Emerging Challenge of Antibiotic Resistance: Combination of Ceftazidime – Avibactam and Aztreonam under Threat

OBJECTIVE: Our study aimed to evaluate the emerging resistance to ceftazidime-avibactam (CAZ-AVI) -aztreonam drug combination for Carbapenem-resistant organisms (CRO) using synergy testing and also to evaluate the incidence of clinical recovery like septic shock, number of patients requiring mechanical ventilation, need for dialysis and mortality. METHODS: A prospective observational study was conducted over nine months on patients with sepsis admitted to the medical intensive care unit (MICU) of BLK-MAX super-speciality hospital, New Delhi. CRO isolates were examined for resistance to aztreonam and CAZ-AVI, and XpertOCarb-R (cepheid) panel was used to identify the genetic mechanism of resistance. To determine the isolate's susceptibility or resistance to the combination, a synergy test between CAZ-AVI and aztreonam was conducted. Result: A total of 45 patients who grew CRO in their blood & body fluid cultures were enrolled in the study over 9 months. The patients' ages ranged from 26 to 83, with a mean of 62. 55% of patients were above 65. Among these 45 patients, comorbidities were hypertension (35%), DM (35%), CAD (24%), malignancy (40%) and COPD (11%) Amongst the CROs, Klebsiella was the commonest organism isolated (n=29; 64.4%) followed by Escherichia coli (n=11; 24.4%) and Pseudomonas aeruginosa (n=5;11.1%). The CRO isolates were collected from blood (n =17;37.7%), lower respiratory tract samples (n = 12;26.6%), urine (n =8; 17.7%), pus (n = 4; 8.8%) and other body fluid cultures (n = 4; 8.8%). 51.1% (n= 23) of isolates were NDM producers, 6.6% (n=3) were OXA-48 producers and 37.7% (n=17) were NDM and OXA-48 co-producers. 88.8% (n=40) organisms were resistant to CAZ-AVI and only 11.1% (n=5) isolates were susceptible to CAZ-AVI. CRO isolates also showed a high resistance to aztreonam (n=38;84.4%). 75.5% of organisms (n=34) showed positive synergy testing to the ceftazidime-avibactam-aztreonam combination; on other hand, synergy testing was negative for ceftazidime-avibactam-aztreonam combination in 24.4% of the isolates (MIC of aztreonam < 4ug/ml for enterobacterales and < 8 ug/ml for pseudomonas considered as susceptible). 82.2% (n=37) patients with CRO infections were in septic shock requiring vasopressor and inotropic support 17% of patients were managed with oxygen therapy by facemask alone. 55% (n=25) of patients required ventilatory support, and among these patients, 13% (n=6) were managed with NIV and another 13% required intubation & invasive mechanical ventilation but were denied consent for endotracheal intubation by the family and were managed on NIV only. Renal replacement therapy in form of haemodialysis and CRRT was required by 24% patients with CROs. The mortality in patients with CROs was 40% (n=18). 42% patients were discharged and 17% were lost to follow-up as they went LAMA. CONCLUSION: Our study revealed alarming (24.4%) resistance to the ceftazidime-avibactam and aztreonam combination therapy in carbapenem-resistant gram-negative organisms. This highlights the need for synergy testing of this combination therapy before its empirical use against carbapenem-resistant gram-negative organisms, to reduce the risk of treatment failure and curb the progression of antibiotic resistance.