Minocycline for the Treatment of Multidrug and Extensively Drug-Resistant A

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 excellent 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 resistant 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 activity against many bacterial investigation of its use for the treatment of species, including Acinetobacter species MDR Acinetobacter infections, including those [12, 19–21]. caused by carbapenem-resistant and XDR Resistance to tetracyclines is conferred strains, has occurred due to its in vitro activity through a variety of mechanisms, including against A. baumannii, more favorable pharma- efflux pumps, ribosomal protection proteins, cokinetics compared to tigecycline, and its chemical molecule modification and target site safety profile. This review will focus on the modifications. Among Gram-negative organ- tetracycline mechanisms of action and resis- isms, the main mechanism leading to tetracy- tance, the in vitro activity of minocycline in cline resistance is through efflux pumps. The the presence and absence of these resistance differences in gene-encoding efflux proteins mechanisms, the pharmacokinetics and phar- account for the differences in resistance phe- macodynamics of minocycline, and finally the notypes to the different agents within the clinical experience with minocycline for the tetracycline class. There are over 20 efflux pump treatment of invasive infections due to A. encoding genes that have been detected in baumannii. Gram-negative organisms, with the most common being TetA. These efflux pumps lead to a Compliance with Ethics Guidelines decrease in tetracycline intracellular concentration by exchanging a proton for the tetracy- This article is based on previously conducted cline cation complex [12, 18]. In vitro efflux studies and does not involve any new studies of pumps seen in A. baumannii are effective in Infect Dis Ther transporting out tetracycline and doxycycline, tigecycline-resistant A. baumannii can remain but with the exception of the TetB pump, not susceptible to minocycline. Importantly, these minocycline. Recent work by Lomoskaya and RND pumps can be selected with clinically rel- colleagues confirmed that the absence of TetB in evant concentrations of tigecycline (but not A. baumannii has a negative predictive value of minocycline) and serve as a mechanism for the 100% for minocycline resistance (93/93 TetB well-described development of tigecycline negative strains were minocycline susceptible), resistance while on therapy [26]. whereas the presence of TetB has a 93% positive predictive value for minocycline resistance, with only 11/165 (6.7%) isolates being suscep- In Vitro Activity tible to minocycline when TetB was present [22]. Thus, the gene encoding for TetB repre- It has been shown that minocycline has sents a potential target for rapid diagnostic gene increased activity against MDR Acinetobacter testing to quickly determine minocycline compared to other early generation tetracycli- susceptibility. nes because of its ability to overcome many of Tigecycline was synthetically designed to the tetracycline resistance mechanisms (most overcome these efflux pumps and has activity if notably TetA). A. baumannii containing oxacili- either TetA or TetB is present. Unfortunately, nases or metalo-beta-lactamase genes has been although tigecycline was developed to overcome reported to retain a susceptibility profile to many of the efflux pump resistance mechanisms minocycline similar to organisms without these commonly seen with tetracyclines, rapid devel- genes [27]. In one in vitro study, using CLSI opment of different resistance mechanisms have breakpoints, minocycline displayed a 30% been observed. Current literature suggests that improved susceptibility compared to doxycy- the development of such resistance has been cline and nearly 60% improved susceptibility associated with the TetX gene and, perhaps most compared to tetracycline against A. baumannii importantly for A. baumannii, the overexpression [12]. Thus, minocycline susceptibility should be of various efflux pumps (AdeABC, AdeIJK, determined by testing directly and not be AdeFGH, AbeM, AdeDE) [23, 24]. determined by a surrogate class approach (i.e. Resistance-nodulation-division (RND)-type tigecycline and doxycycline resistance does not efflux pumps, such as AdeABC, have been clo- necessarily equal minocycline resistance). sely associated with the development of tige- In vitro, minocycline has frequently been cycline resistance. These pumps have been shown to be one of the only available treatment shown to be more efficient than other types of options for difficult to treat multi drug-resistant efflux pumps in that they export drugs into the Acinetobacter infections, and as described above is extracellular, rather than periplasmic, space. often the second most active agent behind col- Up-regulation of these AdeABC pumps have istin. The antimicrobial activity of minocycline been associated with higher MICs and increased against A. baumannii was recently evaluated in resistance to tigecycline in vitro. Data from two large surveillance studies from different parts Hornsey and colleagues reported overexpres- of the world: the SENTRY antimicrobial surveil- sion of the AdeABC efflux pump in two cases of lance program (2007–2011) [12] and the Tigecy- tigecycline resistance, which emerged after cline Evaluation and Surveillance Trial (T.E.S.T, tigecycline therapy, as well as a laboratory 2005–2011) [28]. In the SENTRY program, 79.1% mutant with an elevated MIC. In this study, of A. baumannii were susceptible to minocycline susceptibility was restored in a resistant isolate (second only to colistin, which had a 98.8% by interrupting the AdeB, which further sup- susceptibility rate), while in the T.E.S.T., A. bau- ports a role of AdeABC in tigecycline resistance mannii had a susceptibility rate of 84.1%, ranging [25]. between 68.5% in East South Central US and Interestingly, the RND pumps previously 97.4% in New England. Similarly, multidrug-re- mentioned do not appear to impact minocy- sistant A. baumannii (defined as resistance to 3 or cline susceptibility, and therefore more classes of antibiotics among beta-lactams, Infect Dis Ther aminoglycosides, carbapenems or fluoro- 100 mg every 12 h, serum concentrations have quinolones) were susceptible to minocycline in ranged from approximately 0.7 to 3.9 lg/mL 72.1% of cases, (ranging between 54% in the East [21, 34, 35]. Similarly, data reported in the South Central US, and 92.3% in New England). package insert for intravenous minocycline Furthermore, a study by Castanheira and state peak and trough concentrations of colleagues assessed A. baumannii isolates col- 2.52–6.63 and 0.82–2.64 lg/mL, respectively lected between 2007 and 2011 and showed that [36]. The protein binding of minocycline is the only two antimicrobials with greater than similar to that of tetracycline, with approxi- 50% susceptibility rates were minocycline and mately 76% of the drug being protein-bound colistin. Reports of minocycline retaining its [30, 33]. The half-life of minocycline following activity in patient isolates that have developed a single dose of either 200 mg or 100 mg is colistin resistance during colistin therapy also approximately 12–24 h, which remains clini- exist [29]. Importantly, minocycline suscepti- cally unchanged in patients with renal dys- bility remains high and is not impacted by function [21, 33, 34, 37]. Minocycline is carbapenem resistance. Colton and colleagues primarily metabolized by the liver and excreted reported that isolates retained MIC50 values of through the hepatobiliary system, with only a B4.0 lg/mL for minocycline against Acinetobac- small amount of drug eliminated through the ter species, including carbapenem-resistant iso- renal route (5–12%) unchanged in the urine lates [30]. A study performed in Thailand in [33, 37]. For these reasons, it has been hypoth- CRAB confirmed these results with findings of esized that minocycline elimination is inde-

