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The Evolution of Antimicrobial Agents Used for the Management of CARTIs: A Focus on a New Class of Antimicrobials"the Ketolides
Author(s):
Streptococcus pneumoniae
Numerous issues exist surrounding themanagement of community-acquiredrespiratory tract infections (CARTIs).Most CARTIs are initially treated empirically,preferably based on guidelines developedby professional organizations,1,2 but realisticallythe selection is often determined bythe physician's habitual practice pattern–apractice pattern based on successful pasttreatment experiences.3 Unfortunately, theuse of inadequate empiric therapies forCARTIs will inevitably result in a progressiveincrease in antibiotic resistance amongCARTI pathogens. An increase in multidrugresistant (MDRSP) has already been documented.4
Other factors of concern include the failureof some antibiotic classes to cover themost common pathogens for CARTIs, bacteriostaticactivity rather than bactericidaleffect against CARTI pathogens, the effect ofprolonged exposure to subinhibitory levelsof an antibiotic, and the potential for collateraldamage caused by a spectrum of antibioticactivity that also targets non—respiratorytract organisms.
The approval of the first member of a newclass of antibiotics in the United States, theketolides, will provide healthcare practitionersa new choice for the treatment ofCARTIs. Members of the ketolide class possessnumerous attributes that comparefavorably with existing empiric therapies.These attributes include bactericidal activityagainst the most prevalent CARTI pathogens;excellent tissue penetration; effectivenessagainst infections caused by multidrugresistantorganisms; a tailored spectrum ofactivity; and, for some patients, a shortercourse of therapy than most of the currentantibiotic regimens. There are severalketolides in various stages of clinical development,including telithromycin, RWJ-415663,CP-654743, and TE-802. The availability ofa new class of antibiotics will prompt thepharmacy and therapeutic committees ofhealth plans to consider including a ketolideon the formulary.
The goal of this article is to provide managedcare and other formulary decision makerswith an overview of the chemicalcharacteristics of the ketolide class; to comparethe characteristics of ketolides andother classes of antimicrobials; and to providea review of the safety and efficacyresearch currently conducted for ketolidesnow available in the United States. Basic toformulary decisions is an understanding ofthe defining characteristics of a new drugclass and the differentiating attributes of theagents within that class.
The Ketolides
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Chemical Structure. Derived from erythromycinA, ketolides retain the 14-member macrolactone ring and theD-desosamine sugar at position 5. However,ketolides have a number of structural differencesthat improve on both the activity andthe pharmacokinetics of the macrolides. Theonly structural modification necessary toclassify a compound as a ketolide is thereplacement of the L-cladinose moiety witha 3-ketone. The earliest macrolides quicklydegrade within an acidic environment,resulting in erratic absorption and gastricirritation.5 The removal of the L-cladinosemoiety maintains the improved acid stabilityof second-generation macrolides byavoiding ketalization. Replacement with the3-ketone enables ketolides to overcome themost common forms of bacterial resistance,macrolide-efflux ()-encoded efflux andinducible MLSB resistance.6,7
Other molecular characteristics alsoimprove ketolide activity. Telithromycinpossesses a carbamate extension with analkyl-aryl group at positions 11/12; thisextension enhances ribosomal binding affinity,allowing telithromycin to remain potentagainst erythromycin-resistant strains.6 Telithromycin,HMR-3004, and HMR-3787 alsohave a 6-methoxy group, which furtherimproves acid and molecular stability bypreventing ketalization.8
Mechanism of Action. Like macrolides,ketolides exert their antimicrobial activityby preventing the translation of bacterialmessenger ribonucleic acid (RNA), whichinhibits ribosome assembly and protein synthesis.9 In susceptible bacteria, ketolidesand macrolides bind to sites on the 23S ribosomalRNA (rRNA) of the larger 50S ribosomalsubunit. Ketolides and macrolides bothbind primarily to the domain V contact sitein 23S rRNA.10 Both macrolides andketolides also interact with the bindingdomain II on 23S rRNA, but do so quite differently.6,10,11 Ketolides that possess a carbamateextension at positions 11/12 allows forstrong binding to domain II, whereas themacrolides form a weak bond to domainII.7,10 Further, although the binding ofketolides to domain II blocks a specificnucleotide (A752) on that domain from ribosomalassembly,10,12 macrolide binding todomain II renders the base of A752 moreaccessible to chemical modification, likelybecause of allosteric effects.6 Overall,telithromycin has been demonstrated tobind to bacterial ribosomes with 6 to 10times the binding affinity of macrolides.6,10The interaction of the carbamate extensionwith domain II is believed to cause theenhanced binding affinity.6
