REVIEW

Minocycline for the Treatment of Multidrugand Extensively Drug-Resistant A. baumannii:A Review

Jennifer N. Lashinsky . Oryan Henig . Jason M. Pogue .

Keith S. Kaye

Received: February 6, 2017 / Published online: March 29, 2017� The Author(s) 2017. This article is an open access publication

ABSTRACT

Acinetobacter baumannii can cause life-threaten-ing nosocomial infections associated with highrates of morbidity and mortality. In recentyears, the increasing number of infections dueto extensively drug-resistant Acinetobacter withlimited treatment options has resulted in a needfor additional therapeutic agents, and a renais-sance of older, neglected antimicrobials. Thishas led to an increased interest in the use ofminocycline to treat these infections. Minocy-cline has been shown to overcome many resis-tance mechanisms affecting other tetracyclinesin A. baumannii, including tigecycline. Addi-tionally, it has favorable pharmacokinetic and

pharmacodynamic properties, as well as excel-lent in vitro activity against drug-resistant A.baumannii. Available data support therapeuticsuccess with minocycline, while ease of dosingwith no need for renal or hepatic dose adjust-ments and improved safety have made it anappealing therapy. This review will focus on themechanisms of action and resistance to tetra-cyclines in A. baumannii, the in vitro activity,pharmacokinetic and pharmacodynamic prop-erties of minocycline against A. baumannii, andfinally the clinical experience with minocyclinefor the treatment of invasive infections due tothis pathogen.

Keywords: Acinetobacter; Acinetobacterbaumannii; Carbapenem resistance; Extensivelydrug-resistant; Minocycline; Multidrug-resistant; Tetracyclines

INTRODUCTION

Acinetobacter baumannii and other Acinetobacterspecies can cause multidrug-resistant (MDR)nosocomial infections, with high morbidity andmortality rates. MDR A. baumannii, defined as A.baumannii resistant to more than 3 classes ofantimicrobial agents, has been responsible for avariety of healthcare-associated infectionswithin the last two decades [1, 2]. Its ability toresist environmental stress and cleaning

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J. N. Lashinsky (&)Department of Pharmacy, Barnes-Jewish Hospital,Saint Louis, MO, USAe-mail: jennifer.lashinsky@bjc.org

O. Henig � K. S. KayeDepartment of Medicine, University of MichiganMedical School, Ann Arbor, MI, USA

J. M. PogueDepartment of Pharmacy Services, Sinai-GraceHospital, Detroit Medical Center, Detroit, MI, USA

J. M. PogueWayne State University School of Medicine, Detroit,MI, USA

Infect Dis Ther (2017) 6:199–211

DOI 10.1007/s40121-017-0153-2

methods, and to acquire resistance to multipleclasses of antimicrobial agents, have made thispathogen more common, and has become oneof the most difficult to manage causes of out-breaks in the setting of intensive care units(ICUs) [3, 4]. In the Centers for Disease Controland Prevention (CDC) Antibiotic ResistanceThreats report of 2013, MDR A. baumannii wasdeclared a ‘‘serious threat’’ to public health inthe United States [5]. Even more concerning hasbeen the emergence of extensively drug-resis-tant or XDR strains of A. baumannii that areresistant to all but one or two classes ofantimicrobials, and truly pan-drug-resistantstrains resistant to all tested antimicrobials.

Traditionally, carbapenems were consideredthe drugs of choice when treating these highlyresistant A. baumannii, but in recent years thewidespread use of these agents has diminishedtheir clinical activity. Carbapenems were con-sidered appropriate agents to treat infectionscaused by MDR A. baumannii strains, but car-bapenem-resistant A. baumannii (CRAB) hasrapidly increased in frequency. CRAB accountsfor 65% of A. baumannii pneumonia in theUnited States and Europe, while more than 60%of isolates in Asia have been found to be bothpan-drug and carbapenem-resistant [6]. Ananalysis of A. baumannii performed in Detroit,MI reported decreasing susceptibility to thera-pies such as ampicillin–sulbactam and car-bapenems in a rapid fashion. In this study,susceptibility of A. baumannii to ampi-cillin–sulbactam decreased from 89% to 40%,while susceptibility to imipenem decreasedfrom 99% to 42% from 2003 to 2008 [7]. Thehigh resistance rates of these organisms has ledto a situation with limited therapeutic options,where in vitro activity is frequently limited tothe polymyxins, aminoglycosides, tigecyclineand minocycline.

