rifamycins, alone and in combination - cold spring harbor

Rifamycins, Alone and in Combination

David M. Rothstein

David Rothstein Consulting LLC, Lexington, Massachusetts 02421

Correspondence: [email protected]

Rifamycins inhibit RNA polymerase of most bacterial genera. Rifampicin remains part ofcombination therapy for treating tuberculosis (TB), and for treating Gram-positive prostheticjoint and valve infections, in which biofilms are prominent. Rifabutin has use for AIDSpatients in treating mycobacterial infections TB and Mycobacterium avium complex(MAC), having fewer drug–drug interactions that interfere with AIDS medications.Rifabutin is occasionally used in combination to eradicate Helicobacter pylori (pepticulcer disease). Rifapentine has yet to fulfill its potential in reducing time of treatment forTB. Rifaximin is a monotherapeutic agent to treat gastrointestinal (GI) disorders, such ashepatic encephalopathy, irritable bowel syndrome, and travelers’ diarrhea. Rifaximin isconfined to the GI tract because it is not systemically absorbed on oral dosing, achievinghigh local concentrations, and showing anti-inflammatory properties in addition to its anti-bacterial activity. Resistance issues are unavoidable with all the rifamycins when the bio-burden is high, because of mutations that modify RNA polymerase.

The four rifamycins approved for clinical use,rifampicin, rifabutin, rifapentine, and rifax-

imin (Fig. 1), are available as orally formulatedagents derived from rifamycin SV, the naturalproduct of Amycolatopsis mediterranei (aliasStreptomyces mediterranei) (Tupin et al. 2010).The rifamycins are transcriptional inhibitors,and bind specifically to the b subunit of RNApolymerases from a broad range of bacteriawhile showing little or no activity against hu-man RNA polymerases (Chen and Kaye 2009;Forrest and Tamura 2010).

Because rifamycins bind and inhibit mostbacterial RNA polymerases, their spectra of ac-tivity are largely dictated by entry or exclusionfrom the bacterial cytoplasm. Rifampicin haspotent activity against a variety of pathogens,including mycobacteria, Gram-positive cocci

(notably staphylococci and streptococci), Clos-tridium difficile, and has activity against selectGram-negative pathogens Neiserria meningiti-des, N. gonorrhoeae, and Hemophilus influenza.The majority of Gram-negative pathogens arenot susceptible to rifampicin (Chen and Kaye2009; Forrest and Tamura 2010). The otherrifamycins have similar spectra and potency(Table 1), although they differ substantially inpharmacokinetic properties (Table 2).

Rifamycins induce expression of humanP450 cytochrome oxidases, notably CYP3A4,as well as the human P glycoprotein ABC trans-porter, which can cause drug–drug interactionsthat are a major complication in therapy (Bur-man et al. 2001). In a fortunate irony, the in-ducing properties of rifaximin, a drug well de-signed to treat gastrointestinal (GI) disorders, is

Editors: Lynn L. Silver and Karen Bush

Additional Perspectives on Antibiotics and Antibiotic Resistance available at www.perspectivesinmedicine.org

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probably an asset to therapy (see “rifaximin”section below.)

RIFAMYCIN-RESISTANCE POTENTIALAND ITS INFLUENCE ON RIFAMYCINDRUG ADMINISTRATION

The high frequency of rifamycin-resistance de-velopment among all susceptible bacteria is apervasive concern. In particular, rifamycinsare prone to “endogenous resistance develop-ment” (Silver 2011), resulting from mutationsin rpoB encoding the b subunit of RNA poly-merase, the target of rifamycin binding of allsusceptible species. Mutations arise duringDNA replication, unavoidable mistakes that en-code RNA polymerase, which bind rifamycins

less tightly. When the bioburden of susceptiblebacteria exceeds 108, then mutant variants in-evitably contain RNA polymerase that fails tobind rifamycins effectively.

Mutations conferring strong rifampicin re-sistance are cross-resistant to other approvedrifamycins (Williams et al. 1998; Wichelhauset al. 1999; Tupin et al. 2010; Goldstein 2014).No matter how susceptible the original bacteriaare, the mutants will take over a population ex-posed to rifamycins, unless another antibacte-rial agent is also present to nullify their selectiveadvantage. Hence, whenever the bioburden isassumed to be greater than 108, and the goalof therapy is elimination of a pathogen, rifamy-cins are routinely administered in combination.Monotherapy with approved rifamycins is a

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Rifapentine Rifaximin

Figure 1. Chemical structures of approved rifamycins. Clockwise (from top left): rifampicin, rifabutin, rifaximin,and rifapentine.

D.M. Rothstein

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Tabl

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consideration when the bioburden is assumedto be low, for example, as prophylactic therapy.

DNA sequence analysis of resistant isolatesselected in vitro indicates that resistance wasmediated by a single modification in one of12 codons of the rpoB gene of Staphylococcusaureus, resulting in a single change in one of atleast 25 nucleotide sites (Wichelhaus et al. 1999;Murphy et al. 2006; Goldstein 2014). Analysisof rifamycin-resistant clinical isolates of S. aure-us revealed that resistant strains predominantlycontained mutations in one or more of the12 codons in the rpoB gene shown to mediaterifamycin resistance in vitro. Among the resis-tant clinical isolates, single mutational events inthe rpoB gene have been detected within seven ofthese critical codons found by in vitro selection.When clinical isolates containing multiple mu-tations in the rpoB gene are included in the anal-ysis, modifications in all but one of the 12 criticalcodons defined by in vitro selection experimentshave been identified among clinical isolates(Aubry-Damon et al. 1998; Wichelhaus et al.1999; O’Neill et al. 2006). One potential muta-genic hotspot was detected among clinical iso-lates at codon 481 mediating a histidine to as-paragine change (Wichelhaus et al. 2002; O’Neillet al. 2006). Thus, in S. aureus, resistance is me-diated in the laboratory and in the clinic primar-ily by mutations within the rpoB gene, mostlyresiding in cluster I of the rifampin-resistance-determining region (Wichelhaus et al. 2002).

Competitive fitness assays, in which a rifa-mycin-resistant strain and its isogenic rifamy-cin-sensitive parent are cogrown in the absenceof rifampicin for multiple generations, revealthat the proportion of the resistant strain di-minishes, indicating a fitness cost of theserpoB mutations (Wichelhaus et al. 2002; O’Neillet al. 2006). Strains carrying a mutation in co-don 481 of the S. aureus rpoB gene may not showthis fitness deficit (Wichelhaus et al. 2002),which may explain its prevalence among clinicalisolates. However, others have observed dimin-ished fitness of strains carrying this allele as wellas other rpoB mutations (O’Neill et al. 2006).