MIC50 values of 4 mg/L and MIC90 values of pendent of renal function and hepatic function. 8 mg/L for minocycline, with 81.4% of isolates In a study looking at single intravenous being susceptible [31]. doses and repeated oral doses of minocycline, it Additionally, it is important to note that was reported that there was no evidence of minocycline has also displayed high levels of reduced drug clearance in patients with reduced synergistic activity with polymyxins in renal function, but a possible increase in tissue minocycline-resistant isolates, where 0.5 mg/L distribution [33]. This particular study evalu- of polymyxin B restored in vitro susceptibility ated 13 male patients with varying degrees of to minocycline in 167 tested isolates, 88% of renal dysfunction, although none were on which were resistant to minocycline dialysis. The authors found that the decline in monotherapy [32]. This is an important and individual serum levels of minocycline activity encouraging finding given the propensity to use after intravenous infusion was biphasic and combination regimens in the treatment of therefore the pharmacokinetics were consistent CRAB. with a two-compartment model. Both the concentration of antibiotic in urine and the cumulative renal excretion were directly related PHARMACOKINETICS to kidney function, while the overall clearance AND PHARMACODYNAMICS of antibiotic appeared to be independent of renal function. As minocycline does not seem In comparison to other more recently evaluated to accumulate in renal failure, it is believed that antimicrobials, there exist minimal data relat- minocycline can be safely administered to ing to the pharmacokinetics of minocycline. patients with renal insufficiency without Studies which have assessed the pharmacoki- requiring any dose adjustments [33]. netics of minocycline have found that serum While minocycline has not been shown to concentrations are similar to other tetracy- accumulate in renal failure, there exists the clines. Receipt of a 200-mg one-time intra- notion that minocycline use in patients with venous dose has demonstrated peak serum renal insufficiency may enhance uremia seen in concentrations ranging from 3 to 8.75 lg/mL these patients due to the anti-anabolic processes and trough concentrations from 0.6 to 1.9 lg/ associated with the drug on mammalian cells mL [21, 33, 34]. After multiple oral doses of [33]. Although publications have suggested an Infect Dis Ther increase in urea clearance and rises in plasma the free AUC/MIC target to be associated with urea in patients with renal insufficiency receiv- bacteriostasis and 1 log bactericidal activity. In ing minocycline, it is unclear in these analyses this analysis, the authors explored exposure whether or not these were related to antian- response with 6 different A. baumannii isolates abolic actions of the drug or simply a worsening (minocycline MIC’s ranging from 0.03 to of the patients’ renal failure [27]. Authors have 4 mcg/mL) in a rat pneumonia model. In this suggested that there is a critical level of free model, mean fAUC/MIC values associated with tetracycline that may be associated with stasis and 1 log kill were 12.2 (10.6–16.1) and increased urea production and that this level ‘‘is 18.0 (13.1–24.2) mg h/L, respectively [40]. seldom reached at doses of 200 mg/day of In order to interpret these fAUC/MIC values, minocycline’’ [34]. These findings and state- it is essential to evaluate them in the perspec- ments serve as the basis for the package insert tive of achievable free AUCs obtained with for minocycline carrying a warning to not approved dosing strategies. As has been previ- exceed a total daily dosage of 200 mg in 24 h in ously stated in this section, scant pharmacoki- patients with renal impairment (CrCl \80 mL/ netic data of minocycline are available, and no min) [36]. However, assuming that a minocy- studies overtly evaluate AUC exposures. How- cline dose of 200 mg BID is needed, based on ever, the analysis by Welling and colleagues pharmacokinetic and pharmacodynamic prop- published 40 years ago does report on clearance erties (described below), we would recommend rates in patients with normal renal function and against dose adjustment downward in these various degrees of renal insufficiency [26]. patients due to concerns of underexposure Interestingly, in this analysis, they found the (since the half-life and presumably clearance of clearance rate was the lowest in patients with the drug would not be expected to change). normal renal function (1.18 L/h), and slightly Rather, we would suggest that clinicians be higher in patients with renal insufficiency aware of potential antianabolic actions and (1.84–2.01 L/h). Using the basic pharmacoki- closely monitor blood urea nitrogen levels and netic equation Dose = AUC/Clearance, and the for signs/symptoms of uremia, given the serious known protein binding of *76%, one can esti- nature of infections due to A. baumannii and the mate free AUC exposures and ultimately AUC/ need to meet PK/PD targets. MIC ratios with various minocycline dosing Minocycline achieves high tissue penetra- regimens for different organism MICs. For tion and displays excellent oral bioavailability patients receiving 200–400 mg daily of allowing for expanded clinical uses by giving minocycline, total area under the concentration providers the ability to easily switch between time curve exposures would be expected to the intravenous and oral formulations. range from 100 to 340 mg h/L, resulting in a Minocycline