In the setting of carbapenem resistance, sul-bactam (typically administered as ampi-cillin–sulbactam) is potentially an option forthe treatment of A. baumannii; however, opti-mal dosing strategies for sulbactam remainpoorly defined and resistance is increasing.Polymyxins are often considered an importanttreatment option for CRAB in the setting ofsulbactam resistance, but unacceptably high

nephrotoxicity rates and an inability to safelyachieve pharmacodynamic targets has raisedconcern regarding the use of these agents. Inmouse lung models of A. baumannii pneumo-nia, colistin was unable to achieve bacteriostasiseven with the maximum tolerated doses against2 of the 3 strains tested [8]. Furthermore, datasuggest a clinically relevant increase in resis-tance of A. baumannii to colistin [9–11]. A recentsurveillance study in the United States showedthat 5.3% of all Acinetobacter strains were resis-tant to colistin [9], while another surveillancestudy in Greece reported an increase in colistinresistance from 1% in 2012 to 21.1% in 2014among 1116 CRAB isolates [10]. An analysisfrom the Eurofins Surveillance Networkdemonstrated that resistance to carbapenemsamong Acinetobacter more than doubled inrecent years (21.0% in 2003–2005 and 47.9% in2009–2012) as did resistance to colistin (2.8% in2006–2008 and 6.9% in 2009–2012). This sameanalysis demonstrated that rates of resistance tominocycline actually decreased over this timeperiod from 56.5% in 2003–2005 to 30.5% in2009–2012 [11]. Currently, when CRAB infec-tions demonstrate resistance to ampicillin–sul-bactam (up to 74% in the SENTRY program werenot susceptible to ampicillin–sulbactam perCLSI breakpoints) [12] and to colistin, theremaining alternatives for treatment are extre-mely limited.

While certain aminoglycosides can retainactivity in vitro against CRAB, data suggest thataminoglycoside monotherapy is inadequate forinfections occurring outside the urinary tract,and concerns remain regarding nephrotoxicityassociated with this class. A meta-analysisreported that patients receiving aminoglycosidetherapy had higher mortality rates and higherrates of microbiological failure than patientsreceiving beta-lactams or fluoroquinolones [13].Antimicrobials such as tigecycline, ceftola-zone–tazobactam and ceftazidime–avibactamhave more recently come to market; but,unfortunately, these newer agents are not idealfor CRAB. Ceftolazone–tazobactam and cef-tazidime–avibactam have minimal utility in thetreatment of CRAB, given the usual mecha-nisms of resistance to carbapenems are class Dor B carbapenemases. Both of these

200 Infect Dis Ther (2017) 6:199–211

carbapenemases readily hydrolyze these cepha-losporins and these enzymes are not inhibitedby either tazobactam or avibactam [11]. Whiletigecycline shows excellent in vitro activityagainst CRAB, enthusiasm surrounding thisagent has been tempered due to pharmacoki-netic limitations of the drug, the developmentof resistance while on therapy, and its inabilityto demonstrate non-inferiority in the treatmentof hospital-acquired and ventilator-associatedpneumonia [14–17]. Due to the continuedemergence and dissemination of resistant A.baumannii and the limited number of thera-peutic options, other agents such as minocy-cline have been investigated for their utility inthe treatment of these pathogens.

Minocycline is a second-generation tetracy-cline that was first introduced in the 1960s.While the oral formulation remained available,the intravenous formulation was taken off theUS market in 2005 due to decreased use. It wasre-introduced in 2009 and has become animportant option for the treatment of mul-tidrug-resistant organisms, in particular CRAB.Following reintroduction of minocycline to themarket for the treatment of serious infections,including an FDA-approved indication forinfections caused by Acinetobacter, there hasbeen renewed interest in its use. Furtherinvestigation of its use for the treatment ofMDR Acinetobacter infections, including thosecaused by carbapenem-resistant and XDRstrains, has occurred due to its in vitro activityagainst A. baumannii, more favorable pharma-cokinetics compared to tigecycline, and itssafety profile. This review will focus on thetetracycline mechanisms of action and resis-tance, the in vitro activity of minocycline inthe presence and absence of these resistancemechanisms, the pharmacokinetics and phar-macodynamics of minocycline, and finally theclinical experience with minocycline for thetreatment of invasive infections due to A.baumannii.

