Efficacy of Ceftazidime-avibactam Plus Aztreonam in Patients With Bloodstream Infections Caused by Metallo-β-lactamase–Producing Enterobacterales

Abstract

Background In vitro data support the use of combination of aztreonam (ATM) with ceftazidime-avibactam (CAZ-AVI), but clinical studies are lacking. The aim of our study was to compare the outcome of patients with bloodstream infections (BSIs) due to MBLs-producing Enterobacterales treated either with CAZ-AVI plus ATM or other active antibiotics (OAAs). Methods Prospective observational study including patients admitted to three hospitals in Italy and Greece. The primary outcome measure was the 30-day all-cause mortality. Secondary outcomes were clinical failure at day 14 and length of stay (LOS) after BSI diagnosis. Cox regression analysis including a propensity score (PS) for receiving CAZ-AVI plus ATM was performed to evaluate primary and secondary outcomes. A PS-based matched analysis was also performed. Results We enrolled 102 pts with BSI, 82 had infections caused by NDM-producing (79 K.pneumoniae and 3 E.coli) and 20 by VIM-producing (14 K.pneumoniae, 5 Enterobacter spp, 1 M.morganii) strains. The 30-day mortality rate was 19.2% in CAZ-AVI/ATM group vs 44% in OAAs group (p=0.007). The PS-adjusted analysis showed that the use of CAZ-AVI/ATM was associated with lower 30-day mortality (HR 0.37, 95% CI 0.13-0.74, p=0.01), lower clinical failure at day 14 (HR 0.30, 95% CI 0.14-0.65, p=0.002) and shorter LOS (sHR 0.49, 95% CI 0.30-0.82, p=0.007). The PS-matched analysis confirmed these findings. Conclusions CAZ-AVI/ATM combination offers therapeutic advantage compared to OAAs for patients with BSI due to MBL-producing Enterobacterales. Further studies are warranted.

Treatment options for K. pneumoniae, P. aeruginosa and A. baumannii co-resistant to carbapenems, aminoglycosides, polymyxins and tigecycline: an approach based on the mechanisms of resistance to carbapenems

“…The available evidence, predominantly based on real rife observational data, suggests the superiority of beta-lactam-based therapy (i.e., double-carbapenem [ 166 ] or newer β-lactam–β-lactamase combination regimens such as ceftazidime/avibactam [ 66 , 167 – 170 ], meropenem/vaborbactam [ 66 , 171 ] or imipenem/relebactam [ 172 ]) over older antimicrobial options (including polymyxins, aminoglycosides, tigecycline and their combinations) against carbapenem-resistant Enterobacterales. Furthermore, in a recent multicenter observational study, the combination of ceftazidime/avibactam with aztreonam was associated with significantly lower clinical failure, mortality and length of stay compared to other active agents (including combinations of polymyxins, tigecycline, aminoglycosides and fosfomycin) for bloodstream infection by MBL-producing Enterobacterales (predominantly K. pneumoniae ) [ 83 ]. Moreover, ceftazidime/avibactam has been used successfully as salvage therapy against infections by carbapenem-resistant K. pneumoniae that have failed various combination regimens [ 173 ].…”

“…Prolonged or continuous infusion of ceftazidime/avibactam does not seem to improve PD target attainment compared to the standard 2 h infusion [ 182 ]. However, the optimal regimen for the combination of ceftazidime/avibactam with aztreonam for MBL-producing Enterobacterales remains unclear [ 13 , 83 ]. In the largest cohort, the regimen used was: ceftazidime/avibactam 2 + 0.5 g every 8 h (administered as a prolonged 8 h infusion in half of the patients and as a 2 h infusion in the rest) and aztreonam 2 g every 8 h (administered as a 2 h infusion) [ 83 ].…”

“…However, the optimal regimen for the combination of ceftazidime/avibactam with aztreonam for MBL-producing Enterobacterales remains unclear [ 13 , 83 ]. In the largest cohort, the regimen used was: ceftazidime/avibactam 2 + 0.5 g every 8 h (administered as a prolonged 8 h infusion in half of the patients and as a 2 h infusion in the rest) and aztreonam 2 g every 8 h (administered as a 2 h infusion) [ 83 ]. Based on a recent study using a hollow-fiber infection model comparing the effect of various regimens on bacterial killing and suppression of resistance, the following were proposed [ 183 ]: (1) simultaneous administration of ceftazidime/avibactam with aztreonam is preferred to staggered administration (ceftazidime/avibactam first, followed by aztreonam), (2) continuous infusion and standard 2 h infusion appear to be equally effective, (3) a total daily dose of 8 g aztreonam may be superior to 6 g. However, only two NDM-1-producing E. coli and K. pneumoniae strains were used in the study and validation of these results in more strains is necessary [ 183 ].…”

Treatment of Bloodstream Infections Due to Gram-Negative Bacteria with Difficult-to-Treat Resistance

“…They are not inhibited by old beta-lactamases inhibitors (clavulanic acid or tazobactam) or by new ones (avibactam, relebactam or vaborbactam), but they remain susceptible to aztreonam [ 12 ] ( Table 1 ). The ability of these enzymes to spread rapidly is demonstrated by their capacity to cause outbreaks in non-endemic regions, as recently occurred in the outbreak of NDM-producing K. pneumoniae in Tuscany [ 13 , 14 ].…”

Current treatment options for infections caused by carbapenem-resistant Enterobacteriaceae in patients with hematological malignancies

“…Излечение было отмечено у 6 больных, ле тальный исход -у 3, рецидив инфекции -у 1. В печа ти этого года представлено проспективное наблюда тельное исследование из 2 центров Италии и 1 центра Греции по использованию сочетания цефтазидима авибактама с азтреонамом в лечении инфекций, вы званных энтеробактериями с продукцией МБЛ [59]. В исследование были включены 102 больных, у 82 из них были детектированы продуценты группы NDM (79 K. pneumoniae и 3 E. coli), у 20 -группы VIM (14 K. pneumoniae, 5 Enterobacter spp., 1 Morganella morganii).…”