These competitive fitness experiments pre-dict that rifamycin-resistant strains would notcompete well in the longer run, in an environ-

ment lacking rifamycins. However, laboratoryexperiments might exaggerate the long-termfitness deficits of rifamycin-resistant strains,because of the possible acquisition of compen-satory mutations that would reduce the handi-cap of rifamycin-resistant alleles (O’Neill et al.2006).

Rifamycin resistance in Mycobacterium tu-berculosis, the pathogen responsible for TB, isalso predominantly mediated by mutations inits rpoB gene. Rifamycin resistance selected invitro results in modifications in homologousregions of the rifampin-resistance-determiningregion compared with S. aureus or Escherichiacoli (Murphy et al. 2006; Goldstein 2014). Clin-ical isolates of resistant strains of M. tuberculosissimilarly contain mutations in the key codonsencoding the capacity to bind rifamycins(Goldstein 2014). Rifamycin-resistant strainsof M. tuberculosis were also associated with acompetitive fitness disadvantage (Billingtonet al. 1999; Mariam et al. 2004).

The most important consideration of en-dogenous resistance potential, in all therapeuticareas, can be summarized as follows. If the in-fecting population of rifamycin-susceptiblebacteria exceeds 108, then there are a handfulof rifamycin-resistant mutants in the infectingpopulation. In this situation, selection clearlyfavors the resistant mutant(s), resulting in theirrapid overgrowth despite any minor growth def-icits of the rifamycin-resistant strains.

TUBERCULOSIS (TB)

Rifampicin was approved by the Food and DrugAdministration (FDA) in 1971 for the treatmentof TB. Combination therapy had already beenestablished as the standard of care, with the dis-covery that streptomycin monotherapy, firsttested in 1946, resulted in short-lived improve-ments, with the frequent emergence of strep-tomycin-resistant bacteria (Fox et al. 1999;Nuermberger et al. 2010; Field et al. 2012).Combination therapy of streptomycin togeth-er with para-aminosalicylic acid and, subse-quently, with isoniazid in the early 1950s,made for a considerably more robust therapy,although 18 to 24 mo of treatment were required



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(Fox et al. 1999; Mitchison and Davies 2012).The inclusion of rifampicin resulted in fewerrelapses, and it was found that therapy couldbe shortened to 9 mo, and with subsequent im-provements to the current 6-mo regimen.

Rifampicin was found to have unique bac-tericidal activity against persistent M. tubercu-losis using in vitro and cell culture systems (Foxet al. 1999). Human studies of multiple combi-nations of drugs confirmed the importance ofrifampicin (Jindani et al. 2003). Isoniazid wasparticularly active in the first week against met-abolically active bacteria, whereas rifampicincontributed to bactericidal activity during thefirst week. Rifampicin continued to act in thecoming months against the persistent, metabol-ically quiescent population of bacteria, oftenresiding inside of host cells. More recently, pyr-azinamide was found to contribute bactericid-al activity against the persistent population(Mitchison and Davies 2012). These studiesled to the combination therapy that is used totreat susceptible M tuberculosis infections, thatis, 2 mo of isoniazid, rifampicin, pyrazinamide,and ethambutol, followed by 4 mo of continu-ation therapy consisting of daily dosing withisoniazid and rifampicin (Jindani et al. 2014).

Nausea is one common side effect of com-bination therapy, although generally it is notsufficient to stop therapy. Drug-induced hepa-titis is rare, occurring in 2.5% of patients, and isgenerally attributed to the isoniazid and/orpyrazinamide components. Flu-like syndromeis experienced by a small minority of patientsexposed to rifampicin and, rarely among thisminority, can include thrombocytopenia, he-molytic anemia, and acute renal failure, result-ing in discontinuation of therapy. The occur-rence of these events is not dose related andmay involve immune response to the drug (Bur-man et al. 2001; Mitnick et al. 2009).

With such a complex regimen and its sideeffects, adherence becomes an important issueand the main reason for treatment failure.Shortening therapy would be a major advance.One strategy is to raise the dose of rifampicin,which at 600 mg/d in the standard formulation,is at the low end of the curve to achieve optimalefficacy (Mitnick et al. 2009; Mitchison and Da-

vies 2012), with the additional knowledge thathigher doses generally are tolerable (Boeree et al.2015). Another possibility for shortening ther-apy is the incorporation of other drugs.

Rifapentine, approved by the FDA in 1998for TB therapy, is a slightly more potent rifa-mycin derivative than is rifampicin, and has afive-fold increased exposure as a result of a lon-ger half-life (Burman et al. 2001; Mitnick et al.2009; Nuermberger et al. 2010). Preclinicalstudies suggested that if rifapentine replacedrifampicin, TB therapy might be shortened(Mitchison and Davies 2012). The results of arecent phase 3 clinical trial showed that the last4 mo of the 6-mo therapy could be simplifiedwith weekly dosing of rifapentine and moxiflox-acin (a quinolone), but not shortened (Jindaniet al. 2014).

Rifabutin is a potent antimycobacterialagent that partitions mostly into tissues as op-posed to plasma (Burman et al. 2001; Mitnicket al. 2009). Rifabutin was approved in 1994 forthe treatment of infections caused by Mycobac-terium avium complex (MAC) (O’Brien andVernon 1998; Mitnick et al. 2009). Rifabutin isa weaker inducer of CYP3A4, thereby diminish-ing drug–drug interactions, and is therefore of-ten chosen for tuberculosis therapy for AIDSpatients. In essence, patients are administereda watered-down version of TB chemotherapyin an attempt to minimize difficult drug–drug interactions; rifabutin can increase theelimination of essential antiretroviral medica-tions, while the retroviral medications can in-crease the half-life of rifabutin, which can resultin hepatotoxicity (Burman et al. 2006; Zhanget al. 2011; Regazzi et al. 2014).

Adherence issues leading to interrupted TBtherapy can result in incomplete killing of per-sistent bacteria, requiring prolonged therapy.Interrupted therapy can also result in the selec-tion of resistant M. tuberculosis mutants, forexample, rifamycin-resistant mutants. Selectionof resistant mutants leads to treatment failure,requiring a change from first-line agents to sec-ond-line agents.