Compliance with Ethics Guidelines

This article is based on previously conductedstudies and does not involve any new studies of

human or animal subjects performed by any ofthe authors.

MECHANISMS OF ACTIONAND RESISTANCE

Tetracyclines are a broad-spectrum class ofantimicrobials, including tetracycline, doxycy-cline, minocycline and tigecycline, which enterGram-negative organisms through outer mem-brane protein channels and cause conforma-tional changes to the RNA by binding with the30S ribosomal unit. Tetracyclines bind wherethe codon of the mRNA is recognized by theanticodon of the tRNA [18]. This binding blocksthe entry of aminoacyl transfer RNA into thesite A of the ribosome, which prevents elonga-tion of the peptide chain [12]. It has beenobserved that alterations to the hydrophilicsurface of the tetracycline molecule interfereswith the antimicrobial activity of the drug,while alterations in the hydrophobic surface ofthe drug are less likely to interfere [18]. Doxy-cycline and minocycline are the more lipophiliccounterparts of tetracycline, which allows forincreased tissue penetration, increased antibac-terial activity, longer half-lives and broaderspectrums of activity against many bacterialspecies, including Acinetobacter species[12, 19–21].

Resistance to tetracyclines is conferredthrough a variety of mechanisms, includingefflux pumps, ribosomal protection proteins,chemical molecule modification and target sitemodifications. Among Gram-negative organ-isms, the main mechanism leading to tetracy-cline resistance is through efflux pumps. Thedifferences in gene-encoding efflux proteinsaccount for the differences in resistance phe-notypes to the different agents within thetetracycline class. There are over 20 efflux pumpencoding genes that have been detected inGram-negative organisms, with the most com-mon being TetA. These efflux pumps lead to adecrease in tetracycline intracellular concen-tration by exchanging a proton for the tetracy-cline cation complex [12, 18]. In vitro effluxpumps seen in A. baumannii are effective in

Infect Dis Ther (2017) 6:199–211 201

transporting out tetracycline and doxycycline,but with the exception of the TetB pump, notminocycline. Recent work by Lomoskaya andcolleagues confirmed that the absence of TetB inA. baumannii has a negative predictive value of100% for minocycline resistance (93/93 TetBnegative strains were minocycline susceptible),whereas the presence of TetB has a 93% positivepredictive value for minocycline resistance,with only 11/165 (6.7%) isolates being suscep-tible to minocycline when TetB was present[22]. Thus, the gene encoding for TetB repre-sents a potential target for rapid diagnostic genetesting to quickly determine minocyclinesusceptibility.

Tigecycline was synthetically designed toovercome these efflux pumps and has activity ifeither TetA or TetB is present. Unfortunately,although tigecycline was developed to overcomemany of the efflux pump resistance mechanismscommonly seen with tetracyclines, rapid devel-opment of different resistancemechanisms havebeen observed. Current literature suggests thatthe development of such resistance has beenassociated with the TetX gene and, perhaps mostimportantly forA. baumannii, the overexpressionof various efflux pumps (AdeABC, AdeIJK,AdeFGH, AbeM, AdeDE) [23, 24].

Resistance-nodulation-division (RND)-typeefflux pumps, such as AdeABC, have been clo-sely associated with the development of tige-cycline resistance. These pumps have beenshown to be more efficient than other types ofefflux pumps in that they export drugs into theextracellular, rather than periplasmic, space.Up-regulation of these AdeABC pumps havebeen associated with higher MICs and increasedresistance to tigecycline in vitro. Data fromHornsey and colleagues reported overexpres-sion of the AdeABC efflux pump in two cases oftigecycline resistance, which emerged aftertigecycline therapy, as well as a laboratorymutant with an elevated MIC. In this study,susceptibility was restored in a resistant isolateby interrupting the AdeB, which further sup-ports a role of AdeABC in tigecycline resistance[25].

Interestingly, the RND pumps previouslymentioned do not appear to impact minocy-cline susceptibility, and therefore

tigecycline-resistant A. baumannii can remainsusceptible to minocycline. Importantly, theseRND pumps can be selected with clinically rel-evant concentrations of tigecycline (but notminocycline) and serve as a mechanism for thewell-described development of tigecyclineresistance while on therapy [26].

