What is the recommended empiric therapy for patients suspected of having a carbapenem-resistant (Carb R) infection while awaiting assay results?

Empiric Therapy for Suspected Carbapenem-Resistant Infections

For patients with suspected carbapenem-resistant (Carb R) infections, initiate empiric therapy with intravenous polymyxins (colistin or polymyxin B) as the backbone, with strong consideration for adjunctive inhaled colistin, while awaiting definitive assay results. 1

Risk Stratification and Initial Assessment

Before initiating empiric therapy, rapidly assess for specific risk factors that increase likelihood of carbapenem resistance:

• Known colonization/infection with ESBL-producing Enterobacteriaceae or ceftazidime-resistant P. aeruginosa within the last 3 months 2
• Presence of severe sepsis or septic shock 2
• Recent antibiotic exposure (third-generation cephalosporins, fluoroquinolones, or piperacillin-tazobactam in the last 3 months) 2
• Recent hospitalization (within the last 12 months) or residence in nursing facility with indwelling devices 2
• Healthcare setting with known high prevalence of multidrug-resistant organisms 1

Empiric Antibiotic Regimen

Primary Recommendation

Intravenous polymyxins (colistin or polymyxin B) plus adjunctive inhaled colistin 1

• This combination is recommended for infections caused by pathogens sensitive only to polymyxins 1
• Intravenous polymyxin B may have pharmacokinetic advantages over intravenous colistin, though clinical data in certain infections are limited 1
• Inhaled colistin should be administered promptly after being mixed with sterile water 1

Site-Specific Modifications

For nosocomial spontaneous bacterial peritonitis or healthcare-associated intra-abdominal infections:

• Carbapenem alone OR carbapenem plus daptomycin, vancomycin, or linezolid if high prevalence of multidrug-resistant Gram-positive bacteria or sepsis is present 1

For hospital-acquired or ventilator-associated pneumonia with suspected carbapenem resistance:

• Intravenous polymyxins (colistin or polymyxin B) plus adjunctive inhaled colistin 1
• Avoid tigecycline monotherapy for Acinetobacter species 1

For febrile neutropenia in high-risk patients with suspected resistance:

• Add a second Gram-negative agent or glycopeptide to antipseudomonal β-lactam when resistant infection is suspected or in centers with high rates of resistant pathogens 1

Alternative Empiric Options Based on Local Epidemiology

For ESBL-Producing Enterobacteriaceae (if carbapenemase not yet confirmed):

Ceftazidime-avibactam is highly effective for KPC and OXA-48 producers 2, 3

• Demonstrated efficacy in ceftazidime non-susceptible Gram-negative infections with 70.1% combined clinical and microbiological cure rate 3
• Active against certain ESBL groups (TEM-1, SHV-12, CTX-M-15, CTX-M-27, KPC-2, KPC-3, OXA-48) 3

For Carbapenem-Resistant Acinetobacter baumannii:

Triple therapy with colistin, sulbactam, and tigecycline showed superior outcomes in network meta-analysis 1

• Colistin-based therapy demonstrated higher clinical cure rates than tigecycline monotherapy 1
• Ampicillin-sulbactam or cefoperazone-sulbactam (categorized as sulbactam) are preferred sulbactam formulations 1

For Carbapenem-Resistant Enterobacteriaceae with Known MIC Data:

High-dose extended-infusion meropenem (6g/day as 3-hour infusion) for isolates with MICs ≤16 mg/L 1

• This approach may salvage carbapenem therapy in select cases 1

Critical Pitfalls to Avoid

Do not use tigecycline monotherapy for hospital-acquired/ventilator-associated pneumonia caused by Acinetobacter species, as it is associated with treatment failure 1

Avoid rifampicin as adjunctive therapy with colistin for Acinetobacter infections, as increased microbial eradication was not associated with improved clinical outcomes 1

Do not delay empiric therapy while awaiting susceptibility results, as inappropriate initial antimicrobial therapy is associated with mortality rates up to 86.1% in carbapenem-resistant infections 1

Monitor for nephrotoxicity closely when using aminoglycosides, colistin, or vancomycin, particularly in patients with cirrhosis or renal impairment 1

• Serum levels of aminoglycosides and vancomycin must be monitored to decrease risk of renal failure 1

Transition to Targeted Therapy

Once susceptibility results are available:

For confirmed carbapenemase-producing Enterobacteriaceae:

• Ceftazidime-avibactam for KPC and OXA-48 producers 2
• Meropenem-vaborbactam for KPC-producing Enterobacteriaceae 2
• Imipenem-cilastatin-relebactam for certain carbapenem-resistant infections 2

For extensively drug-resistant organisms:

• Tigecycline at high doses plus carbapenem in continuous infusion 1
• Addition of intravenous colistin may be necessary in severe infections 1

Duration of therapy: 7 days is recommended for most hospital-acquired and ventilator-associated pneumonia once appropriate therapy is established 1