is the most lipophilic of all the free AUC of 24–82 mg h/L. Thus, even in the tetracyclines because it has a greater partial worst case scenario, where the highest clearance coefficient at a neutral pH, and therefore is rate (2.01 L/h) and highest MIC in the suscep- believed to be the most potent, with a longer tible range (4 mcg/mL) is utilized, a dose of half-life, better oral absorption and enhanced 200 mg BID (total AUC = 199 mg h/L, free AUC tissue penetration compared to other tetracy- 48 mg h/L) would be expected to achieve bac- clines. Previous literature has shown that teriostasis (fAUC/MIC = 12), and in most sce- minocycline has approximately a 20-fold higher narios bactericidal activity would be expected. affinity to the ribosome than tetracycline and Importantly, however, these data are limited in vitro can inhibit translation 2–7 times more in their interpretability given the large variance efficiently than tetracycline [18, 38, 39]. in clearance rates reported, the use of 200-mg The minocycline-free area under the con- daily doses (as opposed to 400-mg daily doses), centration time curve to MIC ratio (fAUC/MIC) and the small study sample sizes. Additionally, is the pharmacokinetic/pharmacodynamic even though minocycline is considered highly parameter best associated with effect. Recent bioavailable with *90% being orally absorbed, work by Tarazi and colleagues have identified it is unknown if there were confounding factors Infect Dis Ther impacting absorption in this study, and it is 9.8%), urine (2, 1.6%), and others (3, 2.4%). Of possible that higher doses and intravenous the patients treated, 94 patients received administration could lead to increased expo- minocycline combined with another antimi- sures further leading to enhanced bactericidal crobial agent, 12 patients were treated with activity. Although modern pharmacokinetic minocycline monotherapy, and 11 patients data are urgently needed for minocycline received monotherapy with either minocycline administered in both its oral and intravenous or doxycycline, with the exact agent not speci- formulations, data currently available are fied [40]. A majority of the patients (72.5%) encouraging. Importantly, additional PK studies received minocycline intravenously. The most of IV minocycline in normal subjects, criti- common dose used was 100 mg twice daily, cally-ill patients and infected patients, and in with or without a loading dose of 200 mg patients with chronic renal impairment are (overall, 61 subjects received a loading dose). planned (Mike Dudley, personal One study included patients treated with IV communication). minocycline 200 mg twice daily [16], and in another study patients treated with oral minocycline 200 mg every 6 h [46]. Treatment CLINICAL EXPERIENCE was administered for a duration that ranged OF MINOCYCLINE FOR MDR between 2 days to 7 weeks, according to the GRAM-NEGATIVE BACILLI source of infection [44]. Median durations of therapy from each study is presented in Table 1. Overview of Clinical Data Overall, the clinical success rate of monotherapy or combination treatment was 78.2%. Currently, there have been no randomized, Microbiological cure (defined differently across controlled trials that evaluate the efficacy of studies) was reported in 4 studies and ranged minocycline in treatment of MDR Gram-nega- from 50% and 89% (Table 1). tive bacterial infections; however, clinical data provide evidence of its potential role in the Clinical Data for Monotherapy treatment of these difficult to treat pathogens. Between the years 1998 and 2015, seven retro- Twenty-three patients in five of the studies were spective studies [16, 41–47] evaluated the use of treated with either minocycline or doxycycline oral or intravenous minocycline alone or in as monotherapy for A. baumannii infection combination with other antimicrobials for the [42–46]. As previously stated, in one study there treatment of MDR A. baumannii. One factor was no differentiation between treatment with complicating interpretation of these studies is minocycline and doxycycline, and therefore the the variety of different definitions used by dif- data are presented together [40]. The age of the ferent investigators. MDR A. baumannii was patients ranged between 15 and 85 years defined as resistance to 3 or more antimicrobial (Table 1). Of the 22 known sources of A. bau- classes in one study [42] and resistance to all mannii isolates, 16 (73%) were from the respi- frequently tested beta-lactams in another study ratory tract, 4 (18%) from soft tissues, and 2 [44]. CRAB was defined as carbapenem-resistant (9%) from the bone. There were no bloodstream [16, 45] and pan-drug-resistant A. baumannii infections in this group. The route of minocy- was defined as A. baumannii resistant to all cline administration was reported in 12 patients antibiotics excluding polymyxins [46]. and was intravenous in most cases (92%). The The seven studies included 126 patients most commonly used dose was 100 mg twice between 17 and 85 years old (Table 1), who had daily, although one study treated patients with 141 identifiable isolates that included the fol- 200 mg BID. The number of subjects who lowing sources: respiratory tract (91, 74.6%), received a loading dose could not be deter- blood (22, 18%), bone (11, 9%), skin and soft mined. The duration of treatment ranged tissue (including surgical site infections) (12, between 2 days for an unknown source and Table 1 Clinical experience with minocycline for Acinetobacter infections