In Vitro Activity

It has been shown that minocycline hasincreased activity against MDR Acinetobactercompared to other early generation tetracycli-nes because of its ability to overcome many ofthe tetracycline resistance mechanisms (mostnotably TetA). A. baumannii containing oxacili-nases or metalo-beta-lactamase genes has beenreported to retain a susceptibility profile tominocycline similar to organisms without thesegenes [27]. In one in vitro study, using CLSIbreakpoints, minocycline displayed a 30%improved susceptibility compared to doxycy-cline and nearly 60% improved susceptibilitycompared to tetracycline against A. baumannii[12]. Thus, minocycline susceptibility should bedetermined by testing directly and not bedetermined by a surrogate class approach (i.e.tigecycline and doxycycline resistance does notnecessarily equal minocycline resistance).

In vitro, minocycline has frequently beenshown to be one of the only available treatmentoptions for difficult to treat multi drug-resistantAcinetobacter infections, and as described above isoften the second most active agent behind col-istin. The antimicrobial activity of minocyclineagainst A. baumannii was recently evaluated intwo large surveillance studies fromdifferentpartsof the world: the SENTRY antimicrobial surveil-lance program (2007–2011) [12] and the Tigecy-cline Evaluation and Surveillance Trial (T.E.S.T,2005–2011) [28]. In the SENTRY program, 79.1%of A. baumannii were susceptible to minocycline(second only to colistin, which had a 98.8%susceptibility rate), while in the T.E.S.T., A. bau-manniihad a susceptibility rate of 84.1%, rangingbetween 68.5% in East South Central US and97.4% in New England. Similarly, multidrug-re-sistant A. baumannii (defined as resistance to 3 ormore classes of antibiotics among beta-lactams,

202 Infect Dis Ther (2017) 6:199–211

aminoglycosides, carbapenems or fluoro-quinolones) were susceptible to minocycline in72.1% of cases, (ranging between 54% in the EastSouth Central US, and 92.3% in New England).

Furthermore, a study by Castanheira andcolleagues assessed A. baumannii isolates col-lected between 2007 and 2011 and showed thatthe only two antimicrobials with greater than50% susceptibility rates were minocycline andcolistin. Reports of minocycline retaining itsactivity in patient isolates that have developedcolistin resistance during colistin therapy alsoexist [29]. Importantly, minocycline suscepti-bility remains high and is not impacted bycarbapenem resistance. Colton and colleaguesreported that isolates retained MIC50 values ofB4.0 lg/mL for minocycline against Acinetobac-ter species, including carbapenem-resistant iso-lates [30]. A study performed in Thailand inCRAB confirmed these results with findings ofMIC50 values of 4 mg/L and MIC90 values of8 mg/L for minocycline, with 81.4% of isolatesbeing susceptible [31].

Additionally, it is important to note thatminocycline has also displayed high levels ofsynergistic activity with polymyxins inminocycline-resistant isolates, where 0.5 mg/Lof polymyxin B restored in vitro susceptibilityto minocycline in 167 tested isolates, 88% ofwhich were resistant to minocyclinemonotherapy [32]. This is an important andencouraging finding given the propensity to usecombination regimens in the treatment ofCRAB.

PHARMACOKINETICSAND PHARMACODYNAMICS

In comparison to other more recently evaluatedantimicrobials, there exist minimal data relat-ing to the pharmacokinetics of minocycline.Studies which have assessed the pharmacoki-netics of minocycline have found that serumconcentrations are similar to other tetracy-clines. Receipt of a 200-mg one-time intra-venous dose has demonstrated peak serumconcentrations ranging from 3 to 8.75 lg/mLand trough concentrations from 0.6 to 1.9 lg/mL [21, 33, 34]. After multiple oral doses of

100 mg every 12 h, serum concentrations haveranged from approximately 0.7 to 3.9 lg/mL[21, 34, 35]. Similarly, data reported in thepackage insert for intravenous minocyclinestate peak and trough concentrations of2.52–6.63 and 0.82–2.64 lg/mL, respectively[36]. The protein binding of minocycline issimilar to that of tetracycline, with approxi-mately 76% of the drug being protein-bound[30, 33]. The half-life of minocycline followinga single dose of either 200 mg or 100 mg isapproximately 12–24 h, which remains clini-cally unchanged in patients with renal dys-function [21, 33, 34, 37]. Minocycline isprimarily metabolized by the liver and excretedthrough the hepatobiliary system, with only asmall amount of drug eliminated through therenal route (5–12%) unchanged in the urine[33, 37]. For these reasons, it has been hypoth-esized that minocycline elimination is inde-pendent of renal function and hepatic function.

