From the Guidelines
The treatment of MDR, XDR, and PDR Enterobacteriales infections should be guided by the most recent and highest quality evidence, with a focus on carbapenems, combination therapy, and novel agents, as recommended by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines 1.
Key Considerations
- MDR Enterobacteriales are resistant to at least one agent in three or more antimicrobial categories, while XDR strains remain susceptible to only one or two categories, and PDR Enterobacteriales are resistant to all available antimicrobial agents.
- For MDR infections, carbapenems (meropenem 1g IV q8h or imipenem 500mg IV q6h) often remain effective, as supported by the ESCMID guidelines 1.
- For XDR infections, combination therapy is typically required, such as meropenem 2g IV q8h plus polymyxin E (colistin) 9 million units loading dose followed by 4.5 million units q12h, with therapy duration of 7-14 days depending on infection site and clinical response.
- For PDR infections, novel agents like ceftazidime-avibactam (2.5g IV q8h), meropenem-vaborbactam (4g IV q8h), or imipenem-relebactam (1.25g IV q6h) may be necessary, as highlighted in the ESCMID guidelines 1.
Infection Control Measures
- Infection control measures including contact precautions, dedicated equipment, and enhanced environmental cleaning are essential to prevent transmission, as emphasized by the ESCMID guidelines 1.
- These resistant organisms have developed through mechanisms including extended-spectrum beta-lactamases, carbapenemases, and mutations affecting drug targets or permeability, making them increasingly difficult to treat with conventional antibiotics.
Treatment Recommendations
- Treatment should be guided by susceptibility testing whenever possible, and the ESCMID guidelines provide recommendations for the treatment of infections caused by MDR-GNB in hospitalized patients 1.
- The guidelines address the targeted treatment of infections caused by third-generation cephalosporin-resistant Enterobacterales (3GCephRE), CR Enterobacterales (CRE), CR P. aeruginosa (CRPA) and CR A. baumannii (CRAB), and provide recommendations for the antibiotic of choice and the use of combination antibiotic therapy.
From the FDA Drug Label
Plazomicin has concentration-dependent bactericidal activity as measured by time kill studies. In vitro studies demonstrated a plazomicin post-antibiotic effect ranging from 0.2 to 2. 6 hours at 2× MIC against Enterobacteriaceae. Resistance to aminoglycosides includes production of aminoglycoside modifying enzymes (AMEs), alteration of the ribosomal target through production of 16S rRNA methyltransferases, up-regulation of efflux pumps and reduced permeability into bacterial cell due to loss of outer membrane porins Plazomicin is not inhibited by most AMEs known to affect gentamicin, amikacin and tobramycin, including acetyltransferases (AACs), phosphotransferases (APHs) and nucleotidyltransferases (ANTs). Plazomicin may have reduced activity against Enterobacteriaceae that overexpress certain efflux pumps (e.g., acrAB-tolC) or lower expression of porins (e.g., ompF or ompK36). Activity of plazomicin was demonstrated in vitro against Enterobacteriaceae in the presence of certain beta-lactamases, including extended-spectrum beta-lactamases (TEM, SHV, CTX-M, AmpC), serine carbapenemases (KPC-2, KPC-3), and oxacillinase (OXA-48).
MDR, XDR, and PDR in Enterobacteriales:
- MDR (Multi-Drug Resistance): Plazomicin has shown activity against Enterobacteriaceae with certain beta-lactamases, including extended-spectrum beta-lactamases.
- XDR (Extensively Drug-Resistant): The drug label does not provide direct information on XDR.
- PDR (Pan-Drug Resistance): The drug label does not provide direct information on PDR. Plazomicin may be effective against some MDR Enterobacteriaceae, but its effectiveness against XDR and PDR is unknown 2.
From the Research
Definition of MDR, XDR, and PDR
- MDR (Multidrug-resistant) is defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories 3
- XDR (Extensively drug-resistant) is defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories 3
- PDR (Pandrug-resistant) is defined as non-susceptibility to all agents in all antimicrobial categories 3
Treatment of MDR Enterobacteriaceae
- Carbapenem-sparing strategies should be considered to avoid the selection of carbapenemase-producing Enterobacteriaceae 4
- B-lactams/b-lactamase inhibitors, mainly piperacillin-tazobactam, are a good alternative to carbapenems for the treatment of ESBL-producing strains 4
- Combination therapy may be preferred over monotherapy for CRE (Carbapenem-resistant Enterobacteriaceae) 4
Treatment of XDR Pseudomonas aeruginosa
- Combination therapy with a traditional antipseudomonal β-lactam and a second agent from a different antibiotic class may be used to increase the likelihood of administering empiric antipseudomonal therapy with in vitro activity 5
- Novel agents such as β-lactam/β-lactamase inhibitor combinations and cefiderocol have been recently approved and may be effective against MDR-P. aeruginosa 5
- Bacteriophages may be a promising candidate for combatting recurrent and refractory infections with MDR/XDR-P. aeruginosa 5
Treatment of MDR and XDR Acinetobacter baumannii
- Triple therapy with colistin, sulbactam, and tigecycline had the highest clinical cure rate in a systematic review and network meta-analysis 6
- Combination therapy of colistin with sulbactam demonstrates superiority in terms of microbiological cure with a safety profile similar to that of colistin monotherapy 6
Antimicrobial Activities of New Agents
- Ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/relebactam, and meropenem/vaborbactam are new β-lactam/β-lactamase inhibitor combinations that have shown potent activity against Pseudomonas aeruginosa isolates 7
- These agents may be effective against MDR-P. aeruginosa, including isolates nonsusceptible to piperacillin/tazobactam, meropenem, imipenem, and/or ceftazidime 7