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Two of the main mechanisms of resistanceto macrolides are target-site alterationand active drug efflux.13 Target-site alterationis encoded by erythromycin resistancemethylase () genes, and is calledMLSB resistance.6,14 This -mediatedresistance alters the ribosomal structure ondomain V6 and reduces binding affinity forthe antibiotic.14 The binding of telithromycinat domain II allows telithromycinto maintain antibiotic activity againstbacteria that have base mutations atdomain V.11,15-17 In resistance caused byactive drug efflux, the gene codes formembrane-bound proteins to pump 14- and15-membered macrolides out of bacterialcells.18 This type of resistance is not seenwith ketolides, 16-membered macrolides,lincosamides, or streptogramins.5
Telithromycin: The First KetolideApproved for Use in the United States
Although there are numerous compoundsin the ketolide class in the preclinical orclinical trial phase of development, telithromycinis the only ketolide approved foruse in the United States. Telithromycin isindicated for the treatment of acute exacerbationsof chronic bronchitis (AECB), acutebacterial sinusitis (AS), and community-acquiredpneumonia (CAP) of mild-to-moderateseverity caused by susceptible strainsof designated microorganisms in patients≥18 years of age.19
In Vitro Activity
S pneumoniae
S pneumoniae
S pneumoniae
S pneumoniae
erm
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Gram-positive Pathogens. Telithromycinhas demonstrated effective in vitro activityagainst gram-positive pathogens responsiblefor respiratory tract infections (RTIs).20Telithromycin has good activity against, regardless of penicillin ormacrolide susceptibility. The minimuminhibitory concentration (MIC) break pointsindicating susceptibility, intermediate susceptibility,and resistance to telithromycinare <1, 2, and ≥4 mcg/mL for .19Against penicillin-susceptible strains,telithromycin has an in vitro MIC90 of 0.015mcg/mL.21 Telithromycin MIC90 values werelow against strains of that werepenicillin resistant (0.25-1.0 mcg/mL) and/orerythromycin resistant (0.06-1.0 mcg/mL).22-27Even against isolateswith B resistance or the gene,the telithromycin MIC90 remained low(each 0.06 mcg/mL).28
Spneumoniae
S pneumoniae
During the first year (2000-2001) of theProspective Resistant Organism Trackingand Epidemiology for the Ketolide Telithromycin (PROTEKT) study, over 10 000 isolates were collected in theUnited States. Of these, 99.7% were susceptibleto telithromycin.4 During the secondyear of the study (2001-2002), nearly 40%of the isolates exhibitedresistance to one or more of the antibacterialstested. Of these resistant isolates, 75%were MDRSP. Telithromycin was highlyeffective against MDRSP, with 99.5% ofthe isolates susceptible to telithromycin at≤1 mcg/mL.29
Staphylococcusaureus
Telithromycin also demonstrates activityagainst methicillin-susceptible (MIC90: ≤0.25 mcg/mL).30-32
Haemophilus influenzae
H influenzae
H influenzae
Gram-negative Pathogens. Telithromycinhas demonstrated good in vitro activityagainst gram-negative pathogensresponsible for RTIs. The MIC breakpoints indicating susceptibility, intermediatesusceptibility, and resistance totelithromycin are ≤4, 8, and ≥16 mcg/mLfor .19 In the firstyear of the PROTEKT study, more than2700 isolates of were collected;an MIC90 of 4 mcg/mL was obtained fortelithromycin, demonstrating susceptibility.4 susceptibility to telithromycinis unaffected by beta-lactamaseproduction or ampicillin resistance.4,30,33-35
Moraxella catarrhalis
M catarrhalis
Against ,telithromycin MIC90 values range from 0.03to 0.125 mcg/mL.26,31-33,35,36 susceptibility was unaffected by beta-lactamaseproduction.34,35
Mycoplasmapneumoniae
C pneumoniae
M pneumoniae
C pneumoniae
Atypical and Intracellular Organisms.Of importance (especially when treatment isinitiated in the absence of culture data),telithromycin is potent against and . Low MIC90ranges of telithromycin have been reportedfor (≤0.015 mcg/mL) and (≤0.025 mcg/mL).37-41
Pharmacokinetics
Absorption and Distribution. Theabsolute bioavailability of a single 800-mgdose of telithromycin is 57%; this wasobserved in both young (18-40 years) andolder (65-85 years) subjects.42 Plasma concentrationsand pharmacokinetic parametersof telithromycin were not altered by ahigh-fat breakfast; therefore, telithromycinmay be administered without regard tomeals.43 Steady-state concentrations oftelithromycin are reached after 2 to 3 daysof repeated administration; at steady state,an 800-mg dose of telithromycin produces amean peak plasma concentration (Cmax) of2.27 mg/L within 1 hour and an area underthe 24-hour plasma concentration curve(AUC24) of 12.5 mcg*h/mL.19,44
Telithromycin 800 mg once dailyachieves high drug concentrations inbronchial tissue, epithelial lining fluid, andalveolar macrophages.36,45-47 Telithromycinconcentrations at these sites remainedabove the telithromycin MICs for most of themajor respiratory pathogens throughout the24-hour administration period.36,46 A numberof in vitro studies have demonstrated thepreferential uptake of telithromycin by polymorphonuclearneutrophils.48,49 High telithromycinconcentrations were also seen inwhite blood cells,50 which may contribute tothe delivery of telithromycin to sites ofinfection.
