Treatment of Bloodstream Infections Due to Gram-Negative Bacteria with Difficult-to-Treat Resistance
Abstract
:1. Introduction
2. DTR Pathogens: Mechanisms of Antibiotic Resistance and Epidemiology
2.1. Enterobacteriales
2.2. ESBL-Producing Enterobacteriales
2.3. Carbapenem-Resistant Enterobacteriales
2.4. Pseudomonas aeruginosa
2.5. Acinetobacter baumannii Complex
3. Novel Treatment Options
3.1. Ceftolozane/Tazobactam
3.2. ESBL
3.3. DTR Pseudomonas aeruginosa
3.4. CRE and DTR Acinetobacter
3.5. Ceftazidime/Avibactam
3.6. ESBL
3.7. CRE
3.8. DTR P. aeruginosa
3.9. DTR Acinetobacter
4. Imipenem/Relebactam
4.1. ESBL
4.2. CRE
4.3. DTR P. aeruginosa
4.4. DTR Acinetobacter
5. Meropenem/Vaborbactam
5.1. ESBL
5.2. CRE
5.3. DTR Pseudomonas aeruginosa and DTR Acinetobacter
6. Cefiderocol
6.1. ESBL
6.2. CRE
6.3. DTR Pseudomonas aeruginosa
6.4. DTR Acinetobacter
7. Other New Antibiotics
7.1. Aztreonam/Avibactam
7.2. Plazomicin
7.3. Eravacycline
7.4. Murepavadin
7.5. Cefepime/Zidebactam
7.6. Meropenem/Nacubactam
7.7. Ceftaroline/Avibactam
7.8. Cefepime/Enmetazobactam
8. Role of Combination Therapy and Duration of Treatment for DTR GNB BSI
9. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
BL/BLI | β-lactam/β-lactamase inhibitor |
BSI | blood stream infections |
CRE | carbapenem-resistant Enterobacteriales |
CAZ/AVI | ceftazidime/avibactam |
C/T | ceftolozane/tazobactam |
cIAI | complicated intra-abdominal infections |
cUTI | complicated urinary tract infections |
DTR | difficult-to-treat resistance |
ESBL | Extended-spectrum Beta-lactamase |
GNB | Gram-negative bacteria |
HAP | hospital acquired pneumonia |
IMP | imipenemase |
KPC | Klebsiella pneumoniae carbapenemases |
MBL | metallo β-lactamases |
MDR | multidrug resistant |
NDM | new Delhi metallo beta-lactamase |
PDR | pandrug resistant |
NP | nosocomial pneumonia |
OXA | oxacillinases |
VAP | Ventilator associated pneumonia |
VIM | Verona integron-borne metallo-β-lactamase |
XDR | extensive drug resistance |
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Molecular Class | Enzymes | Activity against Penicillins | Activity against Cephalosporins | Activity against Carbapenems | Activity against Aztreonam | Inhibited by Carbapenems | Inhibited by Clavulanic Acid | Inhibited by Tazobactam | Inhibited by Avibactam | Inhibited by Vaborbactam and Relebactam | Relevant Organisms | Geographic Distribution |
---|---|---|---|---|---|---|---|---|---|---|---|---|
A (serine penicillinases) | ESBL (TEM, SHV, CTX-M, others) | Yes | Yes, except cefamycins | No | Yes | Yes | Yes | Yes | Yes | Yes | E. coli Klebsiella spp. P. mirabilis | Worldwide spread. Community and nosocomial infections |
KPC | Yes | Yes | Yes Strong activity | Yes | No | No | No | Yes | Yes | E. coli K. pneumoniae K. oxytoca S. marcescens Enterobacter spp. C. freundii | Worldwide United States South and Central America Europe (mainly Italy and Greece) | |
B (metallo-β-lactamases) | MBLs (VIM, IMP, NDM, others) | Yes | Yes | Yes Strong activity | No | No | No | No | No | Yes | E. coli K. pneumoniae K. oxytoca, S. marcescens, Enterobacter spp. C. freundii | NDM: Asia (mainly India, Pakistan and Bangladesh); Italy (Tuscany) IMP and VIM: Europe (Romania, Poland and Denmark) |
C (cephalosporinases) | AmpC type (CMY-2, DHA-1, FOX-1, others) | Yes | Yes except cefepime, including cefamycins | No | Yes | Yes | No | No High concentrations | Yes | Yes | K. pneumoniae E. coli Enterobacter spp. S. enteritidis C. freundii S. marcescens A.baumannii | Worldwide spread. Community and nosocomial infections |