In a study looking at single intravenousdoses and repeated oral doses of minocycline, itwas reported that there was no evidence ofreduced drug clearance in patients with reducedrenal function, but a possible increase in tissuedistribution [33]. This particular study evalu-ated 13 male patients with varying degrees ofrenal dysfunction, although none were ondialysis. The authors found that the decline inindividual serum levels of minocycline activityafter intravenous infusion was biphasic andtherefore the pharmacokinetics were consistentwith a two-compartment model. Both the con-centration of antibiotic in urine and thecumulative renal excretion were directly relatedto kidney function, while the overall clearanceof antibiotic appeared to be independent ofrenal function. As minocycline does not seemto accumulate in renal failure, it is believed thatminocycline can be safely administered topatients with renal insufficiency withoutrequiring any dose adjustments [33].

While minocycline has not been shown toaccumulate in renal failure, there exists thenotion that minocycline use in patients withrenal insufficiency may enhance uremia seen inthese patients due to the anti-anabolic processesassociated with the drug on mammalian cells[33]. Although publications have suggested an

Infect Dis Ther (2017) 6:199–211 203

increase in urea clearance and rises in plasmaurea in patients with renal insufficiency receiv-ing minocycline, it is unclear in these analyseswhether or not these were related to antian-abolic actions of the drug or simply a worseningof the patients’ renal failure [27]. Authors havesuggested that there is a critical level of freetetracycline that may be associated withincreased urea production and that this level ‘‘isseldom reached at doses of 200 mg/day ofminocycline’’ [34]. These findings and state-ments serve as the basis for the package insertfor minocycline carrying a warning to notexceed a total daily dosage of 200 mg in 24 h inpatients with renal impairment (CrCl\80 mL/min) [36]. However, assuming that a minocy-cline dose of 200 mg BID is needed, based onpharmacokinetic and pharmacodynamic prop-erties (described below), we would recommendagainst dose adjustment downward in thesepatients due to concerns of underexposure(since the half-life and presumably clearance ofthe drug would not be expected to change).Rather, we would suggest that clinicians beaware of potential antianabolic actions andclosely monitor blood urea nitrogen levels andfor signs/symptoms of uremia, given the seriousnature of infections due to A. baumannii and theneed to meet PK/PD targets.

Minocycline achieves high tissue penetra-tion and displays excellent oral bioavailabilityallowing for expanded clinical uses by givingproviders the ability to easily switch betweenthe intravenous and oral formulations.Minocycline is the most lipophilic of all thetetracyclines because it has a greater partialcoefficient at a neutral pH, and therefore isbelieved to be the most potent, with a longerhalf-life, better oral absorption and enhancedtissue penetration compared to other tetracy-clines. Previous literature has shown thatminocycline has approximately a 20-fold higheraffinity to the ribosome than tetracycline andin vitro can inhibit translation 2–7 times moreefficiently than tetracycline [18, 38, 39].

The minocycline-free area under the con-centration time curve to MIC ratio (fAUC/MIC)is the pharmacokinetic/pharmacodynamicparameter best associated with effect. Recentwork by Tarazi and colleagues have identified

the free AUC/MIC target to be associated withbacteriostasis and 1 log bactericidal activity. Inthis analysis, the authors explored exposureresponse with 6 different A. baumannii isolates(minocycline MIC’s ranging from 0.03 to4 mcg/mL) in a rat pneumonia model. In thismodel, mean fAUC/MIC values associated withstasis and 1 log kill were 12.2 (10.6–16.1) and18.0 (13.1–24.2) mg h/L, respectively [40].