Metabolism and Elimination. CytochromeP450 3A4 and noncytochrome P450isoenzymes metabolize approximately 70%of a telithromycin dose.19 There are 4 majormetabolites, one of which (RU 76363, an Noxidepyridine derivative) has demonstratedantibacterial activity, but at 6% to 25% ofthat of telithromycin.51
Telithromycin is eliminated by variouspathways, with 7% excreted unchanged inthe feces, 13% excreted unchanged in urine,and 37% metabolized in the liver.19 Telithromycinhas an overall terminal half-life of9.8 hours.44
Dosing in Special Populations. Therewere only minor differences in the pharmacokineticsof telithromycin in elderlypatients and in patients with moderate-to-severehepatic impairment; no dose adjustmentis required in these patient groups. Inpatients with severe renal failure (CLCR <30mL/min) who received once-daily telithromycinfor 5 days, mean steady-state Cmaxand AUC24 were 1.5 and 2.0 times higher,respectively, than normal volunteers.52 However, the dosage of telithromycin in patientswith severe renal impairment has not beenestablished.19
Pharmacodynamics
S pneumoniae
Spneumoniae
H influenzae,
In the previous article, Dr Nicolau reportsthat bactericidal antibiotics have a lowerpropensity to induce resistance comparedwith bacteriostatic agents, as bactericidalantibiotics quickly eradicate susceptiblepathogens. In vitro studies have been performedto determine the pharmacodynamicsof telithromycin. The rate and extent ofkilling in were examined at aconcentration corresponding to the unbound2-hour level in serum following administrationof a dose of 800 mg (0.6 mg/L) oftelithromycin.53 Telithromycin demonstratedexcellent bactericidal activity against , exhibiting an extremely fastkill rate (3 log10 CFU [colony formingunits]/mL after 1 hour) in all strains tested,regardless of whether the strain was penicillinsusceptible or not. Telithromycinexhibits a slower kill rate against but is bactericidal at 24 hours at a concentrationof 4 times the MIC.54 In addition,telithromycin has been determined toexhibit concentration-dependent killing.55
Drug Interactions
The absorption of telithromycin is unaffectedby agents that alter the gastric pH ofthe stomach; coadministration of ranitidineor magnesium/aluminum hydroxidesdid not affect the pharmacokinetics oftelithromycin.19,56
Because telithromycin is a competitiveinhibitor of cytochrome P450 CYP 3A4,coadministration of telithromycin with adrug that is a CYP 3A4 inhibitor or substratemay increase the plasma concentrations ofthe coadministered drug. Coadministrationof ketoconazole and itraconazole withtelithromycin resulted in a 1.98-fold and1.53-fold increase in AUC24 for telithromycin,respectively. Because there were nosignificant changes to the QTc interval frombaseline for either product, telithromycindose adjustment is not necessary.19,57Coadministration of telithromycin and cisaprideresulted in a 95% increase in the cisapridesteady-state Cmax; coadministration ofcisapride with telithromycin is contraindicated,as cisapride is known to increase thepotential for QT interval irregularities andventricular arrhythmias.19 Coadministrationof telithromycin with pimozide is also contraindicateddue to the risk of increasedplasma concentrations of pimozide.19
An 8.9-fold increase in AUC and a 5.3-foldincrease in Cmax of simvastatin were seenwhen coadministered with telithromycin.19Similar interactions are also possible withother hydroxymethyl glutaryl coenzyme Areductase inhibitors metabolized by CYP3A4; therapy with simvastatin, lovastatin, oratorvastatin (but not pravastatin, fluvastatin,or rosuvastatin) should be suspendedduring telithromycin therapy.19,58Coadministration of telithromycin withintravenous and oral midazolam led to 162%and 511% increases in the AUC of midazolam,respectively.18 For midazolam and theother benzodiazepines metabolized by CYP3A4 (such as triazolam), caution is recommended,and dosage adjustments should bemade as necessary.19
