Infect Dis Ther DOI 10.1007/s40121-017-0153-2 REVIEW Minocycline for the Treatment of Multidrug and Extensively Drug-Resistant A. baumannii: A Review Jennifer N. Lashinsky . Oryan Henig . Jason M. Pogue . Keith S. Kaye Received: February 6, 2017 Ó The Author(s) 2017. This article is an open access publication ABSTRACT pharmacodynamic properties, as well as excel- lent in vitro activity against drug-resistant A. Acinetobacter baumannii can cause life-threaten- baumannii. Available data support therapeutic ing nosocomial infections associated with high success with minocycline, while ease of dosing rates of morbidity and mortality. In recent with no need for renal or hepatic dose adjust- years, the increasing number of infections due ments and improved safety have made it an to extensively drug-resistant Acinetobacter with appealing therapy. This review will focus on the limited treatment options has resulted in a need mechanisms of action and resistance to tetra- for additional therapeutic agents, and a renais- cyclines in A. baumannii, the in vitro activity, sance of older, neglected antimicrobials. This pharmacokinetic and pharmacodynamic prop- has led to an increased interest in the use of erties of minocycline against A. baumannii, and minocycline to treat these infections. Minocy- finally the clinical experience with minocycline cline has been shown to overcome many resis- for the treatment of invasive infections due to tance mechanisms affecting other tetracyclines this pathogen. in A. baumannii, including tigecycline. Addi- tionally, it has favorable pharmacokinetic and Keywords: Acinetobacter; Acinetobacter Enhanced content To view enhanced content for this baumannii; Carbapenem resistance; Extensively article go to http://www.medengine.com/Redeem/ 29F7F0607D680466. drug-resistant; Minocycline; Multidrug- resistant; Tetracyclines J. N. Lashinsky (&) Department of Pharmacy, Barnes-Jewish Hospital, Saint Louis, MO, USA INTRODUCTION e-mail: [email protected] O. Henig Á K. S. Kaye Acinetobacter baumannii and other Acinetobacter Department of Medicine, University of Michigan species can cause multidrug-resistant (MDR) Medical School, Ann Arbor, MI, USA nosocomial infections, with high morbidity and mortality rates. MDR A. baumannii, defined as A. J. M. Pogue Department of Pharmacy Services, Sinai-Grace baumannii resistant to more than 3 classes of Hospital, Detroit Medical Center, Detroit, MI, USA antimicrobial agents, has been responsible for a variety of healthcare-associated infections J. M. Pogue within the last two decades [1, 2]. Its ability to Wayne State University School of Medicine, Detroit, MI, USA resist environmental stress and cleaning Infect Dis Ther methods, and to acquire resistance to multiple nephrotoxicity rates and an inability to safely classes of antimicrobial agents, have made this achieve pharmacodynamic targets has raised pathogen more common, and has become one concern regarding the use of these agents. In of the most difficult to manage causes of out- mouse lung models of A. baumannii pneumo- breaks in the setting of intensive care units nia, colistin was unable to achieve bacteriostasis (ICUs) [3, 4]. In the Centers for Disease Control even with the maximum tolerated doses against and Prevention (CDC) Antibiotic Resistance 2 of the 3 strains tested [8]. Furthermore, data Threats report of 2013, MDR A. baumannii was suggest a clinically relevant increase in resis- declared a ‘‘serious threat’’ to public health in tance of A. baumannii to colistin [9–11]. A recent the United States [5]. Even more concerning has surveillance study in the United States showed been the emergence of extensively drug-resis- that 5.3% of all Acinetobacter strains were resis- tant or XDR strains of A. baumannii that are tant to colistin [9], while another surveillance resistant to all but one or two classes of study in Greece reported an increase in colistin antimicrobials, and truly pan-drug-resistant resistance from 1% in 2012 to 21.1% in 2014 strains resistant to all tested antimicrobials. among 1116 CRAB isolates [10]. An analysis Traditionally, carbapenems were considered from the Eurofins Surveillance Network the drugs of choice when treating these highly demonstrated that resistance to carbapenems resistant A. baumannii, but in recent years the among Acinetobacter more than doubled in widespread use of these agents has diminished recent years (21.0% in 2003–2005 and 47.9% in their clinical activity. Carbapenems were con- 2009–2012) as did resistance to colistin (2.8% in sidered appropriate agents to treat infections 2006–2008 and 6.9% in 2009–2012). This same caused by MDR A. baumannii strains, but car- analysis demonstrated that rates of resistance to bapenem-resistant A. baumannii (CRAB) has