Undertreatment can also select for mu-tants. For example, when AIDS patients weretreated with intermittent rifabutin-based ther-

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apy, the exposure to rifamycin was diminishedto avoid drug–drug interactions with AIDSmedications. The majority of these AIDS pa-tients were cured. For those patients who expe-rienced relapses, however, usually a rifamycin-resistant mutant strain had been selected duringtherapy (Burman et al. 2006). There are alter-native antibacterials to treat drug-resistant TB(Mitnick et al. 2009; Nuermberger et al. 2010;Field et al. 2012), but to lose the use of rifamy-cins, the most powerful killing agent, is a serioussetback for an AIDS patient.

THE USE OF RIFAMPICIN AS A SINGLEAGENT FOR PROPHYLACTIC TREATMENTOF LATENT TB

A positive skin test for TB in the absence of clin-ical symptoms may indicate latent TB, a symp-tom-free quiescent infection. In the UnitedStates, most cases of TB are the result of reacti-vated infection (Horsburgh and Rubin 2011).The expectation is that 5% to 15% of latentcarriers in the United States are expected to de-velop an active infection during their lifetimes(Getahun et al. 2015), an estimate that may be amoving target depending on immigration, theproportion of immune-compromised individ-uals, etc. Therefore, prophylactic treatment toprevent active outbreak is a consideration.

Because the bioburden is low, latent TB isoften treated by shortened therapies of 3 to4 mo. In fact, a variety of treatment options isused, including rifampicin and isoniazid for 3mo or for 4 mo, rifapentine and isoniazid week-ly for 3 mo, isoniazid alone for 3, 4, 6, or 9 mo,and rifampicin monotherapy for 3 or for 4 mo(Stagg et al. 2014; Getahun et al. 2015). Al-though these treatments are probably effective(i.e., result in a reduced conversion to active TBcompared with untreated patients), it has beenchallenging to standardize treatment. It is prob-ably difficult to determine the medical supe-riority of a particular treatment to prevent anoutbreak of active TB, an infrequent event, asthe end point of clinical trials. As mentionedpreviously, rifampicin is a well-tolerated drug,so there is a temptation to use rifampicinmonotherapy, diminishing adherence issues

and costs. A word of caution, however, is thatthe failure of latent TB treatment may be rareand may not appear immediately, but the neg-ative consequence of failure could be severe,such as a lifetime of battling an M. tuberculosisstrain that has been selected for resistance torifamycins. Although the bioburden for anyone patient harboring a latent TB infection islow, the communal bioburden of a group ofsuch patients can be predicted to include a ri-fampicin-resistant mutant, which could be se-lected in the unlucky individual undergoing ri-fampicin as a stand-alone therapy. If the severityof selecting a resistant pathogen (and not sim-ply a failed therapy) has not been properly takeninto account, the rifampicin stand-alone strat-egy perhaps should be abandoned.

The 3-mo isoniazid-rifampicin daily thera-py is a more intuitively appealing choice to treatlatent TB, because isoniazid would protectagainst development of a rifampicin-resistantactive infection. However, this strategy will notbe secure if the frequency of isoniazid resistancerises, as currently the susceptibility of the latent-ly infecting bacteria is not determined beforetreatment.

RIFAMYCINS IN COMBINATION THERAPYBEYOND THE REALM OF MYCOBACTERIA;TREATING PEPTIC ULCER DISEASE

It is generally accepted that combination anti-biotic therapy is necessary to eradicate Helico-bacter pylori from stomach tissue, to cure pepticulcer disease. Rifabutin, with its tissue penetrat-ing ability, has been shown to be effective incombination with amoxicillin and other antibi-otics in a series of small clinical trials (Gisbertand Calvet 2012). A practical strategy is to userifabutin in combination as a backup if first-linetherapy fails, knowing that rifamycin resistanceis currently infrequently encountered in H. py-lori strains. Amoxicillin resistance is also veryrare. Gisbert and Calvet envision the role ofrifabutin to be one reserved for the more recal-citrant cases of peptic ulcer disease, not to beoverused, to prevent selection of rifampicin-resistant M. tuberculosis in the populace, for ex-ample, among latent carriers of TB, during the10–12 d required for therapy.



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RIFAMPICIN AND SYSTEMICGRAM-POSITIVE INFECTIONS

The possibility of using rifampicin in com-bination therapy against Gram-positive infec-tions was recognized early after its approvalfor treating TB. Rifamycins have potent activityagainst both staphylococci and streptococci,the predominant pathogens causing systemicinfections, such as bacteremia, abscesses, endo-carditis, and foreign body infections. If a part-nering drug could prevent the emergence ofrifampicin-resistant mutants, then the combi-nation could provide great benefit (Sanders1976). It is very important that the pharmaco-kinetic properties of the partnering drug aresuitable, that is, that the second drug is alwayssufficiently present to prevent outgrowth of thetiny minority of rifampicin-resistant organ-isms, while allowing rifampicin, with its favor-able potency and tissue penetration, to exert itsactivity (Achermann et al. 2013).

In vitro evaluation of rifampicin combina-tions did not provide clear-cut guidance inchoosing a second drug. Isobolograms ortime-kill curves often showed apparent syner-gy at sub-minimum inhibitory concentration(MIC) levels of two drugs, while showing inter-ference or antagonism at higher concentrations,particularly when rifampicin was tested in com-bination with bactericidal drugs (Perlroth et al.2008; Forrest and Tamura 2010). In general,these studies minimized the apparent benefitof pairing rifampicin with bactericidal agents,while exaggerating benefits of bacteriostaticagents, such as minocycline (Forrest and Ta-mura 2010).

Animal models did not provide compellingsupport for rifampicin adjunct therapy, exceptfor foreign-body models described in the nextsection. Native valve endocarditis models andbacteremia models (mouse, rat, and rabbit)have provided inconsistent support for rifampi-cin adjunct therapy with linezolid, daptomycin,or fusidic acid. However, there was no evidencefor greater efficacy of rifampicin as an adjunctwith vancomycin, the mainstay drug for seriousGram-positive infections (Perlroth et al. 2008;Forrest and Tamura 2010).

