Newest Antibiotics for Multidrug-Resistant Pathogens
Overview of Novel Agents
The newest antibiotics for MDR pathogens include beta-lactam/beta-lactamase inhibitor combinations (ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, ceftolozane-tazobactam), the novel siderophore cephalosporin cefiderocol, the aminoglycoside plazomicin, and the tetracycline derivatives eravacycline and tigecycline. 1, 2
Gram-Negative MDR Pathogens
Carbapenem-Resistant Enterobacteriaceae (CRE)
Bloodstream Infections
- Ceftazidime-avibactam 2.5 g IV q8h infused over 3 hours is the preferred first-line agent for KPC-producing CRE (2D recommendation) 1
- Meropenem-vaborbactam 4 g IV q8h infused over 3 hours is equally effective for CRE bloodstream infections (2C recommendation) 1, 3
- Imipenem-cilastatin-relebactam 1.25 g IV q6h represents another carbapenem/beta-lactamase inhibitor option (2C recommendation) 1
- Treatment duration: 10-14 days depending on source control and clinical response 1, 3
- Polymyxin-based combination therapy remains an option when newer agents are unavailable, with colistin loading dose 5 mg CBA/kg IV followed by maintenance dosing based on creatinine clearance (2D recommendation) 1
Pneumonia
- Ceftazidime-avibactam 2.5 g IV q8h for at least 7 days, extending to 10-14 days for hospital-acquired/ventilator-associated pneumonia 1, 3
- Combination therapy with colistin (loading 5 mg CBA/kg, maintenance 2.5 mg CBA × [1.5 × CrCl + 30] q12h) plus meropenem 1 g IV q8h by extended infusion when newer agents unavailable (2D recommendation) 1
- Tigecycline 100 mg IV loading, then 50 mg IV q12h should never be used as monotherapy due to poor lung concentrations and outcomes 4
Complicated Urinary Tract Infections
- Ceftazidime-avibactam 2.5 g IV q8h for 5-7 days (2D recommendation) 1
- Meropenem-vaborbactam 4 g IV q8h for 5-7 days (2C recommendation) 1
- Imipenem-cilastatin-relebactam 1.25 g IV q6h for 5-7 days (2C recommendation) 1, 5
- Plazomicin 15 mg/kg IV q12h for 5-7 days (2D recommendation) 1
- Aminoglycosides (gentamicin 5-7 mg/kg/day IV once daily or amikacin 15 mg/kg/day IV once daily) for 5-7 days (2D recommendation) 1
Complicated Intra-Abdominal Infections
- Ceftazidime-avibactam 2.5 g q8h PLUS metronidazole 500 mg q6h for 5-7 days (2D recommendation) 1
- Imipenem-cilastatin-relebactam 1.25 g IV q6h for 5-7 days (2C recommendation) 1
- Tigecycline 100 mg IV loading, then 50 mg IV q12h for 5-7 days (2D recommendation) 1
- Eravacycline 1 mg/kg IV q12h for 5-7 days (2D recommendation) 1
Multidrug-Resistant Pseudomonas aeruginosa
Primary Treatment Options
- Ceftolozane-tazobactam 1.5 g IV q8h is the preferred agent for DTR-PA infections when susceptible (2C recommendation) 1, 5
- Ceftazidime-avibactam 2.5 g IV q8h for carbapenem-resistant P. aeruginosa (2C recommendation) 1
- Imipenem-cilastatin-relebactam 1.25 g IV q6h for CRPA infections (2C recommendation) 1
- Cefiderocol 2 g IV q8h represents a novel siderophore cephalosporin option for MDR Pseudomonas 1, 2
- Antimicrobial susceptibility testing of new beta-lactam/beta-lactamase inhibitors is mandatory to guide treatment (2D recommendation) 1
Duration by Infection Site
- Pneumonia: at least 7 days, extending to 10-14 days for HAP/VAP 1, 3
- Bloodstream infections: 7-14 days depending on source control 3
- Complicated UTI: 5-7 days 1
Carbapenem-Resistant Acinetobacter baumannii (CRAB)
Pneumonia (First-Line)
- Colistin IV (loading 5 mg CBA/kg, maintenance 2.5 mg CBA × [1.5 × CrCl + 30] q12h) PLUS meropenem 2 g IV q8h PLUS adjunctive inhaled colistin for 10-14 days 4
- The loading dose is critical even in renal impairment to avoid 2-3 days of subtherapeutic levels 4
- Sulbactam 9-12 g/day in 3-4 divided doses as 4-hour infusions when MIC ≤4 mg/L, preferred in renal impairment 4
Bloodstream Infections
- Colistin IV (same dosing) with or without carbapenem for 10-14 days, extending to 2 weeks if severe sepsis/septic shock 4