D (oxacillinases) | OXA (OXA-48, OXA-23, OXA-11, OXA-181, others) | Yes § | Yes Weak activity against cefepime and ceftazidime | Yes Weak activity * | Yes | No | Weak | Weak | Yes | No | A. baumannii P. aeruginosa E.coli K. pneumoniae P. mirabilis C. freundii | Relatively common in Europe (Mediterranean countries)., Northern Africa and Middle Eastern countries Extremely rare in United States |
ESBL | CRE-KPC | CRE-OXA48 | CRE-MBL | DTR P. Aeruginosa | DTR Acinetobacter | |
---|---|---|---|---|---|---|
BL/BLI Combination | ||||||
• Ceftolozane/Tazobactam | 1 | |||||
• Ceftazidime-Avibactam | ||||||
• Imipenem-Relebactam | 2 | 3 | ||||
• Meropenem-Vaborbactam | ||||||
• Aztreonam-Avibactam | 4 | 5 | ||||
• Cefepime/Zidebactam | ||||||
• Meropenem/Nacubactam | ||||||
• Ceftaroline/Avibactam | ||||||
Novel Cephalosporine | ||||||
• Cefiderocol | ||||||
Novel Amynoglicoside | ||||||
• Plazomicin | 6 | 7 | 8 | 8 | ||
Novel Tetracycline | ||||||
• Eravacyclin | ||||||
• Murepavadin |
Drug Name | Dosing for Patients with Normal Kidney Function | Comments |
---|---|---|
Ceftolozane-tazobactam | 1.5 (ceftolozane 1 g + tazobactam 0.5 g) IV q 8 h iv for UTI and IAI 3 g (ceftolozane 2 g + tazobactam 1 g) IV q 8 h for NP | PROS: rapid tissue distribution (including lung); safe; limited activity also against S.maltophilia CONS: no activity against most anaerobes, staphylococci and enterococci; variably susceptibility of AmpC producers, two dosages, lower success in patients with CRRT |
Ceftazidime-avibactam | 2/0.5 g IV q 8 h | PROS: rapid tissue distribution (including lung); safe; approved for empiric and targeted therapy of DTR GNB; combination treatment with aztreonam against MBL CONS: no activity against most anaerobes staphylococci and enterococci; lower success in patients with CRRT; resistance |
Imipenem-relebactam | 1.25 g (imipenem 500/cilastatin 500/relebactam 250 mg) IV q 6 h | PROS: possible activity in strains resistant to both ceftolozane/tazobactam and ceftazidime/avibactam CONS: risk of neurotoxicity |
Meropenem-vaborbactam | 2/2 g IV q 8 h | PROS: promising efficacy in the setting of pneumonia and/or other severe KPC -CRE infections; resistance selection overall lower than ceftazidime/avibactam CONS: not active against Amber class B or D carbapenemases |
Cefiderocol | 2 g IV q 8 h (2 g IV q 6 h if CrCl > 120 mL/min) | PROS: novel siderophore cephalosporin; promising for the treatment of DTR A. baumannii no activity also against S. maltophilia CONS: not activity against gram positives and anaerobes |
Plazomicin | 15 mg/kg IV q 24 h | PROS: once daily dose; carbapenem or β-lactam/β-lactamase inhibitor sparing alternative for UTI CONS: no activity against anaerobes, A. baumannii, S. maltophilia,; lower risk for aminoglycosides associated toxicity |
Eravacycline | 1 mg/kg IV/oral q 12 h | PROS: oral formulation, activity also against gram positive (including MRSA, VRE) bacteria, anaerobes, S. maltophilia CONS: suboptimal urinary pharmacokinetics; limited data in pneumonia and BSI; no activity against P. aeruginosa |
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Bassetti, M.; Vena, A.; Sepulcri, C.; Giacobbe, D.R.; Peghin, M. Treatment of Bloodstream Infections Due to Gram-Negative Bacteria with Difficult-to-Treat Resistance. Antibiotics 2020, 9, 632. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9090632
Bassetti M, Vena A, Sepulcri C, Giacobbe DR, Peghin M. Treatment of Bloodstream Infections Due to Gram-Negative Bacteria with Difficult-to-Treat Resistance. Antibiotics. 2020; 9(9):632. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9090632
Chicago/Turabian StyleBassetti, Matteo, Antonio Vena, Chiara Sepulcri, Daniele Roberto Giacobbe, and Maddalena Peghin. 2020. "Treatment of Bloodstream Infections Due to Gram-Negative Bacteria with Difficult-to-Treat Resistance" Antibiotics 9, no. 9: 632. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9090632