Clinical publications have included casestudies of one or a handful of patients under-going combination therapy, including rifampi-cin, to treat native valve endocarditis and/orbacteremia, with mixed results (Forrest andTamura 2010). In addition, several small pro-spective clinical combination trials were per-formed (Van der Auwera et al. 1985; Dworkinet al. 1989; Levine et al. 1991; Heldman et al.1996; Schrenzel et al. 2004). The difficultywith all of these trials is they were under-powered to be convincing, given that the base-line benefit of monotherapy was substantial.How could a trial convincingly show benefitwhen each arm of the study contained fewerthan 20 subjects, and when monotherapy waseffective in most patients? However, one clini-cal trial showed approximate equivalence inmedical outcome and a qualitative advantageof orally administered combination therapy(rifampicin with fleroxacin, a quinolone) totreat bacteremia, compared with IV-adminis-tered vancomycin, reducing hospitalizationsby 11 d per patient (Schrenzel et al. 2004). TheAmerican Heart Association has not endorsedrifampicin combination therapy for treatingnative valve endocarditis or bacteremia. Perhapsa well-powered clinical study, with a carefullydesigned and optimized protocol, would clarifythis issue.

RIFAMPICIN IN COMBINATION THERAPYTO TREAT PROSTHETIC JOINT INFECTIONS

Rifampicin combination therapy has more ob-vious advantages in treating prosthetic jointinfections (PJIs), mostly resulting from staph-ylococcal infections following hip or knee re-placements (Zimmerli et al. 2004). The foreignbody provides a surface devoid of host innatedefenses, and an opportunity for biofilms todevelop. The bacteria secrete exopolysaccha-rides that can adhere to the device surface, andprovide a barrier, protecting bacteria fromphagocytes, antibodies, and antibiotics (Coster-ton et al. 1999; Jacqueline and Caillon 2014).MICs for most drugs are 100–1000 times high-er in biofilms (Jacqueline and Caillon 2014).However, rifampicin retains more activity

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against biofilms of staphylococci than other an-tibiotics (Widmer et al. 1990; Amorena et al.1999; Saginur et al. 2006; Perlroth et al. 2008;Gomes et al. 2012; Jacqueline and Caillon2014). Rifampicin, in addition, shows activityagainst biofilms of Propionibacterium acnes,another prominent PJI pathogen (FurustrandTafin et al. 2012).

Animal models of foreign body infectionsreinforce the idea that rifampicin has a uniqueantibacterial role in PJI. In the guinea pig cagemodel, staphylococci are injected into cages thathave been surgically implanted subcutaneouslyin guinea pigs (Zimmerli et al. 1982). This mod-el system can test for efficacy of antibioticsagainst both the planktonic cells, and biofilmson cage surfaces. The combinations of rifampi-cin with linezolid (Baldoni et al. 2009), withdaptomycin (John et al. 2009), and with fosfo-mycin (Mihailescu et al. 2014), showed im-proved results compared with monotherapy,and potential for clinical efficacy. An experi-mental rabbit model of PJI also showed thatrifampicin and daptomycin were an effectivepair against methicillin-resistant S. aureus(MRSA) infection of a joint implant comparedwith daptomycin monotherapy, resulting in thesuppression of resistance to daptomycin and torifampicin. Similar results were observed forvancomycin paired with rifampicin (Saleh-Mghir et al. 2011). An experimental rat model,using a titanium wire implanted into the tibia tosimulate a foreign body implant, suggested thatrifampicin combinations with both linezolidand vancomycin reduced MRSA more effective-ly than monotherapy with linezolid or vanco-mycin (Vergidis et al. 2011). It is encouragingand consistent that rifampicin combinationsshown efficacy in these three distinct animalmodels of PJI.

Approximately 1% of patients having aprosthetic implant experience PJI. Clinical evi-dence showed that some PJI infections could besuccessfully treated by using combination anti-biotic therapy with rifampicin playing a centralrole. For the 11 patients in the first study, re-moval of the implant to treat the infection (thestandard of care) was not practical (Widmeret al. 1992). Before antibiotic administration,

patients had a surgical procedure to physicallyclean the area surrounding the implant, remov-ing hopelessly infected and inflamed tissue (de-bridement) while leaving the prosthesis in place.Treatment of PJIs with a rifampicin/ciproflox-acin combination was successful in nine of 11patients who showed no symptoms of infectionafter 2 yr of follow-up. These results were suffi-ciently encouraging to launch a prospective,blinded randomized trial in which patientswere enrolled with early PJI infections, mostlyof S. aureus, to determine whether adjunct ther-apy with rifampicin was beneficial (Zimmerliet al. 1998). All patients were treated initiallywith an IV course of the b-lactam flucloxacillinor vancomycin for 2 wk. The test group wasalso treated with rifampicin during the initial2-wk treatment. For the long-term continua-tion phase, the control group was administeredoral ciprofloxacin monotherapy, while the testgroup was administered both oral ciprofloxacinand rifampicin. All 12 patients able to completethe test regimen were cured of the infection,whereas only seven of 12 patients administeredciprofloxacin monotherapy were cured. Morerecently, a clinical study of 43 patients infectedprimarily with MRSA reinforced the conceptthat prosthetic retention also applies to MRSAinfections (Peel et al. 2013).

The clinical evidence supporting PJI regi-mens includes numerous additional case stud-ies, but still does not carry the statistical powerof pivotal clinical trials for obtaining drug ap-proval. In the absence of this well-documentedapproval process, with a defined FDA label pre-scribing drug administration, the medical pro-fession has resorted to guidances representingthe current thinking of experts in the field.In the Infectious Disease Society of America(IDSA) guidance (Osmon et al. 2013), therewas consensus in the definition of PJI, methodsof detection of infections, the use of antibacte-rial therapy, and when to attempt to salvage aprosthesis without surgical removal. There wasrecognition of alternative preferences for partic-ular procedures and antibiotic strategies. How-ever, on the idea of the centrality of rifampicinin treating these biofilm-prone infections, thecommittee reached consensus.



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Prosthetic valve endocarditis, similar to PJI,involves infection of a prosthetic surface proneto biofilm infections. The latest guidelines fromThe European Society of Cardiology (ESC) hasendorsed rifampicin combination therapy totreat endocarditis associated with prostheticvalves, but not native valve endocarditis (Habibet al. 2015).

RIFAXIMIN TREATMENT OF GIDISORDERS; GENERAL PROPERTIESOF RIFAXIMIN

Rifaximin is an oral drug confined to the GItract. Its oral bioavailability is ,0.4% (Darkohet al. 2010). Stool samples contained 8000 mg/ml of rifaximin after 3 d of treatment at800 mg/d (Jiang et al. 2000). It has been shownthat bile salts increase rifaximin solubility, sug-gesting that there may be a gradient of rifaximinactivity that diminishes as the drug proceedsthrough the GI tract as bile salts diminish inconcentration (Darkoh et al. 2010).

