Minocycline Alone and in Combination with Polymyxin B, Meropenem, and Sulbactam against Carbapenem-Susceptible and -Resistant Acinetobacter baumannii in an In Vitro Pharmacodynamic Model

Abstract

Acinetobacter baumannii is recognized as an urgent public health threat by the Centers for Disease Control and Prevention (CDC). Current treatment options are scarce, particularly against carbapenem-resistant Acinetobacter baumannii (CRAB). We simulated the impact of minocycline standard (200mg load+100mg Q12h) and high-dose (700mg load+ 350mg Q12h), polymyxin B (2.5mg/kg Q12h), sulbactam (1g Q6h and 9g/24h as continuous infusion) and meropenem (intermittent 1 or 2g Q8h and 6g/24h as continuous infusion) alone or in combination against CRAB and non-CRAB isolates by simulating human therapeutic dosing regimens in a 72-hour, in vitro pharmacodynamic model (IVPD). There were no monotherapy regimens that demonstrated bactericidal activity against the tested non-CRAB and CRAB. Resistance development was common in monotherapy regimens. Against the CRAB isolate, the triple combination of high-dose minocycline (fAUC/MIC 21.21), polymyxin B (fAUC/MIC 15.63), and continuous infusion sulbactam (67% T>MIC) was the most consistently active regimen. Against non-CRAB, the triple therapy regimen of high-dose minocycline (fAUC/MIC 84.84) with continuous infusion meropenem (100%T>MIC) and continuous infusion sulbactam (83%T>MIC), as well as the double therapy of high-dose minocycline (AUC/MIC 84.84) with continuous infusion meropenem (100%T>MIC) resulted persistently bactericidal activity. In conclusion, triple therapy with high dose minocycline, continuous infusion sulbactam, and polymyxin B produced the most significant kill against the carbapenem-resistant Acinetobacter baumannii, with no regrowth and minimal resistance development.

Polymyxin B Combined with Minocycline: A Potentially Effective Combination against blaOXA-23-harboring CRAB in In Vitro PK/PD Model

“…Polymyxin B and minocycline combination extended the survival time in a neutropenic murine pneumonia model [ 18 ]. Maya et al reported a triple therapy combination against CRAB using an in vitro PK/PD model [ 24 ] which demonstrated that minocycline (700 mg loading dose plus 350 mg q12h) and polymyxin B (0.25 mg/kg) combined with sulbactam (9 g, continuous infusion in 24 h) could maintain a bactericidal effect for 96 h with no bacterial regrowth and minimal resistance development [ 24 ].…”

Clinical outcomes and safety of polymyxin B in the treatment of carbapenem-resistant Gram-negative bacterial infections: a real-world multicenter study

“…Our combination therapy was similar to that of most other research [ 9 , 20 ]. It has been reported that the development of resistance was observed over a course of 72 h with PMB monotherapy against CRAB isolates [ 38 ]. Several clinical trials demonstrated that the increased use of colistin has led to the development of colistin resistance.…”

Virulence Potential and Treatment Options of Multidrug-Resistant (MDR) Acinetobacter baumannii

“…The susceptibility to tigecycline or polymyxins at present remains satisfactory [ 120 , 121 ]. A global surveillance from 2007–2011 suggested the escalating susceptibility of minocycline ranging from 72.5% to 91.7% [ 122 , 123 ]. In a study from Italy, an increase in resistance to the latest generation of antimicrobials has been observed in sepsis cases [ 124 ].…”

“…In a recent study from North India, a combination therapy of tetracycline with nalidixic acid showed a synergistic effect on MDR isolates of A. baumannii [ 182 ]. Minocycline has shown considerable results through an in vitro pharmacodynamics model against carbapenem-resistant and susceptible isolates of A. baumannii in monotherapy and combination with other antimicrobials [ 123 ]. Data from a few investigations have shown that more than 90% of isolates of A. baumannii were susceptibile to minocycline [ 183 ].…”