Spotlight on multidrug-resistant gram-negative infections: New developments for an old problem

Antimicrobial resistance has become increasingly dire as the rapid emergence of drug resistance, especially gram-negative pathogens, has outpaced the development of new antibiotics. At a recent virtual symposium, Dr Hsu Li Yang, Vice Dean (Global Health) and Programme Leader (Infectious Diseases), NUS Saw Swee Hock School of Public Health, presented epidemiological data on multidrug-resistant (MDR) gram-negative bacteria (GNB) in Asia, while Dr Tan Thuan Tong, Head and Senior Consultant, Department of Infectious Diseases, Singapore General Hospital (SGH), focused on the role of ceftazidime-avibactam in MDR GNB infections. Dr Andrea Kwa, Assistant Director of Research, Department of Pharmacy, SGH, joined the panel in an interactive fireside chat, to discuss challenges, practical considerations, and solutions in MDR gram-negative infections. This Pfizer-sponsored symposium was chaired by Dr Ng Shin Yi, Head and Senior Consultant of Surgical Intensive Care, SGH.

Epidemiology of MDR GNB
“Antimicrobial resistance and drug-resistant infections are common in most parts of Asia, including Singapore,” said Hsu. “Data up to 2016 in this region showed that more than 50 percent of Acinetobacter baumannii isolates are carbapenem resistant. For Enterobacterales, less than 5 percent of Escherichia coli isolates are resistant to carbapenems, but the figure is two- to threefold for Klebsiella pneumoniae.”

Prior to the COVID-19 pandemic, carbapenem-resistant Enterobacterales (CRE) in Singapore was increasing in frequency. Many carbapenemase genotypes have been found locally, including OXA, NDM, KPC, VIM, IMP, and mcr. [Antimicrob Agents 2019;54:381-399]

“During the pandemic, infection control measures were increased, social distancing was implemented, and international travel was severely restricted. It would be interesting to see the impact of these measures on the incidence of MDR organisms,” commented Hsu.

MDR GNB: Serious clinical consequences
In a systematic review, the mortality rate with CREs is high with current treatment options. Mortality was up to 50 percent for the tigecycline-gentamicin combination, up to 64 percent for tigecycline-colistin, and up to 67 percent for carbapenem-colistin,” said Tan. [Antimicrob Agents Chemother 2014;58:654-663]

Delays in the prescription of an adequate antibiotic treatment results in increased mortality rates. Therefore, patient stratification for risk factors of MDR GNB infection is crucial to optimize the prescription of an adequate empiric antimicrobial therapy. Risk factors for MDR GNB include baseline patient characteristics (eg, age >70 years, comorbidities such as diabetes or malignancy), epidemiological background (eg, prior hospitalization, ICU admission, travel from high endemic area), recent antibiotic therapy, prior colonization with certain microorganisms, and indwelling devices. [Expert Rev Anti Infect Ther 2017;15:55-65]

In vitro activity
Ceftazidime-avibactam combines the novel beta-lactamase inhibitor avibactam with the 3rd generation cephalosporin ceftazidime.

“Ceftazidime-avibactam exhibits in vitro activity against majority of metallo-beta-lactamase (MBL)-negative Enterobacteriaceae and P. aeruginosa isolates with ceftazidime-nonsusceptible, meropenem-nonsusceptible, colistin-resistant, and MDR phenotypes,” presented Tan. “It inhibited 97.2–100 percent of Enterobacteriaceae that carried extended-spectrum beta-lactamases (ESBL), AmpC cephalosporinases, and carbapenemases. It also inhibited 91.3 percent of carbapenem-nonsusceptible P. aeruginosa in which no acquired beta-lactamase was detected.” [Antimicrob Agents Chemother 2018;62:e02569-17]

A large Asia-Pacific study involving 42 medical centres in nine countries corroborated these findings. Ceftazidime-avibactam demonstrated potent in vitro activity against all Enterobacteriaceae isolates tested (n=9,149; 99.0 percent susceptible) and was the most active against isolates that were MBL-negative (99.8 percent susceptible). Against P. aeruginosa isolates (n=2,038), 92.6 percent of all isolates and 96.1 percent of MBL-negative isolates were susceptible to ceftazidime-avibactam. [Antimicrob Agents Chemother 2018;62:e02569-17]