The activity spectrum of rifaximin in stan-dard MIC testing is similar to that of rifampi-cin: very potent activity against Gram-positivestaphylococci and streptococci, C. difficile, andNeisseria, and modest activity against H. influ-enza (Table 1). Rifaximin has high MICs againstmost Gram-negative bacteria, such as Entero-bacteriaceae, and these strains would normallybe considered resistant, for example, MICs inthe range of 16 mg/ml, 32 mg/ml, or higher(Rivkin and Gim 2011). However, rifaximin isa broad-spectrum agent in the GI tract, becauseits very high nominal concentration greatly ex-ceeds the MICs of Gram-negative bacteria.

Rifaximin has few downside effects, given itsGI localization. In clinical trials, it has been dif-ficult to distinguish adverse events observed inthe rifaximin test group and the placebo groupeven after 6 mo of dosing, and rifaximin is de-void of drug–drug interactions characteristicof rifampicin (Rivkin and Gim 2011). The useof rifaxamin has been explored in several GIindications, with growing formal FDA approv-als: traveler’s diarrhea (TD) in 2004, reductionin recurrence of hepatic encephalopathy (HE)in 2010, and irritable bowel syndrome (IBS) inMay 2015.

RIFAXIMIN AS AN EFFECTOR OF THEPREGNANE RECEPTOR IN THE GI TRACT

Rifaximin, like rifampicin, is classified as astrong inducer of the CYP3A4 enzyme in hepa-tocyte cell culture testing. This induction is me-diated by the binding of either rifamycin to thepregnane X receptor, a master regulator of genesinvolved in xenobiotic detoxification, bile bio-synthesis, and other functions (Hirota 2015).However, because rifaximin is confined to theGI tract in vivo, there is no significant inductionof CYP3A4 in the liver in humans, and conse-quently, rifaximin causes no drug–drug inter-actions characteristic of rifampicin (Rivkin andGim 2011). However, when rifaximin binds tothe pregnane receptor in the GI tract, it inhibitsNF-kB, a transcription factor, preventing itfrom activating proinflammatory genes of itspathway (Hirota 2015).

An elegant set of preclinical studies usingthe mouse model of inflammatory bowel dis-ease (IBD) suggests the importance of rifaximinas an effector of the pregnane receptor. Micethat were subjected to chemical insult were pro-tected from the worst signs of colon damageby rifaximin administration. However, this pro-tection only occurred in the isogenic strain ofmouse humanized for the pregnane receptorgene; the rodent pregnane receptor fails to re-spond to rifamycins (Ma et al. 2007; Cheng et al.2010). The most likely explanation for the dif-ferent response of the isogenic mouse contain-ing the humanized pregnane receptor is thatrifaximin, acting as agonist of the pregnane re-ceptor, was responsible for the protection fromcolon damage.

Additional support for the involvement ofthe pregnane receptor in IBD comes from hu-man studies. The expression of pregnane recep-tor target genes was significantly reduced in pa-tients having IBD (Langmann et al. 2004).

RIFAXIMIN AND THE TREATMENT OF IBD

IBD is actually composed of two multifactorialdiseases having some common symptoms andgenetic predispositions (Cho and Brant 2011).Ulcerative colitis (UC) causes inflammation

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and ulcers specifically in the lining of the colon,and Crohn’s disease (CD) can afflict the colonor other regions of the GI tract, and all of itslayers. Antibacterial treatments are a consider-ation because aspects of the inflammatory re-sponse may be directed by interactions withthe microbiome. The pregnane receptor genehas specific polymorphisms that raise the riskof contracting UC, CD, or both (Dring et al.2006). This specificity of genetic predispositionsuggests that interaction of rifaximin with thepregnane receptor could have a non-antibacte-rial benefit (described in the previous section),in addition to its antibacterial activity in treat-ing both diseases.

Eighty-three patients were enrolled in adouble-blind randomized trial to determinewhether rifaximin ameliorated CD symptoms.Progress was monitored with the CD activityindex (CDAI) self-assessment. The group thatreceived rifaximin for 12 wk experienced a 52%remission rate, whereas placebo remission ratewas 33%. The difference was not statisticallysignificant, although the subset of patientswho entered the study with a high C-reactiveprotein (CRP) score (a biomarker for inflam-mation) did show a significant difference (Pran-tera et al. 2006).

In a second double-blind randomized trialof 402 patients, treated either with rifaximin asdescribed above or placebo, a 62% remissionwas observed in the rifaximin group comparedwith 43% in the placebo group (Prantera et al.2012). After an additional 12 wk, the remissionrate in the rifaximin group was 45%, whereasthe remission rate in the placebo group was29%. The rifaximin treatment showed somelasting benefit compared with placebo. Howev-er, the diminished rate of the test group raisesthe possibility that additional rifaximin treat-ments might be necessary to sustain benefit.Rifaximin was generally well tolerated in boththese studies, with no serious adverse events.Again, the subgroup that had the high CRP levelat the initiation of the study (indicating a stron-ger baseline inflammatory response) experi-enced a more significant benefit, suggestingthat the anti-inflammatory properties of rifax-imin could be beneficial to this subgroup.

Several small clinical studies of UC patientsrefractory to steroid use were tested with rifax-imin as an adjunct therapy. All patients weretreated with mesalazine, a nonsteroidal anti-in-flammatory agent that localizes in the colon.The addition of rifaximin resulted in reductionin stool frequency, diminished rectal bleeding,and in sigmoidoscopic score compared with theplacebo group, objective criteria that were en-couraging of future testing (Guslandi 2011).

Rifaximin treatment resulted in significantrelief of IBD symptoms, however transient thesechanges might be. Rifaximin treatment was welltolerated with few serious side effects. Positiveeffects could be a consequence of rifaximin’santibacterial activity, and its anti-inflammatoryactivity as effector of the pregnane receptor, par-ticularly among patients who may be prone toinflammation (i.e., patients having high CRPlevels).

RIFAXIMIN AS A TREATMENT IN IRRITABLEBOWEL SYNDROME (IBS)

IBS is characterized by irregular bowel patterns,recurrent abdominal pain, bloating, and flatu-lence, but is devoid of the physical signs of in-flammation and ulcers that are characteristic ofIBD. Although IBS is not as serious or lifethreatening as IBD is, IBS afflicts up to 15% ofthe U.S. population and is a major source ofmorbidity (Iorio et al. 2015). Lactulose gas testsindicated that subjects having IBS were moreprone to bacterial overgrowth in the small in-testine (SIBO) (Saadi and McCallum 2013).Antibacterials are among a variety of medicinesprescribed for IBS because of the possibility ofcorrecting this imbalance in IBS patients (Kas-sinen et al. 2007).