Author, Number Age Source of Treatment route, Co-infection Concurrent treatment Outcome years, design of infection treated dose, duration Clinical Microbiological Adverse events patients improvement improvement Wood GC, 4 Median 37 Respiratory (BAL) Route: IV, LD: none N/A 2 patients: 4 (100%) 3 of 3 tested Not reported 1998 (24–49) One patient had Dose: 100 mg BID Imipenem Retrospective co-bloodstream Duration: TMP-SMZ ? infection 10, 14, 15, 20 days trovaﬂoxacin Grifﬁth ME 8 Median 23.5 Bone and soft Route: oral 7 patients: MRSA, 7 patients: 7 (87.5%) NA One patient with 2005–2006 (19–35) tissue Enterobacteriaceae, eosinophilia and LD: none 4—imipenem (post-operative) P. aeruginosa neutropenia Retrospective Dose: 100 mg BID 2—ancomycin Duration: 1—amikacin 4–7 weeks Chan JD 36 Average 40 Respiratory Route: IV or Oral 49% had 25 patients: 29 (80.6%) NA 10 of the entire 2004–2007 (15–87) (BAL/ LD: 200 mg LD for poly-microbial BAL 20—aminoglycoside cohort (n = 55) mini-BAL) cultures developed AKI IV minocycline Prospective 2—aminoglycosides ? (18.2%); 10 patients had Dose: polymyxin co-bloodstream 6 of 30 with infection Oral—200 mg BID 3—aminoglycoside? aminoglycosides; IV—100 mg BID tigecycline 4 of 7 (57%) with colistin Duration: Mortality: 21.8% 13.3 ± 4.2 days (entire cohort) Goff DA 55 Median 56 Respiratory Route: IV N/A 52 patients: 40 (72.7%) Documented No patient had 2010–2013 (23–85) (respiratory LD: 42 (76%) 19—colistin eradiation: any documented culture): 32 Retrospective received LD of 9—colistin ? doripenem 31 (56%) adverse events ? (including Respiratory 200 mg Presumed deemed to be 8—colistin ? Jankowski BSI: 4 Dose: 100 mg BID eradication: attributable to ampicllin–sulbactam data) BSI: 10 minocycline. Duration: 6—doripenem 12 (22%) Soft tissue: 2 Mortality: 42% Median 9 days 3—colistin ? doripenem Failure:12 (22%) Bone: 2 (2–35) ? ampicillin–sulbactam Urine: 1 3—ampicillin–sulbactam Other: 3 2—ampicillin–sulbactam ?

