Management of MDROs in the ICU and the role of newer antimicrobial agents

Intensive care unit (ICU) patients are at risk of developing serious infections with multidrug-resistant organisms (MDROs), which require appropriate and adequate antibiotic coverage. Early empirical coverage is pivotal in saving patients’ lives. At a recent webinar co-organized by the Society of Infectious Disease (Singapore) and Pfizer, renowned Professor David Paterson, Professor of Medicine and Director, The University of Queensland Centre for Clinical Research, and Consultant Infectious Diseases Physician, Royal Brisbane and Women’s Hospital, Brisbane, Australia, discussed the role of newer antimicrobial agents, including ceftazidime-avibactam (Zavicefta) in the management of MDROs in the ICU. Dr Wong Sin Yew, Infectious Disease Physician at Gleneagles Medical Centre and Mount Elizabeth Novena Specialist Centre, Singapore, chaired the event. 

Asia is one the epicentres of antimicrobial drug resistance, with a high burden of antibiotic-resistant species, including extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae, Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae, New Delhi metallo-β-lactamase 1 (NDM-1)-producing Enterobacteriaceae, and MDR Acinetobacter baumannii, among others. [Int J Antimicrob Agents 2011;37:291-295]

“Across the Asia-Pacific region, many people in the community now carry ESBL-producing organisms in their gut. When they get infections such as peritonitis or early hospital-acquired infections, it is often due to an ESBL-producer,” said Paterson. 

Serious infections caused by ESBLs are often treated by carbapenems, which potentially select for carbapenem-resistance. Piperacillin-tazobactam was investigated in the MERINO trial as a potential carbapenem-sparing option in patients with bloodstream infection (BSI) caused by ceftriaxone-nonsusceptible E. coli or K. pneumoniae, but susceptible to piperacillin-tazobactam. Results showed that piperacillin-tazobactam was inferior to meropenem for BSI caused by ESBL-producers, and associated with an increased risk of mortality at 30 days. [JAMA 2018;320:984-994]

Is there a case for carbapenem-sparing options empirically?
Despite disappointing results with piperacillin-tazobactam, there is potential for other beta-lactam/beta-lactamase inhibitor combinations to be carbapenem-sparing options. 

A meta-analysis found that ceftazidime-avibactam may be a carbapenem-sparing option for the treatment of mild-to-moderate complicated urinary tract and intra-abdominal infections caused by ESBL-producing Enterobacterales species. [Antimicrob Agents Chemother 2020;65:e01052-20] 

Ceftazidime-avibactam meets most of the characteristics of an ideal beta-lactam/beta-lactamase inhibitor combination. “Ceftazidime is a well-trusted beta-lactam with proven safety profile and excellent antipseudomonal activity. Avibactam inhibits most beta-lactamase types including ESBLs, AmpC beta-lactamases of Enterobacter and Pseudomonas, as well as KPC and OXA-48 carbapenemases produced by carbapenem-resistant Enterobacteriaceae (CRE),” said Paterson. “However, it is not active against metallo-beta-lactamases, such as NDM.” 

In comparison, ceftolozane-tazobactam does not inhibit any of the carbapenemases. “Ceftolozane-tazobactam is primarily an antipseudomonal drug. It is not effective against CRE,” said Paterson. 

Clinical efficacy of ceftazidime-avibactam vs carbapenem
Ceftazidime-avibactam demonstrated noninferiority to meropenem for the treatment of hospital-acquired pneumonia and ventilator-associated pneumonia (HAP/VAP) in the REPROVE study. Clinical cure rates were similar for both arms in the clinically evaluable (CE) population and the clinically modified intention-to-treat (cMITT) population (Figure 1). [Lancet Infect Dis 2018;18:285-295] 

Clinical efficacy of ceftazidime-avibactam vs colistin
A prospective, multicentre, observational study compared the efficacy of ceftazidime-avibactam with colistin in KPC-producing CRE. Patients treated with ceftazidime-avibactam were less likely to die and more likely to be discharged home during the first 30 days after starting treatment compared with patients treated with colistin (IPTW-adjusted all-cause hospital mortality, 9 percent vs 32 percent (Figure 2). [Clin Infect Dis 2018;66:163-171] 

“When treating ICU patients, it is helpful to use a 4-point algorithm to inform empiric antibiotic decisions: (1) prior microbiologic isolates from the patient, (2) prior antibiotics used by the patient, (3) duration of ICU stay, and (4) the current epidemiology including outbreaks,” said Paterson. 

He illustrated this with a hypothetical case example of a 65-year-old man with septic shock, whose past medical history included hypertension, smoking, type 2 diabetes, and benign prostatic hypertrophy. He received Cefazolin perioperatively for coronary artery bypass grafting (CABG), with very slow wean. He was mechanically ventilated and was diagnosed with pneumonia (Figure 3). 

Discussion
Situation 1: “Piperacillin/tazobactam is appropriate for some patients with very early hospital-acquired pneumonia but not beyond that for widespread use in established VAP,” said Paterson. Based on the MERINO study, meropenem is a proven choice. Beta-lactam/beta-lactamase inhibitor combinations with activity against ESBL-producers are potential carbapenem-sparing options. However, data are still lacking for bloodstream infections. 

Situation 2: A prolonged ICU stay increases the risk for resistant organisms. “Unfortunately, many agents are not effective against carbapenem-resistant Acinetobacter. It is usually treated with amikacin, polymyxin B, and colistin, none of which are great options,” said Paterson. 

Situation 3: Ceftazidime-avibactam and ceftolozane-tazobactam are active against most carbapenem-resistant P. aeruginosa. “In my opinion, ceftazidime-avibactam would appear most appropriate as a therapy against Klebsiella or Pseudomonas where there is suspected or proven resistance to meropenem,” said Paterson.

Conclusion
“It is important to consider the “resistance risk” when choosing an empiric therapy for seriously ill patients. If there is a risk of ESBL-producers, meropenem is preferred. If the risk is for carbapenem resistant Pseudomonas, ceftolozane-tazobactam or ceftazidime-avibactam are potential options. For KPC or OXA-producing CRE, ceftazidime-avibactam is a good choice,” said Paterson.