“The right drug at the right time with the right dose for the right bug for the right duration.” That, said professor Kristina Crothers, MD, is the general guidance for optimizing antibiotic use (while awaiting an infectious disease consult). In her oral presentation at the annual meeting of the American College of Chest Physicians, “Choosing newer antibiotics for nosocomial pneumonia,” Dr. Crothers asked the question: “Beyond the guidelines: When should novel antimicrobials be used?”
Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are the most common nosocomial infections at 22%, and are the leading cause of death attributable to hospital-acquired infections. They increase mortality by 20%-50%, with an economic burden of about $40,000 per patient. The incidence of multidrug-resistant (MDR) organism infections varies widely by locality, but several factors increase the likelihood: prior broad-spectrum antibiotic exposure within the past 90 days; longer hospitalization; indwelling vascular devices; tracheostomy; and ventilator dependence. The Centers for Disease Control and Prevention lists as “Serious Threat” the HAP/VAP MDR organisms methicillin resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa (PSA) with difficult-to-treat-resistance, and beta-lactamase producing Enterobacterales (ESBL). In the category of “Urgent Threat” the CDC lists: carbapenamase-resistant Enterobacterales (CRE) (carbapenamase producing or non–carbapenemase producing), and carbapenem-resistant Acinetobacter (CRAB), according to Dr. Crothers who is at the University of Washington Veterans Affairs Puget Sound Health Care System, Seattle.
Newer antibiotics for HAP/VAP that are still beyond the guidelines include telavancin and tedizolid as gram-positive agents, and as gram-negative ones: ceftazidime-avibactam, ceftolozane-tazobactam, cefiderocol, imipenem-cilastatin-relebactam and meropenem-vaborbactam, she added.
Tedizolid, Dr. Crothers stated, is a novel oxazolidinone, and is an alternative to vancomycin and linezolid for gram-positive HAP/VAP. In the VITAL noninferiority study versus linezolid with 726 patients, it was noninferior to linezolid for 28-day all-cause mortality (28% vs. 26%), but did not achieve noninferiority for investigator-assessed clinical cure (56% vs. 64%).
Televancin, a semisynthetic derivative of vancomycin, in the ATTAIN studies vs. vancomycin had overall similar cure rates. It is FDA-approved for S. aureus HAP/VAP but not other bacterial causes. It should be reserved for those who cannot receive vancomycin or linezolid, with normal renal function, according to Dr. Crothers. Excluded from first-line treatment of gram-positive HAP/VAP are daptomycin, ceftaroline, ceftobiprole, and tigecycline.
Ceftazidime-avibactam, a third-generation cephalosporin-plus novel beta-lactamase inhibitor has wide activity (Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, PSA and Haemophilus influenzae. It is also active against some extended-spectrum beta-lactamases (ESBLs), ampC beta-lactamases (AmpCs), and K. pneumoniae carbapenemase (KPC)–producing Enterobacterales, but not with metallo-beta-lactamases). Ceftazidime-avibactam is also indicated for HAP/VAP, and has a toxicity profile including nausea, vomiting, and diarrhea.
In the REPROVE trial of ceftazidime-avibactam vs. meropenem for 7-14 days with 527 clinically evaluable patients (37% K. pneumoniae, 30% P. aeruginosa, and 33%-35% VAP), the clinical cure at 21-25 days post randomization was 69% vs. 73%, respectively, with similar adverse events.
Ceftolozane-tazobactam, a novel fifth-generation cephalosporin plus a beta-lactamase inhibitor has activity against PSA including extensively drug-resistant PSA, AmpC, and ESBL-E, but it has limited activity against Acinetobacter and Stenotrophomonas. It is indicated for HAP/VAP, has reduced efficacy with creatine clearance of 50 mL/min or less, increases transaminases and renal impairment, and causes diarrhea. In ASPECT-NP (n = 726) ceftolozane-tazobactam versus meropenem for 8-14 days (HAP/VAP), showed a 28 day-mortality of 24% vs. 25%, respectively, with test of cure at 54% vs. 53% at 7-14 days post therapy. Adverse events were similar between groups.