doripenem Ther Dis Infect 2—others netDsTher Dis Infect Table 1 continued Author, Number Age Source of Treatment route, Co-infection Concurrent treatment Outcome years, design of infection treated dose, duration Clinical Microbiological Adverse events patients improvement improvement

Bishburg E 5 For the entire Respiratory: 3 Route: IV Data cannot be N/A 5 (100%) NA Not reported GNB cohort separated 2009–2012 Soft tissue: 3 LD: none (8) 44–80 Retrospective Bone: 1 Dose: 100 mg BID Duration: 5–18 days (some may have continued oral treatment) Pogue JM 9 Median 50 Respiratory: 3 Route: IV 2 patients 6 patients: 5 (71.4%) 2 of 4 tested 2 patients with 2011 (35–74) Respiratory ? soft LD: none P. aeruginosa 4—colistin (50%) AKI, attributed tissue: 1 to colistin Retrospective Dose: 200 mg BID K. pneumoniae KPC 1—meropenem ? colistin Mortality: 2 (28%) BSI: 3 (5 patients) 1—ampicillin–sulbactam 100 mg BID (2 patients) Duration: median 7 days (3–14) Ning FG 9 Average Respiratory Route: oral 2 patients 9 patients: 9 (100%) 8 (89%) Elevated 38.2 ± 10.7 (sputum): 9 ALT, AST, not 2011–2013 LD: 200 mg MRSA bacteremia high doses of meropenem (23–57) attributed to Wound: 6 and Retrospective Dose: 200 mg QID minocycline cefoperazone–sulbactam BSI: 4 Duration: N/A Infect Dis Ther

6 weeks in post-fracture infections. In one patients with resistant Acinetobacter infections study, clinical success was achieved in 81.8% of where available data support therapeutic suc- subjects [40] and in 100% of subjects in the four cess in these challenging clinical scenarios. other studies. Microbiological cure was not Given the paucity of antimicrobials currently available in this group. available to treat MDR and XDR A. baumannii, further clinical and laboratory evaluation of Adverse Events Data in All Clinical Studies minocycline as an effective treatment alterna- tive for infections caused by resistant pathogens Adverse events were reported in five studies is warranted. Additionally, further studies to [16, 42, 44, 45, 47]. In one study, a patient assess if minocycline monotherapy is sufficient developed eosinophilia and neutropenia [44]. or whether it should be utilized as part of a Two studies reported acute kidney injury (oc- combination therapeutic regimen are needed. curring in 28% and 18.2% of subjects) which was attributed to concomitant colistin or aminoglycoside treatment [16, 45]. One study ACKNOWLEDGEMENTS reported elevated liver enzymes which were attributed to host factors (severity of illness) and No funding or sponsorship was received for this not to the minocycline [46]. Two other studies study or publication of this article. All named reported no adverse reactions or events attrib- authors meet the International Committee of uted to minocycline [42]. Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsi- bility for the integrity of the work as a whole, DISCUSSION and have given final approval for the version to be published. Acinetobacter species are common nosocomial pathogens that have been implicated in serious Disclosures. Jason M. Pogue has served as a infections associated with high morbidity and consultant for The Medicines Company. Keith mortality rates. Historically, carbapenems were S. Kaye has served as a consultant for The Acinetobacter used to treat MDR infections, but Medicines Company. Jennifer N. Lashinsky and in recent years an increase in CRAB has Oryan Henig have nothing to disclose. decreased the therapeutic effectiveness of these agents. Limitations of available treatment Compliance with Ethics Guidelines. This options have left clinicians in need of addi- article is based on previously conducted studies tional therapeutic choices. During the last dec- and does not involve any new studies of human ade, the interest in minocycline has increased or animal subjects performed by any of the due to its in vitro activity against A. baumannii authors. (including MDR and XDR strains), as well as its pharmacokinetic and pharmacodynamic prop- Data Availability. Data sharing is not erties (e.g., its ability to achieve good serum and applicable to this article as no datasets were tissue levels as well as to display bactericidal generated or analyzed during the current study. activity). The ability of minocycline to overcome many resistance mechanisms that Open Access. This article is distributed decrease the activity of other tetracyclines, most under the terms of the Creative Commons notably TetA and RND pumps, has allowed for Attribution-NonCommercial 4.0 International its more widespread use against MDR Acineto- License (http://creativecommons.org/licenses/ bacter. Its favorable safety profile, lack of needed by-nc/4.0/), which permits any noncommer- dose adjustments for renal and hepatic failure, cial use, distribution, and reproduction in any and the easy conversion between IV to PO for- medium, provided you give appropriate credit mulations have enhanced its clinical appeal. to the original author(s) and the source, provide This is particularly true for difficult to manage Infect Dis Ther a link to the Creative Commons license, and dissemination of colistin and carbapenem resistant indicate if changes were made. Acinetobacter baumannii in Central Greece: mechanisms of resistance, molecular identification and epidemiological data. BMC Infect Dis. 2015;15:559.

