Table 6.

Characteristics of antibacterial drugs indicated (or used off-label in selected cases) for treating bloodstream infections (BSI) in critically ill patients

Antibacterials	Activity against MDR pathogens	Class, PD index of choice Suggested dosage in critically–ill patients	Status
Amikacin	Possibly active against MDR-GNB, although increased resistance to classical aminoglycosides has been reported [79, 143]	Aminoglycosides, AUC/MIC 25-30 mg/kg q24h (modified according to TDM)	Approved
Aztreonam	Active against MBL producers not expressing mechanisms of aztreonam resistance (e.g., other beta-lactamases, AmpC hyperexpression, efflux pumps)	Monobactams, T > MIC 1–2 g q8h	Approved
Aztreonam/ Avibactam	ESLBL-PE CPE (all classes of carbapenemases, including MBL)	Monobactams plus BLI, T > MIC 6500 mg aztreonam/2167 mg avibactam q24h on day 1 followed by 6000 mg aztreonam/2000 mg avibactam q24h	In clinical development; potential indications according to phase-3 RCT are cIAI, HAP/VAP (NCT03329092) and serious infections due to MBL-producing bacteria (NCT03580044)
Cefepime	Active against AmpC hyperproducer enterobacterales	Cephalosporins, T > MIC 2 g q8h or continuous infusion	Approved
Cefiderocol	ESBL-PE CPE (all classes of carbapenemases, including MBL) MDR-PA CRAB	Siderophore cephalosporins, T > MIC 2 g q8h	FDA Approved for cUTI caused by susceptible Gram-negative microorganisms, who have limited or no alternative treatment options according to phase-3 RCT are infections due to carbapenem-resistant organisms in different sites (NCT02714595). Pivotal study on HAP/VAP finished (NCT03032380)
Ceftobiprole	MRSA VISA hVISA VRSA	Cephalosporins, T > MIC 500 mg q8 h	Approved for CAP and HAP (excluding VAP) In vitro and/or limited clinical data reporting a possible use as salvage therapy in combination with vancomycin or daptomycin for MRSA bacteremia
Ceftolozane/ Tazobactam	ESBL-PE MDR-PA	Cephalosporins plus BLI, T > MIC 1.5 g q8h (3 g q8h for pneumonia)	Approved for cIAI (in combination with metronidazole) and cUTI Approved by FDA for VAP/HAP, with the CHMP of EMA also recently adopting a positive opinion recommending a change to the terms of the marketing authorization, including also VAP/HAP among approved indications
Ceftaroline	MRSA VISA hVISA VRSA	Cephalosporins, T > MIC 600 mg q12 h	Approved for ABSSSI and CAP In vitro and/or limited clinical data reporting a possible use as salvage therapy in combination with vancomycin or daptomycin for MRSA bacteremia
Ceftazidime		Cephalosporins, T > MIC 6 g q24h continuous infusion	Approved
Ceftazidime/ Avibactam	ESBL-PE CPE (class A and class D carbapenemases) MDR-PA	Cephalosporins plus BLI, T > MIC 2.5 g q8h	Approved for cIAI (in combination with metronidazole), cUTI, HABP/VABP, and infections due to aerobic Gram-negative organisms in adult patients with limited treatment options
Ceftriaxone		Cephalosporins, T > MIC 1–2 g q24h	Approved
Colistin	ESBL-PE CPE (all classes of carbapenemases, including MBL) MDR-PA CRAB	Polymyxins, AUC/MIC 9 MU loading dose, 4.5 MU every 8–12 h (modified according to TDM where available; higher dosages to be possibly considered in patients with ARC [58])	Approved Recommended for serious infections due to susceptible bacteria when other treatment options are limited
Daptomycin	MRSA VRE	Lipopeptides, AUC/MIC 8–10 mg/kg q24h	Approved for cSSTI and right-sided endocarditis
Eravacycline	MRSA VRE ESBL-PE CPE CRAB	Fluocyclines, AUC/MIC 1 mg/kg q12h	Approved for cIAI To be possibly used for BSI due to MDR organisms in absence of dependable alternative options, in combination with other agents (expert opinion)