Pivotal double-blind clinical trials led to ap-proval of rifaximin for treating IBS(D) (diar-rhea type), which was announced by the FDAin May 2015. A total of 1260 IBS subjects wereenrolled in these two parallel randomized dou-ble-blind phase 3 studies. Four weeks aftertreatment in the first study, 40.8% of subjectsadministered rifaximin for 2 wk reported ade-quate relief from IBS symptoms (the primaryendpoint) compared with 32.2% for the place-



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bo group. In the second study, 40.7% of thetest group reported relief from IBS symptomscompared with 31.7% in the placebo control.Similar observations were reported for specificsymptoms such as bloating. All of these resultshad statistically significant differences amonggroups. Ten weeks after treatment, the testgroups continued to report a higher level ofrelief than the placebo groups, although thepercentage reporting adequate relief from allgroups had diminished (Pimentel et al. 2011a).

An important issue for the often-chroniccondition of IBS is the potential for retreatment.In fact, a retrospective study of patients who hadreceived multiple treatments suggested that re-treatment with rifaximin provided comparablebenefit to some subjects (Pimentel et al. 2011b).It is difficult to rule out possible biases of self-selection in patients who decide to seek retreat-ment. For example, patients who particularlybenefited from the first treatment might pref-erentially have enrolled in the trial, or alterna-tively, patients who responded best might nothave relapsed, and then they would not haveenrolled in the second trial. In any case, rifax-imin seems to have provided at least temporarybenefit to IBS subjects, with potential benefitsof retreatment.

RIFAXIMIN TREATMENT OF HEPATICENCEPHALOPATHY (HE)

HE affects up to 80% of patients with cirrhoticliver disease, primarily caused by hepatitis Cinfection, excessive alcohol uptake, and fatty liv-er disease. Thirty to 45% of patients experienceovert HE, which often requires hospitali-zation and is manifested by mental and per-sonality changes, impaired cognition, and de-creased hand–eye coordination (Scott 2014).Toxic levels of ammonia are thought to be thedirect cause of HE. Although there is not a strictcorrelation of plasma ammonia levels and cog-nitive symptoms, successful therapies of non-absorbable disaccharides and/or nonabsorb-able antibiotics, correlated with reduction ofammonia in plasma (Sussman 2015). Lactulose,the approved disaccharide in the United States,passes into the colon where it may shift bac-

terial metabolism away from ammonia produc-tion. Lactulose fermentation in the colon mayalso create a more acid environment, result-ing in ammonia conversion to less permeableNH4

þ ions.Rifaximin was approved in 2010 to prevent

recurrence of overt HE. For the pivotal phase 3trial, 299 patients who had experienced at leasttwo episodes of overt HE in the previous 6 mowere enrolled in the trial, and either treatedwith rifaximin for up to 6 mo, or were assignedto the placebo-controlled arm. Lactulose treat-ment was not a criterion for enrollment but wascontinued for 91% of the patients taking thismedication, in both arms of the trial. Duringthese 6 mo of treatment, 22.1% of the rifaximingroup had a breakthrough HE event comparedwith 45.9% of the placebo group, a statisticallysignificant difference (Bass et al. 2010). The ex-pectation from this trial is that rifaximin willprevent one patient from experiencing an HEbreakthrough for every four patients treated fora 6-mo period.

The data on safety of the rifaximin and pla-cebo arms were comparable (Bass et al. 2010).Small safety differences would be difficult todiscern, because lactulose would be expectedto contribute more than rifaximin to adverseevents. Two cases, however, were terminatedfrom the study because of C. difficile infections,only in the treatment arm. Although the 1% rateof C. difficile infection was not unusual for thispopulation group, the result is one that shouldengender special attention in future investi-gations because C. difficile–associated colitis islife threatening.

The same investigators then performed anopen-label clinical trial, in which all 392 pa-tients were treated with rifaximin for 2 yr. En-rollment criteria required that all subjects hadexperienced an episode of HE within the previ-ous year. The baseline characteristics of the sub-jects were similar to the previous trial, and theprotocol was identical to the previous trial ex-cept for the longer treatment time. The subjectsof this longer trial had a recurrence rate that wascomparable to that of the rifaximin arm of theprevious study. The rate of recurrence was con-siderably lower than the placebo arm of the pre-

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vious study, suggesting that rifaximin treatmentshowed benefit for this prolonged treatmenttime (Mullen et al. 2014).

However, once again, 1% of the subjects (sixpatients) of this trial contracted C. difficile.As in the last trial, this 1% figure was approxi-mately the rate anticipated for patients in acomparable condition (Scott 2014). Again, theappearance of C. difficile infections followingrifaximin treatment is something to monitorclosely in the future to determine whether thereis any contribution of rifaximin in promotingC. difficile–associated colitis.

In comparing antibiotic treatment optionsfor HE patients, rifaximin may be the mostbeneficial (Patidar and Bajaj 2013). Other anti-biotics of low bioavailability, such as neo-mycin, have higher systemic absorption andmore serious safety issues. A reasonable medi-cal approach may be to treat initially with lac-tulose, and then to treat patients having a break-through occurrence of HE with rifaximin.However, it has been shown that generic rifax-imin, which contains the amorphous molecule,is absorbed systemically up to 5 times the levelwhen compared with the brand molecule in therifaximin-a crystal form (Blandizzi et al. 2014),indicating that branded rifaximin is the betterchoice.

TRAVELER’S DIARRHEA (TD)

TD is caused by eating or drinking contaminat-ed food or water, usually while visiting a devel-oping country (see wwwnc.cdc.gov/travel/page/travelers-diarrhea). The most commonagents causing TD are Enterobacteriaceae,such as E. coli (ETEC), which secrete toxins.Although usually a self-limiting disease, espe-cially for the majority of noninvasive Entero-bacteriaceae, occasionally TD initiates post-infectious IBS. TD was the first approval bythe FDA for rifaximin in 2004 to treat uncom-plicated cases of TD—no fever or blood instools—with a 3-d treatment of rifaximin.The studies that led to approval consisted ofthree randomized and double-blind trials thatenrolled subjects visiting Mexico, Guatemala,Jamaica, and Kenya. These trials showed a sig-

nificant reduction in duration of diarrhea com-pared with placebo, or an equivalent responsecompared with ciprofloxacin (Adachi and Du-Pont 2006). A subsequent clinical trial againshowed significant benefit of rifaximin to treatpatients for 3 d, showing approximate equiva-lence in time to resolution compared with cip-rofloxacin. However, the ciprofloxacin groupwas significantly superior in having fewer treat-ment failures, and having a higher rate of mi-crobiological eradication of pathogens (92.5%for ciprofloxacin, 76.7% for rifaximin), andhaving a more favorable response to invasivepathogens (e.g., Shigella) (Taylor et al. 2006).