Coadministration of telithromycin anddigoxin led to a 1.4-fold increase in the AUCof digoxin.59 Although there were no significantchanges in electroencephalogram patternsor signs of digoxin toxicity, monitoringof patients for symptoms of digoxin toxicityis recommended.19 Theophylline, paroxetine,warfarin, and oral contraceptives wereall shown to be unaffected to any significantdegree by telithromycin therapy.19,59-61Because coadministration of theophyllinewith telithromycin may increase gastrointestinaladverse events (ie, nausea, vomiting),it is recommended that the drugs beadministered at least 1 hour apart todecrease the likelihood of these events.19
Clinical Efficacy
The phase 3 clinical program for telithromycinincluded 14 trials conducted inthe United States, South America, Europe,Australia, and South Africa.59,62-74 The therapeuticefficacy of telithromycin 800 mgonce daily for AS, AECB, or CAP was evaluated.All comparative studies were doubleblind; the objective of the trials was todemonstrate equivalence with comparatorantibiotic(s). The primary end point in moststudies was clinical outcome in the per-protocolpopulation at the test of cure visit(days 17-24). Clinical cure was defined aseither improvement or a return to thepatient's preinfection status, or improvementwith residual symptoms but no need for subsequentantimicrobial therapy. A satisfactorybacteriological outcome was defined as theeradication or presumed eradication of theoffending pathogen at the test of cure visitamong bacteriologically evaluable per-protocolpatients.
Acute Bacterial Sinusitis. The efficacyof telithromycin for the treatment of AS hasbeen studied in 3 trials with a total of 1333patients. In these trials, telithromycin 800mg once daily for 5 days was compared with10 days of therapy with amoxicillin/clavulanate500 mg/125 mg 3 times daily,62cefuroxime axetil 250 mg twice daily,63 or a10-day course of therapy with telithromycin800 mg once daily.64
Five- and 10-day regimens of telithromycinwere similarly effective for treatmentof AS. Adults with clinical andradiological evidence of acute sinusitis ofless than 1-month duration were randomizedto telithromycin 800 mg once daily for5 days (n = 170) or 10 days (n = 171). Theresults of the trial demonstrated equivalentclinical cure rates in the per-protocol population(91.1% vs 91.0%) for the 5- and 10-daydosing regimens. A satisfactory bacterial outcomewas achieved in 92.9% (65/70) and89.9% (62/69) of patients, respectively.64
Five days of telithromycin was found tobe as effective as a 10-day course of therapywith cefuroxime axetil. Adults and adolescentswith clinical and radiological evidenceof AS of less than 28 days duration were randomizedto telithromycin 800 mg once dailyfor 5 days (n = 260) or cefuroxime axetil 250mg twice daily for 10 days (n = 125). Clinicalcure rates were similar for telithromycin andcefuroxime axetil in the per-protocol population(85.2% vs 82.0%). A satisfactory bacterialoutcome was observed in 84.0% (84/100)of telithromycin patients and 79.6% (39/49)of cefuroxime patients.63
Five days of telithromycin was also foundto be as effective as a 10-day course of therapywith amoxicillin/clavulanic acid. Adultswith clinical and radiological evidence of ASof less than 28 days duration were randomizedto telithromycin 800 mg once daily for5 days (n = 201) or 10 days (n = 204) oramoxicillin/clavulanic acid 500 mg/125 mg3 times daily for 10 days (n = 202).Clinical cure rates were similar for the 5-day and 10-day regimens of telithromycin(75.3% and 72.9%, respectively) and amoxicillin/clavulanic acid (74.5%) in the per-protocolpopulation.62
In summary, 5 days of therapy with telithromycin800 mg once daily was as effectiveas 10 days of therapy with once-dailytelithromycin, twice-daily cefuroxime axetil,or 3-times—daily amoxicillin/clavulanic acidfor the treatment of AS.