Ertapenem	ESBL-PE	Carbapenems, T > MIC 1 g q12 h	Approved for IAI, CAP, acute gynecological infections, and diabetic food infections
Fosfomycin	ESBL-PE CPE (all classes of carbapenemases, including MBL) MDR-PA MRSA VRE	PEP analogues, unclear [144] 4–6 g q6h continuous infusion	Approved For BSI used in combination with other agents for the treatment of MDR infections with limited treatment options (also for CRAB), although in lack of high-level evidence
Gentamicin	Possibly active against MDR-GNB, although increased resistance to classical aminoglycosides has been reported [79, 143]	Aminoglycosides, AUC/MIC 5–7 mg/kg q24h (modified according to TDM)	Approved
Imipenem/ Cilastatin	ESBL-PE	Carbapenems, T > MIC 0.5–1 g q6h	Approved
Imipenem/ Relebactam	ESBL-PE CPE (class A carbapenemases) Some MDR-PA	Carbapenems plus BLI, T > MIC 500 mg/250–125 mg q6h	FDA approved for the treatment of cUTI and cIAI. The phase-3 RCT are HAP/VAP (NCT02493764) is ongoing.
Meropenem	ESBL-PE	Carbapenems, T > MIC 1–2 g q8h or extended infusion (over 4 h)	Approved
Meropenem/ Vaborbactam	ESBL-PE CPE (class A carbapenemases)	Carbapenems plus BLI, T > MIC 4 g q8h	Approved for cUTI, cIAI, HAP, VAP, and infections due to aerobic Gram-negative organisms in patients with limited treatment options
Piperacillin/ Tazobactam	Possibly active against ESBL-PE, although the results of the MERINO trial discourage the use of piperacillin/tazobactam for severe ESBL-PE infections [145]	Penicillins plus BLI, T > MIC 4.5 g q6h continuous infusion	Approved
Plazomicin	ESBL-PE CPE (all classes of carbapenemases, including MBL, although resistance has been described in NDM-1 producing strains, owing to co-expression of plazomicin-inactivating methyltransferases [146]) MDR-PA CRAB	Aminoglycosides, AUC/MIC 15 mg/kg q24h	An application has been recently submitted to EMA for approval of plazomicin for cUTI and other severe infections (plazomicin is approved by FDA for cUTI)
Tigecycline	MRSA VRE ESBL-PE CPE (all classes of carbapenemases, including MBL) CRAB	Glycylcyclines, AUC/MIC 100–200 mg loading those, then 50–100 mg q12h	Approved for cSSTI (excluding diabetic foot infections) and cIAI For BSI used only in combination with other agents for infections due to MDR organisms in presence of limited alternative therapeutic options
Vancomycin	MRSA	Glycopeptides, AUC/MIC 15–30 mg/kg loading dose, 30–60 mg/kg q12h, or continuous infusion (modified according to TDM)	Approved

ABSSSI acute bacterial skin and skin-structure infections, ARC augmented renal clearance, AUC area under the concentration curve, BLI beta-lactamases inhibitors, BSI bloodstream infections, CAP community-acquired pneumonia, CHMP Committee for Medicinal Products for Human Use, cIAI complicated intra-abdominal infections, CPE carbapenemase-producing Enterobacterales, CRAB carbapenem-resistant Acinetobacter baumannii, cSSTI complicated skin and soft-tissue infections, cUTI complicated urinary tract infections, EMA European Medicines Agency, ESBL-PE extended-spectrum beta-lactamase-producing Enterobacterales, FDA Food and Drug Administration, HAP hospital-acquired pneumonia, MBL metallo-beta-lactamases, NDM New Delhi metallo-beta-lactamase, L-AmB liposomal amphotericin B, MDR multidrug-resistant, MIC minimum inhibitory concentration, MRSA methicillin-resistant Staphylococcus aureus, MU million units, PA Pseudomonas aeruginosa, PD pharmacodynamics, PEP phosphoenolpyruvate, RCT randomized controlled trials, TDM therapeutic drug monitoring, VAP ventilator-associated pneumonia, VRE vancomycin-resistant enterococci