In order to interpret these fAUC/MIC values,it is essential to evaluate them in the perspec-tive of achievable free AUCs obtained withapproved dosing strategies. As has been previ-ously stated in this section, scant pharmacoki-netic data of minocycline are available, and nostudies overtly evaluate AUC exposures. How-ever, the analysis by Welling and colleaguespublished 40 years ago does report on clearancerates in patients with normal renal function andvarious degrees of renal insufficiency [26].Interestingly, in this analysis, they found theclearance rate was the lowest in patients withnormal renal function (1.18 L/h), and slightlyhigher in patients with renal insufficiency(1.84–2.01 L/h). Using the basic pharmacoki-netic equation Dose = AUC/Clearance, and theknown protein binding of *76%, one can esti-mate free AUC exposures and ultimately AUC/MIC ratios with various minocycline dosingregimens for different organism MICs. Forpatients receiving 200–400 mg daily ofminocycline, total area under the concentrationtime curve exposures would be expected torange from 100 to 340 mg h/L, resulting in afree AUC of 24–82 mg h/L. Thus, even in theworst case scenario, where the highest clearancerate (2.01 L/h) and highest MIC in the suscep-tible range (4 mcg/mL) is utilized, a dose of200 mg BID (total AUC = 199 mg h/L, free AUC48 mg h/L) would be expected to achieve bac-teriostasis (fAUC/MIC = 12), and in most sce-narios bactericidal activity would be expected.

Importantly, however, these data are limitedin their interpretability given the large variancein clearance rates reported, the use of 200-mgdaily doses (as opposed to 400-mg daily doses),and the small study sample sizes. Additionally,even though minocycline is considered highlybioavailable with *90% being orally absorbed,it is unknown if there were confounding factors

204 Infect Dis Ther (2017) 6:199–211

impacting absorption in this study, and it ispossible that higher doses and intravenousadministration could lead to increased expo-sures further leading to enhanced bactericidalactivity. Although modern pharmacokineticdata are urgently needed for minocyclineadministered in both its oral and intravenousformulations, data currently available areencouraging. Importantly, additional PK studiesof IV minocycline in normal subjects, criti-cally-ill patients and infected patients, and inpatients with chronic renal impairment areplanned (Mike Dudley, personalcommunication).

CLINICAL EXPERIENCEOF MINOCYCLINE FOR MDRGRAM-NEGATIVE BACILLI

Overview of Clinical Data

Currently, there have been no randomized,controlled trials that evaluate the efficacy ofminocycline in treatment of MDR Gram-nega-tive bacterial infections; however, clinical dataprovide evidence of its potential role in thetreatment of these difficult to treat pathogens.Between the years 1998 and 2015, seven retro-spective studies [16, 41–47] evaluated the use oforal or intravenous minocycline alone or incombination with other antimicrobials for thetreatment of MDR A. baumannii. One factorcomplicating interpretation of these studies isthe variety of different definitions used by dif-ferent investigators. MDR A. baumannii wasdefined as resistance to 3 or more antimicrobialclasses in one study [42] and resistance to allfrequently tested beta-lactams in another study[44]. CRAB was defined as carbapenem-resistant[16, 45] and pan-drug-resistant A. baumanniiwas defined as A. baumannii resistant to allantibiotics excluding polymyxins [46].

The seven studies included 126 patientsbetween 17 and 85 years old (Table 1), who had141 identifiable isolates that included the fol-lowing sources: respiratory tract (91, 74.6%),blood (22, 18%), bone (11, 9%), skin and softtissue (including surgical site infections) (12,

9.8%), urine (2, 1.6%), and others (3, 2.4%). Ofthe patients treated, 94 patients receivedminocycline combined with another antimi-crobial agent, 12 patients were treated withminocycline monotherapy, and 11 patientsreceived monotherapy with either minocyclineor doxycycline, with the exact agent not speci-fied [40]. A majority of the patients (72.5%)received minocycline intravenously. The mostcommon dose used was 100 mg twice daily,with or without a loading dose of 200 mg(overall, 61 subjects received a loading dose).One study included patients treated with IVminocycline 200 mg twice daily [16], and inanother study patients treated with oralminocycline 200 mg every 6 h [46]. Treatmentwas administered for a duration that rangedbetween 2 days to 7 weeks, according to thesource of infection [44]. Median durations oftherapy from each study is presented in Table 1.Overall, the clinical success rate of monother-apy or combination treatment was 78.2%.Microbiological cure (defined differently acrossstudies) was reported in 4 studies and rangedfrom 50% and 89% (Table 1).