Acute Exacerbations of ChronicBronchitis. The efficacy of telithromycin forthe treatment of AECB has been studied in 3trials with a total of 1249 patients. In thesetrials, telithromycin 800 mg once daily for 5days was compared with 10 days of therapyof clarithromycin 500 mg twice daily,65amoxicillin/clavulanate 500 mg/125 mg 3times daily,66 and cefuroxime axetil 500 mgtwice daily.67 In these studies, a clinical diagnosisof AECB was based on Anthonisen criteria(increases in dyspnea, sputumproduction, and sputum purulence).75
Five days of telithromycin was found tobe as effective as a 10-day course of therapywith cefuroxime axetil. Adults with clinicalevidence of AECB were randomized totelithromycin 800 mg once daily for 5 days(n = 182) or cefuroxime axetil 500 mg twicedaily for 10 days (n = 191). Clinical curerates were similar for telithromycin andcefuroxime axetil in the per-protocol population(86.4% vs 83.1%). A satisfactory bacterialoutcome was observed in 76.0% (19/25)of telithromycin patients and 78.6% (22/28)of cefuroxime patients.67
Five days of telithromycin was also foundto be as effective as a 10-day course of therapywith amoxicillin/clavulanate. Adultswith a history of chronic bronchitis orchronic obstructive pulmonary disease withbronchodilator response and clinical evidenceof AECB were randomized totelithromycin 800 mg once daily for 5 days(n = 163) or amoxicillin/clavulanate 500mg/125 mg 3 times daily for 10 days (n =161). Clinical cure rates were similar fortelithromycin and amoxicillin/clavulanate inthe per-protocol population (86.1% vs82.1%), and satisfactory bacterial outcomewas observed in 69.2% (27/39) and 70.0%(21/30) of patients, respectively.66
Further, 5 days of telithromycin wasfound to be as effective as a 10-day course oftherapy with clarithromycin. Adults withclinical evidence of AECB were randomizedto telithromycin 800 mg once daily for 5days (n = 270) or clarithromycin 500 mgtwice daily for 10 days (n = 282). Clinicalcure rates were similar for telithromycin andclarithromycin in the per-protocol population(85.8% vs 89.2%).65
In summary, 5 days of therapy withtelithromycin 800 mg once daily was aseffective as 10 days of therapy with twice-dailyclarithromycin, twice-daily cefuroximeaxetil, or 3-times—daily amoxicillin/clavulanicacid for the treatment of AECB. Concernsof a higher rate of reinfection with a 5-daycourse of therapy for AECB were unsubstantiated.In the head-to-head trial withthe 10-day course of therapy with amoxicillin/clavulanate, the 5-day course of therapywith telithromycin resulted in fewerreinfections (1.3%; 2/160) than amoxicillin/clavulanate (5.7%; 9/160).66
Community-acquired Pneumonia. Theefficacy of telithromycin for the treatment ofCAP has been studied in 8 trials with a totalof 1925 patients.59,68-74 Of these 8 trials, 4were double-blind, randomized trials comparingtelithromycin 800 mg once daily for7 to 10 days with 10 days of therapy withclarithromycin 500 mg twice daily,71,73 10days of amoxicillin 1000 mg 3 timesdaily,70 and 7 to 10 days of trovafloxacin200 mg once daily.72 In these studies, adiagnosis of CAP was based on clinicalsigns, symptoms, and radiological evidenceof bacterial pneumonia.
Ten days of telithromycin was found tobe as effective as a 10-day course of therapywith high-dose amoxicillin. Adults withacute CAP were randomized to 10 days oftherapy with telithromycin 800 mg oncedaily (n = 199) or amoxicillin 1000 mg 3times daily (n = 205). Clinical cure rateswere similar for telithromycin and amoxicillinin the per-protocol population (94.6%vs 90.1%), and satisfactory bacterial outcomewas observed in 90% (36/40) and87.5% (35/40) of patients, respectively.