11. Zilberberg MD, Kollef MH, Shorr AF. Secular trends REFERENCES in Acinetobacter baumannii resistance in respiratory and blood stream specimens in the United States, 2003 to 2012: a survey study. J Hosp Med. 1. Falagas ME, Koletsi PK, Bliziotis IA. The diversity of 2016;11(1):21–6. deﬁnitions of multidrug-resistant (MDR) and pan- drug-resistant (PDR) Acinetobacter baumannii and 12. Castanheira M, Mendes RE, Jones RN. Update on Pseudomonas aeruginosa. J Med Microbiol. Acinetobacter species: mechanisms of antimicrobial 2006;55(Pt 12):1619–29. resistance and contemporary in vitro activity of minocycline and other treatment options. Clin 2. Falagas ME, Bliziotis IA, Siempos II. Infect Dis. 2014;59(Suppl 6):S367–73. Attributable mortality of Acinetobacter baumannii infections in critically ill patients: a systematic 13. Vidal L, Gafter-Gvili A, Borok S, Fraser A, Leibovici review of matched cohort and case-control studies. L, Paul M. Efﬁcacy and safety of aminoglycoside Crit Care. 2006;10(2):R48. monotherapy: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Che- 3. Villegas MV, Hartstein AI. Acinetobacter outbreaks, mother. 2007;60(2):247–57. 1977–2000. Infect Control Hosp Epidemiol. 2003;24(4):284–95. 14. Freire AT, Melnyk V, Kim MJ, Datsenko O, Dzyublik O, Glumcher F, et al. Comparison of tigecycline 4. Dijkshoorn L, Nemec A, Seifert H. An increasing with imipenem/cilastatin for the treatment of hos- threat in hospitals: multidrug-resistant Acinetobacter pital-acquired pneumonia. Diagn Microbiol Infect baumannii. Nat Rev Microbiol. 2007;5(12):939–51. Dis. 2010;68(2):140–51.

5. Centers for Disease Control and Prevention. Track- 15. Pogue JM, Mann T, Barber KE, Kaye KS. Car- ing CRE Infections. 2013. http://www.cdc.gov/hai/ bapenem-resistant Acinetobacter baumannii: epi- organisms/cre/TrackingCRE.html. Accessed Oct demiology, surveillance and management. Expert 2016. Rev Anti Infect Ther. 2013;11(4):383–93.