Clinical Data for Monotherapy

Twenty-three patients in five of the studies weretreated with either minocycline or doxycyclineas monotherapy for A. baumannii infection[42–46]. As previously stated, in one study therewas no differentiation between treatment withminocycline and doxycycline, and therefore thedata are presented together [40]. The age of thepatients ranged between 15 and 85 years(Table 1). Of the 22 known sources of A. bau-mannii isolates, 16 (73%) were from the respi-ratory tract, 4 (18%) from soft tissues, and 2(9%) from the bone. There were no bloodstreaminfections in this group. The route of minocy-cline administration was reported in 12 patientsand was intravenous in most cases (92%). Themost commonly used dose was 100 mg twicedaily, although one study treated patients with200 mg BID. The number of subjects whoreceived a loading dose could not be deter-mined. The duration of treatment rangedbetween 2 days for an unknown source and

Infect Dis Ther (2017) 6:199–211 205

Table1

Clin

icalexperience

withminocyclin

eforAcinetobacter

infections

Autho

r,years,design

Num

ber

of patients

Age

Source

ofinfectiontreated

Treatmentroute,

dose,du

ration

Co-infection

Con

currenttreatm

ent

Outcome

Clin

ical

improvem

ent

Microbiological

improvem

ent

Adverse

events

WoodGC,

1998

Retrospective

4Median37

(24–

49)

Respiratory(BAL)

One

patienthad

co-bloodstream

infection

Route:IV,L

D:n

one

Dose:100mgBID

Duration:

10,1

4,15,2

0days

N/A

2patients:

Imipenem

TMP-SM

Z?

trovafloxacin

4(100%)

3of

3tested

Not

reported

Griffith

ME

2005–2

006

Retrospective

8Median23.5

(19–

35)

Boneandsoft

tissue

(post-operative)

Route:oral

LD:none

Dose:100mgBID

Duration:

4–7weeks

7patients:MRSA

,Enterobacteriaceae,

P.aeruginosa

7patients:

4—im

ipenem

2—ancomycin

1—am

ikacin

7(87.5%

)NA

One

patientwith

eosinophiliaand

neutropenia

ChanJD

2004–2

007

Prospective

36Average

40(15–

87)

Respiratory

(BAL/

mini-B

AL)

10patientshad

co-bloodstream

infection

Route:IV

orOral

LD:200mgLD

for

IVminocyclin

e

Dose:

Oral—

200mgBID

IV—100mgBID

Duration:

13.3

±4.2days

49%

had

poly-m

icrobialBAL

cultu

res

25patients:

20—am

inoglycoside

2—am

inoglycosides?

polymyxin

3—am

inoglycoside?

tigecycline

29(80.6%

)NA

10of

theentire

cohort(n

=55)

developedAKI

(18.2%

);

6of

30with

aminoglycosides;

4of

7(57%

)with

colistin

Mortality:21.8%

(entirecohort)

GoffDA

2010–2

013

Retrospective

(including

Jankow

ski

data)

55Median56

(23–

85)

Respiratory

(respiratory

cultu

re):32

Respiratory

?

BSI:4

BSI:1

0

Softtissue:2

Bone:2

Urine:1

Other:3

Route:IV

LD:42

(76%

)received

LD

of200mg

Dose:100mgBID

Duration:

Median9days

(2–3

5)

N/A

52patients:

19—colistin

9—colistin?

doripenem

8—colistin?

ampicllin

–sulbactam

6—doripenem

3—colistin?

doripenem

?am

picillin–

sulbactam

3—am

picillin–

sulbactam

2—am

picillin–

sulbactam

?doripenem

2—others

40(72.7%

)Docum

ented

eradiation:

31(56%

)

Presum

ederadication:

12(22%

)

Failure:12(22%

)

Nopatienthad

anydocumented

adverseevents

deem

edto

beattributableto

minocyclin

e.

