TABLE 1.

Summary of positive and negative aspects and dosing of potentially useful drugs in the treatment of infections with ESBL- and AmpC-producing Enterobacteriaceae^b

Drug	Positive aspects	Negative aspects	Dosing (for adults with normal renal function) and comments
Meropenem, imipenem, doripenem	Reference drugs, usually active	Ecological impact; less experience with doripenem	Standard dosing is recommended
Ertapenem	Not active against P. aeruginosaa; usually active; convenient for outpatient therapy and deescalation from other carbapenems	Ecological impact if CPE endemicity/outbreak; doubts in cases of septic shock (insufficient dosing?); anecdotal failures described with development of resistance (porin loss)	1 g/day in most situations; for septic shock or high-inoculum infections with borderline MIC isolates, use other alternatives or increase dose to 2 g/day
Piperacillin-tazobactam	Probably noninferior to carbapenems in UTI and biliary tract infections	False susceptibility with some automated systems; inoculum effect (unrelated to ESBLs); heterogeneous resistance rates (5 to 30% among ESBL producers, higher among AmpC producers); doubts in cases of septic shock, pneumonia (CLSI susceptibility breakpoint too high)?	4.5 g every 8 h (extended infusion) or every 6 h
Amoxicillin-clavulanic acid	No inoculum effect; probably noninferior to carbapenems in UTI and biliary tract infections; not active against P. aeruginosaa; convenient for oral switch	Not available for i.v. use in many countries; heterogeneous resistance rates, usually >40% among ESBL producers; AmpC producers are resistant	Intravenous, 2.2 g/8 h; oral, at least 1.250 g/8 h for UTI
Ceftolozane-tazobactam	Areas with large proportions of susceptible isolates	Reserve drug for MDR P. aeruginosa infection; scarce experience so far; 10–30% resistance rates among ESBL producers, lower rates in AmpC producers	1.5 g/8h; approved for cUTI and cIAI (with metronidazole); consider 3 g/8 h for pneumonia
Ceftazidime-avibactam	Large proportion of susceptible isolates	Reserve drug for KPC- or OXA-48-producing Enterobacteriaceae	2.5 g/8 h; approved for cUTI and cIAI (with metronidazole); in Europe, also approved for HAP in case of limited options
Cefotaxime, ceftriaxone, ceftazidime, cefepime	Some ESBL-E may be susceptible; cefepime is usually active against AmpC producers	Most isolates are resistant (except to cefepime in the case of AmpC producers); inoculum effect; ecological impact; clinical data are scarce and contradictory	If used, high doses are recommended (cefotaxime, 1 g/6 h to 2 g/8 h; ceftazidime or cefepime, 2 g/8 h)
Cefoxitin, cefotetan, cefmetazole, moxalactam, flomoxef	Not active against P. aeruginosaa; areas with large proportions of susceptible isolates (ESBL producers); probably useful against UTI for stable patients	AmpC producers are resistant; inoculum effect; observational studies with contradictory results; anecdotally described development of resistance during therapy	High doses; close follow-up needed
Temocillin	Active against ESBL and AmpC producers; not active against P. aeruginosaa	Not available in many countries; comparative studies are lacking	Probably 2 g every 8 h
Gentamicin, tobramycin, amikacin	Active against many ESBL and AmpC producers; useful for UTI	Nephrotoxicity; less efficacious in non-UTI infections; heterogeneous resistance rates	Standard dosing (see Table 2); may be considered empirically as carbapenem-sparing agents (in monotherapy or in combination with a lower-spectrum β-lactam) until microbiological data are available
Tigecycline	Active against most ESBL and AmpC producers; not active against P. aeruginosaa	FDA and EMA warnings for use only if other options are unavailable/unsuitable; probably not a good option for UTI or HAP	100-mg loading dose, 50 mg/12 h; may be an alternative in cIAI
Fosfomycin (i.v.)	Noninferior to piperacillin-tazobactam in cUTI (pending publication of data)	Not available in many countries; scant experience; risk of emergence of resistant subpopulations with monotherapy	4 g/6 h to 6–8 g/8 h
Ciprofloxacin, levofloxacin	Potentially useful for fully susceptible isolates; convenient for oral switch	Ecological impact; most isolates are resistant; failures for isolates with MICs of 0.5–1 mg/liter have been described	For i.v. ciprofloxacin, 400 mg/8–12 h; for oral ciprofloxacin, 500–700 mg/12 h; for levofloxacin (i.v., oral), 750 mg/24 h
Trimethoprim-sulfamethoxazole	Convenient for oral switch	Most isolates are resistant; scant published experience	i.v. or oral, 160/800 mg/8–12 h

^aConsidered a positive aspect in terms of antimicrobial stewardship purposes (avoiding selective pressure on P. aeruginosa).

^bCPE, carbapenemase-producing Enterobacteriaceae; i.v., intravenous.