6. Kim UJ, Kim HK, An JH, Cho SK, Park KH, Jang HC. 16. Pogue JM, Neelakanta A, Mynatt RP, Sharma S, Update on the epidemiology, treatment, and out- Lephart P, Kaye KS. Carbapenem-resistance in comes of carbapenem-resistant acinetobacter gram-negative bacilli and intravenous minocycline: infections. Chonnam Med J. 2014;50(2):37–44. an antimicrobial stewardship approach at the Detroit Medical Center. Clin Infect Dis. 7. Reddy T, Chopra T, Marchaim D, Pogue JM, Alan- 2014;59(Suppl 6):S388–93. gaden G, Salimnia H, et al. Trends in antimicrobial resistance of Acinetobacter baumannii isolates from a 17. Bhavnani SM, Rubino CM, Hammel JP, Forrest A, metropolitan Detroit health system. Antimicrob Dartois N, Cooper CA, et al. Pharmacological and Agents Chemother. 2010;54(5):2235–8. patient-speciﬁc response determinants in patients with hospital-acquired pneumonia treated with 8. Cheah SE, Wang J, Nguyen VT, Turnidge JD, Li J, tigecycline. Antimicrob Agents Chemother. Nation RL. New pharmacokinetic/pharmacody- 2012;56(2):1065–72. namic studies of systemically administered colistin against Pseudomonas aeruginosa and Acinetobacter 18. Nguyen F, Starosta AL, Arenz S, Sohmen D, Don- baumannii in mouse thigh and lung infection hofer A, Wilson DN. Tetracycline antibiotics and models: smaller response in lung infection. J An- resistance mechanisms. Biol Chem. timicrob Chemother. 2015;70(12):3291–7. 2014;395(5):559–75.

9. Queenan AM, Pillar CM, Deane J, Sahm DF, Lynch 19. Dimitriadis P, Protonotariou E, Varlamis S, Poulou AS, Flamm RK, et al. Multidrug resistance among A, Vasilaki O, Metallidis S, et al. Comparative Acinetobacter spp. in the USA and activity proﬁle of evaluation of minocycline susceptibility testing key agents: results from CAPITAL Surveillance methods in carbapenem-resistant Acinetobacter 2010. Diagn Microbiol Infect Dis. baumannii. Int J Antimicrob Agents. 2012;73(3):267–70. 2016;48(3):321–3.

10. Oikonomou O, Sarrou S, Papagiannitsis CC, Geor- 20. Falagas ME, Vardakas KZ, Kapaskelis A, Triarides giadou S, Mantzarlis K, Zakynthinos E, et al. Rapid NA, Roussos NS. Tetracyclines for Infect Dis Ther

