Current management of nosocomial and community-acquired pneumonia in ICU patients with novel antibiotics

Nosocomial pneumonia serves as a paradigm for all severe infections, and appropriate antibiotic therapy is the key determinant of patient outcomes. Most data for the use of antibiotics are derived from studies in non-ICU patients and ignore critical care issues such as fluid resuscitation, mechanical ventilation, and changing renal function. Against the backdrop of increasing antimicrobial resistance and the COVID-19 pandemic, how do we optimize antibiotic administration in the ICU? Professor Andrew Shorr from Washington Hospital Center, Georgetown University, Washington DC, US discussed this burning issue at a Pfizer-sponsored satellite symposium, held during the Asia Pacific Intensive Care Symposium (APICS) 2021. 

Impact of COVID-19 on pneumonia
Several studies have shown that COVID-19 significantly increases the risk of getting ventilator-associated pneumonia (VAP), which is only partially explained by prolonged ventilation duration. “Other possible reasons include breakdown of infection control and innate changes in host immunity,” said Shorr. Importantly, pulmonary dysbiosis caused by COVID-19 and causative organisms of secondary pneumonia are similar to those in other critically ill, ventilated patients. [Crit Care 2021;25:25; J Clin Med 2021;10:555; medRxiv [Preprint] 2021;doi.org/10.1101/2021.01.12.20248588] 

For patients with community-acquired pneumonia (CAP) without confirmed COVID-19, empirical coverage for bacterial pathogens is recommended, but it may not be required for patients with COVID-19 related pneumonia. For patients with concurrent CAP and COVID-19, empirical antibiotic recommendations should be the same as other patients with CAP. [Ann Intern Med 2020;173:304-305]

Multidrug-resistant pathogens in the ICU
The WHO and the US Centers for Disease Control and Prevention have listed carbapenem-resistant Enterobacterales (CRE), Acinetobacter, and multidrug-resistant (MDR) P. aeruginosa among the top priority pathogens for research and development. [https://www.cdc.gov/drugre-sistance/biggest-threats.html;%20https://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-ET_ NM_WHO.pdf] 

Key mechanisms of resistance for Enterobacterales include acquired Klebsiella pneumoniae carbapenemase (KPC), OXA, metallo-carbapenemases and extended-spectrum beta-lactamases (ESBL) with porin loss. For P. aeruginosa, loss of porin OprD plus mutations alter penicillin and cephalosporin susceptibility and acquired metallo-carbapenemases confer carbapenem resistance, while for Acinetobacter, acquired OXA-23, -24, -58 carbapenemases are the main drivers of resistance.

The EPIC III study found that globally, the majority of ICU infections are due to gram-negative bacteria, including Klebsiella, Pseudomonas spp., E coli, Acinetobacter spp., and Enterobacter spp., of which approximately one-third were MDR. Pneumonia was the most common infection, occurring in about 60 percent of patients. [JAMA 2020;15:1478-1487]

“As pathogens vary among locations, global or national data may not be clinically relevant,” said Shorr. “ICU-specific hospital antibiograms are necessary to identify problem pathogens, assess susceptibility rates, and aid the selection of empiric antibiotic therapy.”

Early, appropriate therapy to improve outcomes
Early and appropriate therapy is critical in nosocomial pneumonia. Delays in administering appropriate treatment have been associated with a significant increase in mortality in patients with VAP (Figure 1) in one study. The mean time from diagnosis to initiation of appropriate therapy was 28.6 hours in the delayed group vs 12.5 hours in the early group. [Chest 2002;122:262-268]

“If patients get appropriate antibiotic therapy that kills the pathogen in a timely manner, you reduce the death rates,” emphasized Shorr. “Inappropriate antimicrobial treatment (one which lacks in vitro activity against the causative pathogen) was shown to increase the risk of death by 3.4 times, and for every 5 patients given appropriate therapy, there was one added survivor in a study among critically ill patients with sepsis.” [Crit Care Med 2014;42:2342-2349]

“A strategy to achieve early, appropriate treatment is to initiate empiric treatment early with a broad-spectrum antibiotic that is active against common problem pathogens. Once the susceptibility data of the etiological pathogen are available, therapy may be de-escalated using a narrower-spectrum agent to lower the development of antibiotic resistance,” said Shorr.

The NICE guidelines recommend starting antibiotic treatment as soon as possible after establishing a diagnosis of hospital-acquired pneumonia [HAP], and certainly within 4 hours or within an hour if the person is suspected of, or is at high risk for sepsis. For patients with severe signs and symptoms, or higher risk of resistance, treatment options include piperacillin with tazobactam, ceftazidime, ceftriaxone, cefuroxime, meropenem, and ceftazidime with avibactam. [https://www.nice.org.uk/guidance/cg139]

Role of ceftazidime-avibactam in HAP/VAP
Ceftazidime-avibactam has a broad spectrum of activity against various MDR gram-negative bacteria, including ESBL, AmpC, KPC, and OXA-48-producing Enterobacteriaceae, as well as AmpC Pseudomonas. [Microb Drug Resist 2021;27:342-349] Studies showed that ceftazidime/avibactam had favourable microbiological response rates at test-of-cure for MDR Enterobacteriaceae (78.4 percent vs 71.6 percent) and MDR P. aeruginosa (57.1 percent vs 53.8 percent) vs comparators. [J Antimicrob Chemother 2018;73:2519-2523]

The phase III REPROVE study showed that ceftazidime-avibactam was as effective as meropenem in the treatment of nosocomial pneumonia (HAP or VAP). The study met its primary endpoint, which was clinical cure at the test-of-cure visit. [Lancet Infect Dis 2018:18:285-95)

Ceftazidime-avibactam has also been shown to be more effective than colistin in KPC-producing CRE. The CRACKLE study showed that patients treated with ceftazidime-avibactam had lower mortality rates and higher discharge rates during the first 30 days after starting treatment (Figure 2). [Clin Infect Dis 2018;66:163-171]

Role of ceftaroline in CAP
“The burden of CAP persists, and it remains a common cause of morbidity and mortality,” said Shorr.

Ceftaroline is a 5th-generation cephalosporin with in vitro activity against a range of gram-positive and gram-negative organisms including S. pneumoniae, both methicillin-susceptible and methicillin-resistant S. aureus (MSSA and MRSA, respectively), and Enterobacterales (not ESBLs or CREs). It is more potent in vitro than ceftriaxone against S. pneumoniae and MSSA and has enhanced pharmacokinetic properties in terms of greater lung penetration and less protein binding than ceftriaxone. [J Antimicrob Chemother 2011;66 Suppl 3:iii11-18]

This was shown in a meta-analysis, where patients hospitalized for CAP showed a 60 percent enhancement in clinical cure rates with ceftaroline vs ceftriaxone (odds ratio [OR], 1.66; p<0.001). [J Antimicrob Chemother 2016;71:862-870]

Take-home message
“The resistance among gram-negative and gram-positive organisms is increasing, and this pattern is seen worldwide. Antimicrobial resistance drives inappropriate therapy, and we have to overcome the issues of inappropriate therapy. We have evidence-based options, such as ceftazidime-avibactam and ceftaroline in our armamentarium. It is incumbent upon us, clinicians, to analyse the evidence and apply it in practice to improve patient outcomes,” said Shorr.