- Never use tigecycline monotherapy for pneumonia or bloodstream infections due to poor outcomes and very low lung concentrations (0.01-0.02 mg/L) 4
Critical Monitoring
- Renal function monitoring essential throughout colistin therapy due to 33-39% nephrotoxicity risk 4
- Clinical response assessment at 48-72 hours mandatory 4
- Infectious disease consultation highly recommended for all MDR Acinetobacter infections 4
Gram-Positive MDR Pathogens
Vancomycin-Resistant Enterococci (VRE)
Pneumonia
- Linezolid 600 mg IV q12h for at least 7 days (1C recommendation) 1
Bloodstream Infections
- Linezolid 600 mg IV q12h for 10-14 days (1C recommendation) 1
- Daptomycin 8-12 mg/kg IV daily for 10-14 days (2C recommendation) 1
- High-dose daptomycin PLUS beta-lactams (penicillins, carbapenems, or cephalosporins except cefotaxime/cefazolin) for VRE bacteremia with high daptomycin MIC (3-4 mg/mL) (2C recommendation) 1
- Cardiac surgery combined with antimicrobial therapy required for infective endocarditis 1
Complicated Intra-Abdominal Infections
- Linezolid 600 mg IV q12h for 5-7 days (1C recommendation) 1
- Tigecycline 100 mg IV loading, then 50 mg IV q12h for 5-7 days (2D recommendation) 1
Complicated Urinary Tract Infections
- Linezolid 600 mg IV q12h for 5-7 days (1C recommendation) 1
- Daptomycin 6-12 mg/kg IV daily for 5-7 days (2D recommendation) 1
Uncomplicated Urinary Tract Infections
- Fosfomycin 3 g PO single dose or 3 g PO every other day for 3-7 days (2D recommendation) 1
- Nitrofurantoin 100 mg PO qid for 3-7 days (2D recommendation) 1
- Ampicillin 18-30 g/day IV in divided doses for 3-7 days (2D recommendation) 1
- Amoxicillin 500 mg PO/IV q8h for 3-7 days (2D recommendation) 1
Renal Dose Adjustments
Colistin
- Loading dose remains 5 mg CBA/kg IV regardless of renal function 4
- Maintenance dose: 2.5 mg CBA × (1.5 × CrCl + 30) IV q12h 1
- Monitor renal function closely throughout therapy (1C recommendation) 1
Meropenem-Vaborbactam
Ceftazidime-Avibactam
- CrCl 31-50 mL/min: 1.25 g IV q8h 1
- CrCl 16-30 mL/min: 0.94 g IV q12h 1
- CrCl 6-15 mL/min: 0.94 g IV q24h 1
Aminoglycosides
- Once-daily dosing with extended intervals based on CrCl 1
- Trough levels: gentamicin/tobramycin <1 mcg/mL, amikacin <4-5 mcg/mL 1
Critical Prescribing Considerations
Extended Infusion Strategies
- Meropenem extended infusion over 3 hours when MIC ≥8 mg/L or for CRE infections to optimize pharmacodynamic targets 1, 3
- Ceftazidime-avibactam infused over 3 hours for serious infections 1
- Beta-lactams should maintain plasma concentrations above MIC for at least 70% of dosing interval, with target Cmin/MIC >4-6 in critically ill patients 3
Combination Therapy Principles
- Polymyxin-based combinations require susceptibility-guided partner selection (2D recommendation) 1
- Combination therapy with two in vitro active agents recommended for critically unstable patients with CRE 1
- Never use tigecycline or aminoglycoside monotherapy for pneumonia 4
Common Pitfalls to Avoid
- Skipping colistin loading dose causes 2-3 days of subtherapeutic levels and increases mortality 4
- Using tigecycline monotherapy for bloodstream infections or pneumonia results in poor outcomes 4
- Failing to obtain infectious disease consultation for MDR infections 4
- Not monitoring renal function during colistin or aminoglycoside therapy 1, 4
- Inadequate treatment duration for deep-seated infections or inadequate source control 1, 3
Antimicrobial Stewardship
- Obtain cultures before initiating therapy 1
- Antimicrobial susceptibility testing mandatory to guide definitive therapy and allow de-escalation 1, 3
- Treatment duration individualized based on infection site, source control adequacy, underlying comorbidities, and clinical response 1, 3
- Infectious disease consultation highly recommended for all MDR infections 1, 4