avibactam and Neutropenia

The 68-year-old patient presented with fever, general malaise and physical weakness in neutropenia during a known relapse of acute myeloid leukaemia after allogeneic stem cell transplantation.. Due to immune suppression, an empiric antibiotic therapy with piperacillin/tazobactam was started. The 4MRGN screening was positive. For this reason, therapy was switched empirically to ceftazidime/avibactam plus colistin. A tongue ulcer with abscess formation and phlegmonous soft tissue reaction was revealed as the focus of the infection. Several microbiological probes including a blood culture discovered. Die Vorstellung der 68-jährigen Patientin erfolgte bei hohem Fieber, allgemeinem Unwohlseisn und körperlicher Schwäche in der Neutropenie bei Rezidiv einer akuten myeloischen Leukämie nach allogener Stammzelltransplantation.. Aufgrund der bestehenden Immundefizienz wurde eine kalkulierte antibiotische Therapie mit Piperacillin/Tazobactam begonnen. Bei positivem 4MRGN-Screening wurde diese kalkuliert auf Colistin und Ceftazidim/Avibactam umgestellt. Diagnostiziert wurde ein Zungenulkus mit Abszessbildung und phlegmonöser Weichteilreaktion. In mehreren mikrobiologischen Proben, inklusive einer Blutkultur, gelang der Nachweis eines. Vierfach multiresistente gramnegative Bakterien (4MRGN) sind aufgrund ihrer Resistenz gegenüber 4 bakterizid wirkenden Hauptantibiotikagruppen (Acylureidopenicilline, Cephalosporine der 3. Generation, Carbapeneme, Fluorchinolone) nur schwer therapierbar. Der vorliegende Fall zeigt für Cefiderocol eine gute klinische Wirksamkeit – auch bei Erregern, die gegen Antibiotika wie Colistin und Ceftazidim/Avibactam resistent sind und er verdeutlicht, wie wichtig eine antibiogrammgerechte Therapie ist.

Topics: Aged; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Cefiderocol; Ceftazidime; Cephalosporins; Colistin; Communicable Diseases; Drug Combinations; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Klebsiella pneumoniae; Microbial Sensitivity Tests; Neoplasm Recurrence, Local; Neutropenia

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Drug Combinations; Humans; Microbial Sensitivity Tests; Neutropenia

Avibactam is a new non-β-lactam β-lactamase inhibitor that shows promising restoration of ceftazidime activity against microorganisms producing Ambler class A extended-spectrum β-lactamases (ESBLs) and carbapenemases such as KPCs, class C β-lactamases (AmpC), and some class D enzymes. To determine optimal dosing combinations of ceftazidime-avibactam for treating infections with ceftazidime-resistant Pseudomonas aeruginosa, pharmacodynamic responses were explored in murine neutropenic thigh and lung infection models. Exposure-response relationships for ceftazidime monotherapy were determined first. Subsequently, the efficacy of adding avibactam every 2 h (q2h) or q8h to a fixed q2h dose of ceftazidime was determined in lung infection for two strains. Dosing avibactam q2h was significantly more efficacious, reducing the avibactam daily dose for static effect by factors of 2.7 and 10.1, whereas the mean percentage of the dosing interval that free drug concentrations remain above the threshold concentration of 1 mg/liter (%fT>C(T) 1 mg/liter) yielding bacteriostasis was similar for both regimens, with mean values of 21.6 (q2h) and 18.5 (q8h). Dose fractionation studies of avibactam in both the thigh and lung models indicated that the effect of avibactam correlated well with %fT>C(T) 1 mg/liter. This parameter of avibactam was further explored for four P. aeruginosa strains in the lung model and six in the thigh model. Parameter estimates of %fT>C(T) 1 mg/liter for avibactam ranged from 0 to 21.4% in the lung model and from 14.1 to 62.5% in the thigh model to achieve stasis. In conclusion, addition of avibactam enhanced the effect of ceftazidime, which was more pronounced at frequent dosing and well related with %fT>C(T) 1 mg/liter. The thigh model appeared more stringent, with higher values, ranging up to 62.5% fT>C(T) 1 mg/liter, required for a static effect.

Topics: Animals; Animals, Outbred Strains; Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Colony Count, Microbial; Drug Administration Schedule; Drug Combinations; Female; Lung; Mice; Microbial Sensitivity Tests; Neutropenia; Organ Specificity; Pseudomonas aeruginosa; Pseudomonas Infections; Thigh

The combination of ceftazidime and avibactam possesses potent activity against resistant Gram-negative pathogens, including Pseudomonas aeruginosa. We compared the efficacies of human simulated doses of ceftazidime and ceftazidime-avibactam using a hollow-fiber system and neutropenic and immunocompetent murine thigh infection models. Twenty-seven clinical P. aeruginosa isolates with ceftazidime MICs of 8 to 128 mg/liter and ceftazidime-avibactam MICs of 4 to 32 mg/liter were utilized in neutropenic mouse studies; 15 of the isolates were also evaluated in immunocompetent mice. Six isolates were studied in both the hollow-fiber system and the neutropenic mouse. In both systems, the free drug concentration-time profile seen in humans given 2 g of ceftazidime every 8 h (2-h infusion), with or without avibactam at 500 mg every 8 h (2-h infusion), was evaluated. In vivo activity was pharmacodynamically predictable based on the MIC. Ceftazidime decreased bacterial densities by ≥0.5 log unit for 10/27 isolates, while ceftazidime-avibactam did so for 22/27 isolates. In immunocompetent animals, enhancements in activity were seen for both drugs, with ceftazidime achieving reductions of ≥0.3 log unit for 10/15 isolates, whereas ceftazidime-avibactam did so against all 15 isolates. In vitro, ceftazidime resulted in regrowth by 24 h against all isolates, while ceftazidime-avibactam achieved stasis or better against 4/7 isolates. Mutants with elevated ceftazidime-avibactam MICs appeared after 24 h from 3/7 isolates studied in vitro; however, no resistant mutants were detected in vivo. Against this highly ceftazidime-nonsusceptible population of P. aeruginosa, treatment with human simulated doses of ceftazidime-avibactam resulted in pharmacodynamically predictable activity, particularly in vivo, against isolates with MICs of ≤16 mg/liter, and this represents a potential new option to combat these difficult-to-treat pathogens.

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Ceftazidime; Drug Resistance, Bacterial; Female; Humans; Immunocompetence; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Neutropenia; Pseudomonas aeruginosa; Pseudomonas Infections; Thigh