Table 3.

Characteristics of agents with activity against MDR Gram-negative bacteria

Antimicrobial Agent	Mechanism of Action	Dosage1	Targeted Organisms	Limitations
Carbapenems
Meropenem, Imipenem, and Doripenem (IV)	Inhibits bacterial cell wall synthesis by binding to PBPs	Conventional: 1 gm over 30 min every 8 h High-dose, prolonged infusion: 2 gm over 3 h every 8 h	ESBL-E AmpC-E P. aeruginosa A. baumannii	Prolonged infusion regimens may be added to an active agent for CRE infections Increasing resistance to A. baumannii and P. aeruginosa
Ceftazidime-avibactam (IV)	Ceftazidime: Inhibits bacterial cell wall synthesis by binding to PBPs Avibactam: Inhibits β-lactamases	2.5 gm every 8 h	CRE (if KPC or porin-mediated resistance), MDR P. aeruginosa	•Not active against metallo-β lactamase producers (e.g., NDM) No clinical data to assess efficacy vs. CRE or MDR P. aeruginosa
Ceftolozane-tazobactam (IV)	Ceftolozane: Similar to ceftazidime Tazobactam: Inhibits β-lactamases	1.5 gm every 8 h 3 gm every 8 h for pneumonia and bacteremia	MDR P. aeruginosa	Not active against CRE No clinical data to assess efficacy vs. MDR P. aeruginosa
Polymyxins
Colistin (IV)	Binds to LPS and phospholipids in the outer cell membrane, leading to leakage of intracellular contents	US: Coly-Mycin M: 2.5–5 mg/kg/d of CBA (divided into 2–4 doses)2 Europe: Colomycin: 6–9 million IU/d (divided into 2–3 doses)2	CRE MDR Pseudomonas aeruginosa A. baumannii	Nephrotoxicity and neurotoxicity Suboptimal clinical efficacy when used as monotherapy Optimal dosing regimen and antimicrobial susceptibility testing method unclear Low concentrations in the respiratory tract
Polymyxin B (IV)	Same as colistin	1.5–2.5 mg/kg (15 000–25 000 units) per day	Same as colistin	Same as colistin, except also achieves low concentrations in the urinary tract
Aminoglycosides
Gentamicin and Tobramycin (IV)	Bind to 16S rRNA portion of the 30S ribosomal subunit, blocking mRNA translation.	Extended-interval: 5–7 mg/kg every 24 h Conventional: 2–3 mg/kg loading dose, followed by 1.5–2 mg/kg every 8 h	MDR P. aeruginosa A. baumannii CRE (gentamicin active in up to 50% of isolates; tobramycin rarely active)	Nephrotoxicity and otovestibular toxicity (tobramycin is less toxic than gentamicin) [51] Suboptimal clinical efficacy when used as monotherapy for bacteremia Low concentrations in the respiratory tract Not active vs. NDM-producing CRE
Amikacin (IV)	Same as gentamicin	Extended-interval: 15 mg/kg every 24 h Conventional: 7.5 mg/kg every 12 h	Same as gentamicin, but less active vs. CRE	Same as gentamicin, but less nephrotoxicity and ototoxicity [50]
Tigecycline (IV)	Binds to the 30S ribosomal subunit, blocking the binding of tRNA	100 mg loading dose, followed by 50 mg every 12 h	CRE A. baumannii	Low bloodstream and urinary tract concentrations Use associated with increased mortality in randomized trials Not active vs. P. aeruginosa
Minocycline (IV and oral)	Similar to tigecycline	200 mg loading dose, followed by 100 mg every 12 h	A. baumannii CRE	Limited clinical data supporting its use for A. baumannii infections Less active than tigecycline vs. CRE
Fosfomycin	Inhibits peptidoglycan (and thus cell wall) synthesis	US: oral formulation only: 3 gm sachet in 3–4 oz water (once, or every 2–3 d for 3 doses) Europe: IV formulation available: 2–4 g every 6–8 h	CRE ESBL-E	IV formulation not available in the United States -> use of sachet limited to UTIs Low barrier to development of resistance
Trimethoprim-sulfamethoxazole (IV and oral)	Inhibits synthesis of folic acid at 2 different steps	10-15 mg/kg trimethoprim component per day, in divided doses, every 8-12 h	Stenotrophomonas maltophilia	Myelosuppression May increase creatinine and potassium levels

Abbreviations: IV, intravenous; LPS, lipopolysaccharide; CBA, colistin base activity; IU, international units; CRE, carbapenem-resistant Enterobacteriaceae; MDR, multidrug-resistant; ESBL-E, ESBL-producing Enterobacteriaceae; AmpC-E; AmpC β-lactamase-producing Enterobacteriaceae; UTIs, urinary tract infections; PBP, Penicillin-binding protein; Klebsiella pneumoniae carbapenemase.

¹These recommended dosages are for patients with normal renal function. Dosage adjustments are required in the setting of renal insufficiency for many of these agents.

²For critically ill patients, a loading dose of 270 mg or 9 million IU of colistin should be used.