More recently a meta-analysis summarizedthe results of four double-blind trials, conduct-ed to test for prevention of TD. Subjects weredosed with rifaximin prophylactically during atrip. Subjects of the rifaximin test group had alower rate of contracting TD than did the pla-cebo group. The results taken together showedthat for every four subjects who took rifaximin,one case of TD was prevented (Hu et al. 2012).

In summary rifaximin showed clear benefitin both treating and preventing TD, and equiv-alence or near equivalence to ciprofloxacin inefficacy. An important consideration is thesafety and tolerability of treatment, and hererifaximin has the advantage of confinement tothe GI tract, devoid of systemic safety concernsand drug–drug interactions, and being awell-tolerated drug. Despite these apparentlyfavorable factors, the CDC states that “fluoro-quinolones are the drugs of choice” if TD pa-tients seek chemotherapy, and makes no men-tion of rifaximin despite its approval for thisindication (see wwwnc.cdc.gov/travel/page/travelers-diarrhea).

RIFAXIMIN IS PRONE TO RESISTANCEDEVELOPMENT, DESPITE THE PREVAILINGSENTIMENT TO THE CONTRARY

Resistance to rifaximin is mediated in threeways. In the most frequently encountered mech-anism, mutations arise during DNA replication,unavoidable mistakes that encode RNA poly-merase that binds rifamycins less tightly. Themutations mediating strong resistance to one



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http://wwwnc.cdc.gov/travel/page/travelers-diarrhea





rifamycin are cross-resistant to all approved ri-famycins (Tupin et al. 2010; Goldstein 2014).Hence, whenever the bioburden exceeds 108

bacteria, a mutant strongly resistant to all ap-proved rifamycins has been created by an errorin DNA replication. (For more details, see theabove section on rifamycin resistance.) The oth-er two mechanisms are efflux pumps, whichexpel rifamycins from Gram-negative bacteria,and modifying enzymes, which are rarely en-countered.

It has been suggested that rifaximin is lessprone to resistance development comparedwith other rifamycins (for one of many exam-ples, see Rivkin and Gim 2011). It is conceivablethat the extremely high concentrations of rifax-imin in the GI tract, nominally at least 8000 mg/ml (Jiang et al. 2000), might exceed the MIC ofevery rifamycin-resistant mutant, neutralizingor nullifying their selective advantage. However,the isolation of clinical strains of E. coli fromIBD patients treated with rifaximin for 12 wkrevealed strains having rpoB mutations, an ef-flux pump, or both (Kothary et al. 2013). Rifa-mycin-resistant strains of Enterobacteriaceaeisolated from TD patients were found to be me-diated by mutations in rpoB, by efflux, and inone case by rifaximin inactivation (Hopkins

et al. 2014). Finally, starting with four clinicalisolates from TD patients, rifaximin-resistantstrains were selected that contained rpoB muta-tions, and that showed enhanced expression ofefflux activity (Pons et al. 2012)

A dynamic demonstration that rifaximin se-lects for resistance with facility in vivo is shownin Figure 2 (De Leo et al. 1986). Human volun-teers donated fecal samples, and analysis of themicrobiome showed no detectable rifaximin-resistant mutants before dosing, whereas after5 d of rifaximin treatment, EnterobacteriaceaeEnterococcus, Bacteroides, Clostridium, andanaerobic cocci contained from 30% to 90%rifaximin-resistant strains. After dosing, rifaxi-min selection unwound, resulting in a returnof the population to the original rifamycin-sensitive status. A similar elasticity of the micro-biome with regard to rifamycin susceptibilitywas observed when fecal samples were collectedfrom UC patients following three treatment pe-riods of 10 d each, interspersed by 25 d of wash-out (Brigidi et al. 2002). Rifamycin-resistantmutants became more abundant during rifax-imin treatment, and diminished in frequencyduring washout periods.

The conservation of the rifamycin-bindingsite in the b subunit of RNA polymerase from

100

% 50

Enterobacteriaceae

Bacteroides spp.

Anaerobic cocci Enterococci

Clostridium spp.

00 1 2 4

Weeks

8 16

Figure 2. Percentage of bacteria resistant to rifamycins diminishes in the human gastrointestinal tract afterdiscontinuing rifaximin treatment at week 0. (Data based on De Leo et al. 1986.)

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multiple bacterial genera suggests the impor-tance of retaining the binding site, and a mutantthat has lost the conserved site would prob-ably be less competitively fit. Thus, once rifax-imin was washed out of the GI tract, the lessfit rifaximin-resistant bacteria were probablydisplaced by immigrant rifaximin-sensitivebacteria that were ingested. This transition to arifaximin-sensitive microbiome may be an es-sential condition for future successful cycles ofrifaximin treatment.

A second resistance concern, beyond the ef-ficacy of rifaximin, is the possibility that rifax-imin treatment might endanger patients by se-lecting for rifamycin resistance outside of the GItract. It has already been documented that rifax-imin treatment can select rifamycin-resistantstrains of S. aureus on the skin (Valentin et al.2011, 2014), perhaps not so remote a danger fora patient with a prosthetic joint who was at riskfor infection. The selection of resistance proba-bly occurred because of the interface of rifaxi-min and S. aureus in the perianal area duringelimination of the drug. The fact that in rela-tively healthy patients, the systemic exposureto rifaximin is very low mitigates the risk ofselection of rifamycin resistance outside of theGI tract. However, it is important to considerthat in less healthy patients, for example, cir-rhotic patients, bioavailability of rifaximin canincrease 10- or 20-fold (Rivkin and Gim 2011).Thus, a physician may have difficult decisionswith regard to therapeutic options and risk ofresistance selection outside of the GI tract, dur-ing 6 mo of rifaximin treatment with lesshealthy patients. Finally, the physician wouldhopefully be aware that branded rifaximin a isthe crystal form that maximally confines rifax-imin to the GI tract; it has the lowest systemicabsorption, whereas generic rifaximin in theamorphous form may have five times the sys-temic exposure (Blandizzi et al. 2014).