Seven or 10 days of telithromycin wasalso found to be as effective as a 10-daycourse of therapy with clarithromycin in2 studies.71,73,76 Adults with CAP were randomizedto telithromycin 800 mg oncedaily for 7 days (n = 195)76 or 10 days(n = 204)71 or clarithromycin 500 mg twicedaily for 10 days (n = 187 and n = 212,respectively). Clinical cure rates were similarfor telithromycin and clarithromycin inthe per-protocol population (88.8% and88.3% for 7 and 10 days of telithromycin vs91.8% and 88.5% for 10 days of clarithromycin,respectively) in each trial. Asatisfactory bacterial outcome was achievedin 80.0% and 89.3% of patients receiving 7and 10 days of telithromycin, and 83.3%and 96.4% of clarithromycin patients ineach trial.
Before the removal of trovafloxacin fromthe outpatient market because of safety concerns,a 7- to 10-day course of therapy withtelithromycin was found to be as effective asa 7- to 10-day course of therapy withtrovafloxacin for CAP. Adults with acuteCAP were randomized to 7 to 10 days oftherapy with telithromycin 800 mg oncedaily (n = 100) or trovafloxacin 200 mg oncedaily (n = 104). Clinical cure rates were similarfor telithromycin and trovafloxacin inthe per-protocol population (90.0% vs94.2%). A satisfactory bacterial outcome wasobserved in 92.9% (13/14) of telithromycinpatients and 100.0% (22/22) of trovafloxacinpatients; this difference did not achieve statisticalsignificance.72
In summary, telithromycin 800 mg oncedaily for 7 to 10 days was found to be aseffective as 7 to 10 days of therapy withhigh-dose amoxicillin, clarithromycin, andtrovafloxacin.
Safety Data, Warnings, and Adverse Events
Like macrolides, telithromycin has thepotential to prolong the QTc interval of theelectrocardiogram in some patients. QTc prolongationmay lead to an increased risk forventricular arrhythmias, including torsadesde pointes. Thus, telithromycin should beavoided in patients with congenital prolongationof the QTc interval, and in patients withongoing proarrhythmic conditions, such asuncorrected hypokalemia or hypomagnesemia,clinically significant bradycardia,and in patients receiving Class IA (eg, quinidineand procainamide) or Class III(eg, dofetilide) antiarrhythmic agents.19 Nocardiovascular morbidity or mortality attributableto QTc prolongation occurred withtelithromycin treatment in 4780 patients inclinical efficacy trials, including 204 patientshaving a prolonged QTc at baseline.
Exacerbations of myasthenia gravis havebeen reported in patients with myastheniagravis treated with telithromycin. This hassometimes occurred within a few hoursafter intake of the first dose of telithromycin.Reports have included life-threateningacute respiratory failure with a rapidonset in patients with myasthenia gravistreated for RTIs with telithromycin.Telithromycin is not recommended inpatients with myasthenia gravis unless noother therapeutic alternatives are available.If other therapeutic alternatives arenot available, patients with myastheniagravis taking telithromycin must be closelymonitored.19
The pooled safety and tolerability datafrom all telithromycin phase 3 clinical trialsdemonstrate that telithromycin 800 mgonce daily for up to 10 days is a safe andwell-tolerated agent for RTIs.59 Most adverseevents were transient and were mild to moderatein severity.
In the controlled phase 3 clinical trials,49.9% (1348/2702) of patients receivingtelithromycin experienced one or moretreatment-emergent adverse events, comparedwith 48.4% (1035/2139) of patientsreceiving a comparator.59 The most frequentlyreported adverse events in the clinicaltrials were gastrointestinal in nature; themost common treatment-related adverseevents in patients receiving telithromycin ora comparator were diarrhea (10.8% vs8.6%), nausea (7.9% vs 4.6%), headache(5.5% vs 5.8%), dizziness (3.7% vs 2.7%),and vomiting (2.9% vs 2.2%).59 A similarnumber of patients discontinued therapywith telithromycin (4.4%) or the comparator(4.3%) because of adverse events; gastrointestinaladverse events such as diarrhea,nausea, and vomiting were most likelyto lead to therapy discontinuation.59
Hepatic adverse events were low and balancedbetween treatment groups (3.4% oftelithromycin subjects, 3.2% of comparatorsubjects). Across all studies, elevations ofalanine aminotransferase (ALT) >3 timesthe upper limit of normal occurred in 1.6%of telithromycin patients and 1.7% of comparatorsubjects.59 Also, since macrolidesare known to impact cardiac repolarization,the QTc interval data for telithromycinwas compared with that ofclarithromycin. Telithromycin was comparablewith clarithromycin in respect toQTc interval changes; the frequency ofsubjects with QTc increases ≥60 ms whilereceiving therapy was low and similarbetween treatment groups, as was the frequencyof subjects with QTc outliers.Further, no subject in either treatmentgroup in clarithromycin-controlled studieshad a QTc value ≥500 ms.59
Telithromycin has also been associatedwith transient visual disturbances, includingblurred vision, difficulty focusing, anddiplopia.59 Reported rates of blurred vision inphase 3 clinical trials were 1.1% fortelithromycin and 0.3% for the comparatoragents.19 Overall, telithromycin was welltolerated among various high-risk patientgroups, including severely ill patients, theelderly, and patients with renal and hepaticinsufficiency.