minocycline actually decreased over this time rapidly increased in frequency. CRAB accounts period from 56.5% in 2003–2005 to 30.5% in for 65% of A. baumannii pneumonia in the 2009–2012 [11]. Currently, when CRAB infec- United States and Europe, while more than 60% tions demonstrate resistance to ampicillin–sul- of isolates in Asia have been found to be both bactam (up to 74% in the SENTRY program were pan-drug and carbapenem-resistant [6]. An not susceptible to ampicillin–sulbactam per analysis of A. baumannii performed in Detroit, CLSI breakpoints) [12] and to colistin, the MI reported decreasing susceptibility to thera- remaining alternatives for treatment are extre- pies such as ampicillin–sulbactam and car- mely limited. bapenems in a rapid fashion. In this study, While certain aminoglycosides can retain susceptibility of A. baumannii to ampi- activity in vitro against CRAB, data suggest that cillin–sulbactam decreased from 89% to 40%, aminoglycoside monotherapy is inadequate for while susceptibility to imipenem decreased infections occurring outside the urinary tract, from 99% to 42% from 2003 to 2008 [7]. The and concerns remain regarding nephrotoxicity high resistance rates of these organisms has led associated with this class. A meta-analysis to a situation with limited therapeutic options, reported that patients receiving aminoglycoside where in vitro activity is frequently limited to therapy had higher mortality rates and higher the polymyxins, aminoglycosides, tigecycline rates of microbiological failure than patients and minocycline. receiving beta-lactams or fluoroquinolones [13]. In the setting of carbapenem resistance, sul- Antimicrobials such as tigecycline, ceftola- bactam (typically administered as ampi- zone–tazobactam and ceftazidime–avibactam cillin–sulbactam) is potentially an option for have more recently come to market; but, the treatment of A. baumannii; however, opti- unfortunately, these newer agents are not ideal mal dosing strategies for sulbactam remain for CRAB. Ceftolazone–tazobactam and cef- poorly defined and resistance is increasing. tazidime–avibactam have minimal utility in the Polymyxins are often considered an important treatment of CRAB, given the usual mecha- treatment option for CRAB in the setting of nisms of resistance to carbapenems are class D sulbactam resistance, but unacceptably high or B carbapenemases. Both of these Infect Dis Ther carbapenemases readily hydrolyze these cepha- human or animal subjects performed by any of losporins and these enzymes are not inhibited the authors. by either tazobactam or avibactam [11]. While tigecycline shows excellent in vitro activity against CRAB, enthusiasm surrounding this MECHANISMS OF ACTION agent has been tempered due to pharmacoki- AND RESISTANCE netic limitations of the drug, the development of resistance while on therapy, and its inability Tetracyclines are a broad-spectrum class of to demonstrate non-inferiority in the treatment antimicrobials, including tetracycline, doxycy- of hospital-acquired and ventilator-associated cline, minocycline and tigecycline, which enter pneumonia [14–17]. Due to the continued Gram-negative organisms through outer mem- emergence and dissemination of resistant A. brane protein channels and cause conforma- baumannii and the limited number of thera- tional changes to the RNA by binding with the peutic options, other agents such as minocy- 30S ribosomal unit. Tetracyclines bind where cline have been investigated for their utility in the codon of the mRNA is recognized by the the treatment of these pathogens. anticodon of the tRNA [18]. This binding blocks Minocycline is a second-generation tetracy- the entry of aminoacyl transfer RNA into the cline that was first introduced in the 1960s. site A of the ribosome, which prevents elonga- While the oral formulation remained available, tion of the peptide chain [12]. It has been the intravenous formulation was taken off the observed that alterations to the hydrophilic US market in 2005 due to decreased use. It was surface of the tetracycline molecule interferes re-introduced in 2009 and has become an with the antimicrobial activity of the drug, important option for the treatment of mul- while alterations in the hydrophobic surface of tidrug-resistant organisms, in particular CRAB. the drug are less likely to interfere [18]. Doxy- Following reintroduction of minocycline to the cycline and minocycline are the more lipophilic market for the treatment of serious infections, counterparts of tetracycline, which allows for including an FDA-approved indication for increased tissue penetration, increased antibac- infections caused by Acinetobacter, there has terial activity, longer half-lives and broader been renewed interest in its use. Further spectrums of