RIFAXIMIN AND C. Difficile—A BATTLEBETWEEN CURE AND RESISTANCESELECTION

It has been suggested that rifaximin could haveutility in treating C. difficile infections (Rivkin

and Gim 2011), as has been reported anecdot-ally. However, treating an invasive pathogen, C.difficile, with rifaximin monotherapy can leadto the failure of therapy because of the selectionof a highly rifamycin-resistant C. difficile strain(Johnson et al. 2009). Therefore, rifaximin doesnot appear to be a suitable first-line monother-apeutic agent for treating C. difficile infections,in which the invading bacterium has to be erad-icated. The mission is to kill the invader, notto rebalance the genome, as is the goal of rifax-imin treatment for HE, IBD, or IBS. Perhaps amore appealing protocol is serial combinationtherapy, in which oral vancomycin would beadministered for a few days, and then, whenthe bioburden has diminished, follow up withrifaximin to eradicate the offending organismwith little chance of rifaximin-resistance devel-opment (Johnson et al. 2009). This protocolcould be used in stubborn cases, in which van-comycin therapy in the past has failed.

Rifaximin-resistant C. difficile has been ob-served occasionally (O’Connor et al. 2008;Johnson et al. 2009; Carman et al. 2012). Itwould be wise to test the pathogen before initi-ating therapy, because of the instances of in-creases in rifamycin-resistant C. difficile patho-gens, which have been reported to be .30%, anastonishing increase in resistance reported inspecific medical centers (Curry et al. 2009;Huang et al. 2013). It is likely that rifaximinwould not be successful in curing patients af-flicted with a highly rifamycin-resistant strain,despite the high nominal concentration of8000 mg/ml reported in fecal samples followingrifaximin therapy (Jiang et al. 2000). Perhapsthe best strategy is to use other options forC. difficile therapy if possible.

SUMMARY

Rifampicin continues to be very effective incombination therapies with careful selectionof partner antibiotics, particularly as a mainstaytherapeutic for treating active and latent TB,as well as selective, serious Gram-positive infec-tions. Rifampicin is well established as the mostessential agent to treat biofilms in PJI infections,and it is possible that its role could expand to



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other serious Gram-positive infections, provid-ed that optimal combinations can be estab-lished and agreed to. One obstacle to clinicalresearch is the lack of entrepreneurial incentivefor an older drug off patent. We all benefit, how-ever, if an infusion of money to finance clinicalresearch is increased in the future, so that theproper evidence can lead the way to improvedtherapies for stubborn Gram-positive infec-tions. Rifabutin is especially useful in treatingTB in AIDS patients, and in preventing MACinfections. Rifabutin also has a role in H. pylorieradication as part of second-line combinationtherapy. Rifapentine, with its increased half-life,has potential to shorten active and latent TBtherapy. Rifaximin, an oral drug confined tothe GI tract, is used to treat GI disorders thatinvolve dysfunction of the GI microbiome. Itsefficacy for at least some indications probablyhas an additional (non-antibacterial) compo-nent as a regulatory effector of the pregnane Xreceptor. The continued exploration of rifaxi-min’s uses is fostered in part by its excellentsafety profile, as a drug confined to the GI tract,with both potent and broad-spectrum antibac-terial activity and a soothing effect of toningdown the anti-inflammatory response.

ACKNOWLEDGMENTS

I thank Andrej Trampuz (Charite–UniversityMedicine Berlin) for his attention and advicefor the section on Gram-positive systemic infec-tions, Michael Cynamon (Syracuse Veterans Af-fairs Medical Center) for lending his expertiseon mycobacterial infections, Simon Hirota(University of Calgary) for his interesting in-sights on rifamycins as effectors of the pregnanereceptor, and A.L. Sonenshein (Tufts UniversitySchool of Medicine) for his critical reading ofthe manuscript.

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June 7, 20162016; doi: 10.1101/cshperspect.a027011 originally published onlineCold Spring Harb Perspect Med

David M. Rothstein Rifamycins, Alone and in Combination

Subject Collection Antibiotics and Antibiotic Resistance

Fosfomycin: Mechanism and ResistanceLynn L. Silver Resistance

The Whys and Wherefores of Antibiotic

Cameron R. Strachan and Julian Davies

Mode of Action and Resistance−−Pleuromutilins: Potent Drugs for Resistant Bugs

Susanne Paukner and Rosemarie Riedl

-Lactamases: A Focus on Current ChallengesβRobert A. Bonomo

Appropriate Targets for Antibacterial DrugsLynn L. Silver Mechanism of Action and Resistance

Approved Glycopeptide Antibacterial Drugs:

et al.Daina Zeng, Dmitri Debabov, Theresa L. Hartsell,

of ResistancePleuromutilins: Mode of Action and Mechanisms Lincosamides, Streptogramins, Phenicols, and

et al.Stefan Schwarz, Jianzhong Shen, Kristina Kadlec,

Enterococci andStaphylococcus aureusDaptomycin in

Mechanism of Action and Resistance to

AriasWilliam R. Miller, Arnold S. Bayer and Cesar A.

Health PathogensResistance to Macrolide Antibiotics in Public

al.Corey Fyfe, Trudy H. Grossman, Kathy Kerstein, et

ResistancePolymyxin: Alternative Mechanisms of Action and

al.Michael J. Trimble, Patrik Mlynárcik, Milan Kolár, et

Antibiotic InhibitionBacterial Protein Synthesis as a Target for

Stefan Arenz and Daniel N. WilsonMechanisms of Action and ResistanceTopoisomerase Inhibitors: Fluoroquinolone

David C. Hooper and George A. Jacoby

through Resistance to the Next GenerationAntibacterial Antifolates: From Development

AndersonAlexavier Estrada, Dennis L. Wright and Amy C.

Overview-Lactamase Inhibitors: Anβ-Lactams and β

Karen Bush and Patricia A. Bradford

Lipopolysaccharide Biosynthetic Enzyme LpxCAntibacterial Drug Discovery Targeting the

Alice L. Erwin

Rifamycins, Alone and in CombinationDavid M. Rothstein

http://perspectivesinmedicine.cshlp.org/cgi/collection/ For additional articles in this collection, see

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rifamycins, alone and in combination - cold spring harbor

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