Mortality:42%

206 Infect Dis Ther (2017) 6:199–211

Table1

continued

Autho

r,years,design

Num

ber

of patients

Age

Source

ofinfectiontreated

Treatmentroute,

dose,du

ration

Co-infection

Con

currenttreatm

ent

Outcome

Clin

ical

improvem

ent

Microbiological

improvem

ent

Adverse

events

BishburgE

2009–2

012

Retrospective

5Fortheentire

GNBcohort

(8)44–8

0

Respiratory:3

Softtissue:3

Bone:1

Route:IV

LD:none

Dose:100mgBID

Duration:

5–18

days

(som

emay

have

continuedoral

treatm

ent)

Datacann

otbe

separated

N/A

5(100%)

NA

Not

reported

PogueJM

2011

Retrospective

9Median50

(35–

74)

Respiratory:3

Respiratory

?soft

tissue:1

BSI:3

Route:IV

LD:none

Dose:200mgBID

(5patients)

100mgBID

(2patients)

Duration:

median7days

(3–1

4)

2patients

P.aeruginosa

K.pneum

oniaeKPC

6patients:

4—colistin

1—meropenem

?colistin

1—am

picillin–

sulbactam

5(71.4%

)2of

4tested

(50%

)2patientswith

AKI,attributed

tocolistin

Mortality:2(28%

)

NingFG

2011–2

013

Retrospective

9Average

38.2±

10.7

(23–

57)

Respiratory

(sputum):9

Wound

:6

BSI:4

Route:oral

LD:200mg

Dose:200mgQID

Duration:

N/A

2patients

MRSA

bacterem

ia

9patients:

high

dosesof

meropenem

and

cefoperazone–sulbactam

9(100%)

8(89%

)Elevated

ALT,A

ST,n

otattributed

tominocyclin

e

Infect Dis Ther (2017) 6:199–211 207

6 weeks in post-fracture infections. In onestudy, clinical success was achieved in 81.8% ofsubjects [40] and in 100% of subjects in the fourother studies. Microbiological cure was notavailable in this group.

Adverse Events Data in All Clinical Studies

Adverse events were reported in five studies[16, 42, 44, 45, 47]. In one study, a patientdeveloped eosinophilia and neutropenia [44].Two studies reported acute kidney injury (oc-curring in 28% and 18.2% of subjects) whichwas attributed to concomitant colistin oraminoglycoside treatment [16, 45]. One studyreported elevated liver enzymes which wereattributed to host factors (severity of illness) andnot to the minocycline [46]. Two other studiesreported no adverse reactions or events attrib-uted to minocycline [42].

DISCUSSION

Acinetobacter species are common nosocomialpathogens that have been implicated in seriousinfections associated with high morbidity andmortality rates. Historically, carbapenems wereused to treat MDR Acinetobacter infections, butin recent years an increase in CRAB hasdecreased the therapeutic effectiveness of theseagents. Limitations of available treatmentoptions have left clinicians in need of addi-tional therapeutic choices. During the last dec-ade, the interest in minocycline has increaseddue to its in vitro activity against A. baumannii(including MDR and XDR strains), as well as itspharmacokinetic and pharmacodynamic prop-erties (e.g., its ability to achieve good serum andtissue levels as well as to display bactericidalactivity). The ability of minocycline to over-come many resistance mechanisms thatdecrease the activity of other tetracyclines, mostnotably TetA and RND pumps, has allowed forits more widespread use against MDR Acineto-bacter. Its favorable safety profile, lack of neededdose adjustments for renal and hepatic failure,and the easy conversion between IV to PO for-mulations have enhanced its clinical appeal.This is particularly true for difficult to manage

patients with resistant Acinetobacter infectionswhere available data support therapeutic suc-cess in these challenging clinical scenarios.Given the paucity of antimicrobials currentlyavailable to treat MDR and XDR A. baumannii,further clinical and laboratory evaluation ofminocycline as an effective treatment alterna-tive for infections caused by resistant pathogensis warranted. Additionally, further studies toassess if minocycline monotherapy is sufficientor whether it should be utilized as part of acombination therapeutic regimen are needed.

ACKNOWLEDGEMENTS

No funding or sponsorship was received for thisstudy or publication of this article. All namedauthors meet the International Committee ofMedical Journal Editors (ICMJE) criteria forauthorship for this manuscript, take responsi-bility for the integrity of the work as a whole,and have given final approval for the version tobe published.

Disclosures. Jason M. Pogue has served as aconsultant for The Medicines Company. KeithS. Kaye has served as a consultant for TheMedicines Company. Jennifer N. Lashinsky andOryan Henig have nothing to disclose.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not involve any new studies of humanor animal subjects performed by any of theauthors.

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analyzed during the current study.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, provide

208 Infect Dis Ther (2017) 6:199–211

a link to the Creative Commons license, andindicate if changes were made.

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