multidrug-resistant Acinetobacter baumannii infec- 31. Thamlikitkul V, Tiengrim S, Seenama C. Compara- tions. Int J Antimicrob Agents. 2015;45(5): tive in vitro activity of minocycline and selected 455–60. antibiotics against carbapenem-resistant Acineto- bacter baumannii from Thailand. Int J Antimicrob 21. Macdonald H, Kelly RG, Allen ES, Noble JF, Kanegis Agents. 2016;47(1):101–2. LA. Pharmacokinetic studies on minocycline in man. Clin Pharmacol Ther. 1973;14(5):852–61. 32. Lomovskaya O NK, Rubio-Aparicio D, Sun D, Giffith DC, Dudley MN. Minocycline acitivity is enhanced 22. Lomovskaya O SD, Rubio-Aparicio D, Nelson K, by polymyxin B in tetB-containing isolates of Dudley M. TetB testing and its absence identifies Acinetobacter baumannii. In: Presented at: IDWeek; minocycline (MINO) susceptible isolates of Acine- October 26–30, 2016; New Orleans, LA. tobacter baumannii (ACB). In: Presented at: IDWeek; October 26–30, 2016; New Orleans, LA. 33. Welling PG, Shaw WR, Uman SJ, Tse FL, Craig WA. Pharmacokinetics of minocycline in renal failure. 23. Montana S, Vilacoba E, Traglia GM, Almuzara M, Antimicrob Agents Chemother. 1975;8(5):532–7. Pennini M, Fernandez A, et al. Genetic variability of AdeRS two-component system associated with 34. Carney S, Butcher RA, Dawborn JK, Pattison G. tigecycline resistance in XDR-Acinetobacter bau- Minocycline excretion and distribution in relation mannii isolates. Curr Microbiol. 2015;71(1):76–82. to renal function in man. Clin Exp Pharmacol Physiol. 1974;1(4):299–308. 24. Pournaras S, Koumaki V, Gennimata V, Kouskouni E, Tsakris A. In vitro activity of tigecycline against 35. Maesen FP, Davies BI, van den Bergh JJ. Doxycy- Acinetobacter baumannii: global epidemiology and cline and minocycline in the treatment of respira- resistance mechanisms. Adv Exp Med Biol. tory infections: a double-blind comparative clinical, 2016;897:1–14. microbiological and pharmacokinetic study. J An- timicrob Chemother. 1989;23(1):123–9. 25. Hornsey M, Ellington MJ, Doumith M, Thomas CP, Gordon NC, Wareham DW, et al. AdeABC-medi- 36. MinocinÒ (Minocycline), USP [package insert]. ated efflux and tigecycline MICs for epidemic Monza (Milan), Italy: Triax Pharmaceuticals; 2010. clones of Acinetobacter baumannii. J Antimicrob Chemother. 2010;65(8):1589–93. 37. Sklenar I, Spring P, Dettli L. One-dose and multiple-dose kinetics of minocycline in patients with 26. Sun D R-AD, Tsivkovski R, King P, Dudley M, renal disease. Agents Actions. 1977;7(3):369–77. Lomovskaya O. Tigecycline (TIG) but NOT Minocycline (MINO) Readily selects for clinically 38. Bergeron J, Ammirati M, Danley D, James L, Norcia relevant efflux-mediated resistance (R) in acineto- M, Retsema J, et al. Glycylcyclines bind to the bacter (ACB). In: Presented at: 53rd Interscience high-affinity tetracycline ribosomal binding site Conference on Antimicrobial Agents and Che- and evade Tet(M)- and Tet(O)-mediated ribosomal motherapy; September 10–13, 2013; Denver, CO. protection. Antimicrob Agents Chemother. 1996;40(9):2226–8. 27. Rizek C, Ferraz JR, van der Heijden IM, Giudice M, Mostachio AK, Paez J, et al. In vitro activity of 39. Olson MW, Ruzin A, Feyfant E, Rush TS 3rd, potential old and new drugs against multidrug-re- O’Connell J, Bradford PA. Functional, biophysical, sistant gram-negatives. J Infect Chemother. and structural bases for antibacterial activity of 2015;21(2):114–7. tigecycline. Antimicrob Agents Chemother. 2006;50(6):2156–66. 28. Denys GA, Callister SM, Dowzicky MJ. Antimicro- bial susceptibility among gram-negative isolates 40. Tarazi ZSM, Dudley MN, Griffith DC. Pharmaco- collected in the USA between 2005 and 2011 as part dynamics of minocycline against Acinetobacter of the Tigecycline Evaluation and Surveillance Trial baumannii in a rat pneumonia model. In: Presented (T.E.S.T.). Ann Clin Microbiol Antimicrob. at: 55th Interscience Conference on Antimicrobial 2013;12:24. Agents and Chemotherapy; September 18-21, 2015; San Diego, CA. 29. Qureshi ZA, Hittle LE, O’Hara JA, Rivera JI, Syed A, Shields RK, et al. Colistin-resistant Acinetobacter 41. Jankowski CA, Balada-Llasat J-M, Raczkowski M, baumannii: beyond carbapenem resistance. Clin Pancholi P, Goff DA. A stewardship approach to Infect Dis. 2015;60(9):1295–303. combating multidrug-resistant Acinetobacter baumannii infections with minocycline. Infect Dis Clin 30. Colton B, McConeghy KW, Schreckenberger PC, Pract 2012;20:4. Danziger LH. I.V. minocycline revisited for infections caused by multidrug-resistant organisms. Am 42. Goff DA, Bauer KA, Mangino JE. Bad bugs need old J Health Syst Pharm. 2016;73(5):279–85. drugs: a stewardship program’s evaluation of Infect Dis Ther

minocycline for multidrug-resistant Acinetobacter carbapenem-resistant Acinetobacter baumannii ven- baumannii infections. Clin Infect Dis. tilator-associated pneumonia. J Intensive Care Med. 2014;59(Suppl 6):S381–7. 2010;25(6):343–8.

43. Wood GC, Hanes SD, Boucher BA, Croce MA, 46. Bishburg E, Bishburg K. Minocycline—an old drug Fabian TC. Tetracyclines for treating multidrug-re- for a new century: emphasis on methicillin-resis- sistant Acinetobacter baumannii ventilator-associated tant Staphylococcus aureus (MRSA) and Acineto- pneumonia. Intensive Care Med. bacter baumannii. Int J Antimicrob Agents. 2003;29(11):2072–6. 2009;34(5):395–401.

44. Grifﬁth ME, Yun HC, Horvath LL, Murray CK. 47. Ning F, Shen Y, Chen X, Zhao X, Wang C, Rong Y, Minocycline therapy for traumatic wound infec- et al. A combination regimen of meropenem, cef- tions caused by the multidrug-resistant Acinetobac- operazone-sulbactam and minocycline for exten- ter baumannii-Acinetobacter calcoaceticus Complex. sive burns with pan-drug resistant Acinetobacter Infect Dis Clin Pract. 2008;16:4. baumannii infection. Chin Med J. 2014;127(6):1177–9. 45. Chan JD, Graves JA, Dellit TH. Antimicrobial treatment and clinical outcomes of