carbapenem/beta-lactamase inhibitor that gained FDA approval in July 2019 for complicated UTIs, including pyelonephritis, and cIAIs, both due to a set of susceptible organisms. The addition of relebactam restores activity against KPC type carbapenemases, but not the other carbapenemases. IMI/REL was compared to imipenem alone in patients with cIAIs and cUTIs and demonstrated non-inferiority, but the trials were not selective for MDR infections. It is expected that IMI/REL will provide an additional therapeutic option against KPC producing GNB.4 In vitro analysis show that 32% of imipenem non-susceptible P. aeruginosa strains from the Study for Monitoring Antimicrobial Resistance Trends (SMART) global surveillance program remain resistant with the addition of relebactam.12 A trial comparing IMI/REL to piperacillin/tazobactam in patients with pneumonia has been completed, but the results are not currently available.

Conclusions

While the rapid development of resistance, particularly in gram-negative bacteria, is concerning, the development of novel agents and their appropriate use has the potential to spare us from a global crisis. Antimicrobial stewardship will be critical to ensure that these agents remain active against MDR bacteria in the future. Clinicians should be well aware of their local antibiograms to help guide empiric antimicrobial therapy. While these newer agents have been able to overcome many modalities of bacterial resistance, no single agent can be employed that will be active against all MDR GNB. Table 1 shows the activity of these new agents against several types of resistance. Of note is that no single agent can work against all types of CRE. Additionally, MDR Acinetobacter poses a significant problem as no agent can be considered a “drug of choice” due to its extensive list of resistance mechanisms. Real-world data will become available as these agents are used in practice, and this data will help illuminate the niche uses that each agent likely possesses. 

Figure 1.

Ruppé E. Ann. Intensive Care. 2015; 5:21.

Table 1.

References

  1. Review on Antimicrobial Resistance. Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations. 2014
  2. Exner M, Bhattacharya S, Christiansen B, et al. Antibiotic resistance: What is so special about multidrug-resistant Gram-negative bacteria? GMS Hyg Infect Control. 2017;12:Doc05. doi: 10.3205/dgkh000290
  3. Ruppé E, Woerther P, Barbier F. Mechanisms of antimicrobial resistance in Gram-negative bacilli. Ann. Intensive Care. 2015; 5:21. doi: 10.1186/s13613-015-0061-0
  4. Petty LA, Henig O, Patel TS, et al. Overview of meropenem-vaborbactam and newer antimicrobial agents for the treatment of carbapenem-resistant Enterobacteriaceae. Infect Drug Resist. 2018;11: 1461-1472. doi: 10.2147/IDR.S150447
  5. Toussaint KA, Gallagher JC. β-Lactam/β-Lactamase Inhibitor Combinations: From Then to Now. Ann Pharmacother. 2015; 49(1): 86-98. doi: 10.1177/1060028014556652
  6. Van Duin D, Bonomo RA. Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation β-Lactam/β-Lactamase Inhibitor Combinations. Clin Infect Dis. 2016;63(2):234–41. doi: 10.1093/cid/ciw243
  7. Karaiskos I, Lagou S, Pontikis K, et al. The “Old” and the “New” Antibiotics for MDR Gram-Negative Pathogens: For Whom, When, and How. Front. Public Health. 2019; 7(151).  doi: 10.3389/fpubh.2019.00151
  8. Baker DE. Omadacycline. Hosp Pharm. 2019;54(2):80-87. doi: 10.1177/0018578718823730
  9. Denervaud-Tendon V, Poirel L, Connolly LE, et al. Plazomicin activity against polymyxin-resistant Enterobacteriaceae, including MCR-1-producing isolates. J Antimicrob Chemother. 2017; 72: 2787–2791 doi:10.1093/jac/dkx239
  10. Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2013. https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf. Accessed July 11, 2019.
  11. Snesrud E, Maybank R, Kwak YI, et al. Chromosomally encoded mcr-5 in colistin nonsusceptible Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2018;62(8). doi: 10.1128/AAC.00679-18.
  12. Young K, Painter RE, Raghoobar SL, et al. In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosa. BMC Microbiol. 2019; 19(150). doi: 10.1186/s12866-019-1522-7 

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