Randomized clinical trial
Prospective randomized, double-blind controlled phase III trials have established noninferiority of ceftazidime-avibactam against carbapenem comparators in complicated urinary tract infections (cUTI) (RECLAIM trials), complicated intra-abdominal infections (cIAI) (RECAPTURE trials), and hospital-acquired pneumonia (REPROVE trial). [Clin Infect Dis 2016;63:6:754-762; Clin Infect Dis 2016;62:1380-1389; Lancet Infect Dis 2018;18:285-295]

In addition, the REPRISE trial demonstrated the efficacy of ceftazidime-avibactam in patients with ceftazidime-resistant Enterobacteriaceae and P. aeruginosa cUTI or cIAI, with best available therapy as the comparator. There was also a numerically higher proportion of patients achieving a favourable microbiological response in the ceftazidime-avibactam arm. [Lancet Infect Dis 2016;16:661-673]

Real-world data
“Several real-world studies have been published on the use of ceftazidime-avibactam for infections caused by carbapenem-resistant organisms,” said Tan. In one case series, 28 out of 38 patients (73.7 percent) with serious infections caused by CRE (n=36) or P. aeruginosa (n=2) achieved clinical microbiological cure following salvage therapy with ceftazidime-avibactam. [Antimicrob Agents Chemother 2017;61:e01964-16]

In the CRACKLE study which compared the efficacy of ceftazidime-avibactam vs colistin in Klebsiella pneumoniae carbapenemase (KPC)–producing CRE, patients treated with ceftazidime-avibactam were less likely to die and more likely to be dis-charged home during the first 30 days after starting treatment (Figure 1). [Clin Infect Dis 2018;66:163-171]

In patients with infections caused by KPC-producing Klebsiella pneumoniae, ceftazidime-avibactam salvage therapy significantly improved survival vs other antimicrobial drug regimens (mortality rates: 36.5 percent vs 55.8 percent; p=0.005). [Clin Inf Dis 2019;68:355-364]

In another study of 57 patients with IAI, HAP, and UTI caused by OXA-48 carbapenemase-producing Enterobacteriaceae, ceftazidime-avibactam salvage therapy showed promising efficacy results. [J Antimicrob Chemother 2018;73:3170-3175]

Among patients with carbapenem-resistant Klebsiella pneumoniae bacteraemia, patients on ceftazidime-avibactam achieved significantly higher rates of clinical success than those who received a carbapenem plus aminoglycoside (p=0.04), colistin (p=0.009), or other regimens (p= 0.004). [Antimicrob Agents Chemother 2017;61:e00883-17]

When the combination of ceftazidime-avibactam and aztreonam (CAZ-AVI + ATM)^# was compared with other active antibiotics (OAA) in patients with bloodstream infections* due to MBL-producing Enterobacterales, the CAZ-AVI + ATM group had a lower 30-day mortality rate (19.2 percent vs 44 percent; p=0.007), lower clinical failure rate at day 14 (p=0.002), and shorter length of stay (p=0.007). [Clin Infect Dis 2020;ciaa586]

Challenges, practical considerations, and solutions
“As with the use of any antibiotic, resistance will develop,” cautioned Tan. “The empirical use of ceftazidime-avibactam should be limited to selected high-risk patients.”

“Rapid novel diagnostics may play a role in screening for antimicrobial resistance and may help to guide empiric antibiotic use in high-risk patients,” added Kwa. “Besides drug choice, the proper application of the drug is paramount, with considerations given to pharmacokinetics and dosing.”

Other than patient carriage, the hospital environment is a potential reservoir for MDR GNB, particularly ward sinks and ICUs. [Antimicrob Resist Infect Control 2020;9:29; Nat Med 2020;26:941-951] “Colonization of sinks are particularly challenging to solve; biofilms form in sink traps and along the pipes, which are not easily removed using disinfectants or heat. Resistant genes get passed between bacteria. When fluids are poured down the sink, the bacteria get aerosolized; this has been known to cause outbreaks,” elaborated Hsu.

“None of the studies thus far has linked surveillance to outcomes. There is a great need to tie in clinical outcomes with surveillance to understand the impact of drug resistance,” he stressed. “Continued surveillance and interventions are necessary to control the spread of MDR GNB, while better antimicrobial agents are critical for treatment.”

Takeaway messages
•         MDR GNB are a persistent and worrying problem.
•         In vitro studies, randomized clinical trial evidence, and real-world studies have demonstrated the efficacy of ceftazidime-avibactam in infections caused by MDR GNB.
•         Proper stratification is required to select patients for risk factors of MDR GNB infection to optimize the prescription of an adequate empiric antimicrobial therapy.