Antibiotic Therapy for Multidrug-Resistant Gram-Negative Infections

Introduction to Combination Therapy

The European Society of Clinical Microbiology and Infectious Diseases recommends avoiding certain combination therapies, such as colistin-carbapenem and colistin-rifampin, due to strong evidence against their use and high to moderate certainty of evidence 1
For patients with severe infections, the European Society of Clinical Microbiology and Infectious Diseases suggests considering combination therapy with two in vitro active antibiotics, such as polymyxin, aminoglycoside, tigecycline, or sulbactam combinations 1

For patients with CRAB and meropenem MIC <8 mg/L, the European Society of Clinical Microbiology and Infectious Diseases recommends considering carbapenem combination therapy with high-dose extended-infusion carbapenem dosing 1
XDR Pseudomonas aeruginosa is defined as being non-susceptible to at least one agent in all but two or fewer antimicrobial categories, and novel β-lactam agents such as ceftolozane/tazobactam and ceftazidime/avibactam are recommended as first-line options for targeted treatment, with imipenem/cilastatin-relebactam and cefiderocol as potential alternatives 2, 3
Ceftolozane-tazobactam is recommended as first-line treatment for severe infections caused by carbapenem-resistant Pseudomonas aeruginosa (CRPA) if it is active in vitro, with a standard dose of 1.5g (ceftolozane 1g/tazobactam 0.5g) IV q8h and appropriate renal adjustments, according to the Clinical Microbiology and Infection and American College of Clinical Microbiology guidelines 1

Monotherapy is generally preferred when using newer agents like ceftolozane/tazobactam or ceftazidime/avibactam, but combination with a second in vitro active drug is suggested for severe infections when using colistin-based regimens, with potential combination options including colistin + carbapenem, colistin + fosfomycin, or colistin + aminoglycoside (if susceptible) 3, 1
The Infectious Diseases Society of America recommends combining colistin with carbapenems when the MIC of the carbapenem is ≤32 mg/L, as supported by the European Society of Clinical Microbiology and Infectious Diseases 4
The recommended dosage for systemic infections due to multidrug-resistant gram-negative bacteria is a loading dose of 5 mg/kg of colistin base activity (CBA) IV, followed by a maintenance dose of 2.5 mg CBA × (1.5 × CrCl + 30) IV every 12 hours, with dose adjustments based on renal function, as recommended by the Infectious Diseases Society of America and the Intensive Care Medicine guidelines 4, 5

The recommended treatment durations are:

Infection Type	Treatment Duration
Complicated urinary tract infections	5-10 days
Complicated intra-abdominal infections	5-10 days
Ventilator-associated or hospital-acquired pneumonia	10-14 days
Bacteremia	10-14 days

Close monitoring of renal function during treatment is recommended, as warned by the National Kidney Foundation and the Infectious Diseases Society of America, due to the risk of nephrotoxicity (8-30% of patients) and acute kidney injury (14-20% of patients) 4

The use of colistin should be reserved for infections proven or strongly suspected to be caused by susceptible bacteria, due to its potential toxicity, as recommended by the American College of Physicians and other medical societies 4
Obtaining infectious disease consultation is strongly recommended for management of CRPA infections, particularly for patients with risk factors, as recommended by the Infectious Diseases Society of America and other medical societies 4, 6, 7