A postmarketing observation study of theeffectiveness and tolerability of telithromycinbegan in Germany in 2001.77 An interimevaluation was performed in July 2002based on data from more than 24 000patients. A low incidence of mild-to-moderateadverse events (2.2%) was reported,led by adverse events affecting the gastrointestinaltract (1.5%), the central nervous system(0.5%), and the skin (0.2%).78 Oculardisorders, such as blurred vision, werereported in 0.2% of patients.
Conclusion
Despite increased awareness about theconsequences of bacterial resistance,79resistance among the most prevalent CARTIpathogens to penicillins and macrolides continuesto increase,4,80-82 threatening the utilityof those antibiotic classes. Ketolides are anew class of antibiotics designed with specificattributes to overcome bacterial resistancemechanisms that now render someempiric therapies ineffective, and, in addition,have the potential to curb the growth ofantimicrobial resistance.
Telithromycin is the first member of theketolide class available in the UnitedStates. It possesses a tailored spectrum ofactivity against the typical and atypicalcausative pathogens for CARTIs, includingMDRSP. Telithromycin exhibits a tailoredspectrum of activity with pharmacokineticand pharmacodynamic attributes (potency,half-life, bactericidal activity, and bindingaffinity at multiple sites) that result in bacterialeradication with a low potential forthe development of resistant organisms. Theefficacy of telithromycin for the treatment ofAS, AECB, and CAP has been demonstratedin numerous phase 3 clinical trials. Thedata confirm that telithromycin is as efficaciousas penicillins, macrolides, cephalosporins,and fluoroquinolones. The safety oftelithromycin has been demonstrated inclinical trials, with adverse events thatwere mild to moderate, transient in nature,and occurring at rates similar to empirictherapies.
When making formulary decisions, it isimportant to consider all of the propertiesand attributes of an agent, especially thosewithin a new class. Critical questions thatshould be asked are: "Do these propertiesand attributes contribute to improvingpatient outcomes?" and "Do the ketolidesoffer economic advantages over empirictherapies in the treatment of CARTIs?" DrDiana Brixner will help to answer these mattersfurther in our next article.
ClinInfect Dis.
1. Mandell LA, Bartlett JG, Dowell SF, et al. Update ofpractice guidelines for the management of community-acquiredpneumonia in immunocompetent adults. 2003;37:1405-1433.
Clin Infect Dis.
2. Bartlett JG, Dowell SF, Mandell LA, et al. Practiceguidelines for the management of community-acquiredpneumonia in adults. Infectious Diseases Society ofAmerica. 2000;31:347-382.
J AntimicrobChemother.
3. Nicolau D. Clinical and economic implications ofantimicrobial resistance for the management of community-acquired respiratory tract infections. 2002;50(suppl S1):61-70.
J Infect.
4. Doern GV, Brown SD. Antimicrobial susceptibilityamong community-acquired respiratory tract pathogensin the USA: data from PROTEKT US 2000-01. 2004;48:56-65.
Drugs.
5. Zhanel GG, Dueck M, Hoban DJ, et al. Review ofmacrolides and ketolides: focus on respiratory tract infections. 2001;61:443-498.
J Antimicrob Chemother.
6. Douthwaite S, Champney WS. Structures of ketolidesand macrolides determine their mode of interaction withthe ribosomal target site. 2001;48(suppl T1):1-8.
Clin Microbiol Infect.
7. Douthwaite S. Structure-activity relationships ofketolides vs macrolides. 2001;7(suppl 3):11-17.
Bioorg Med Chem Lett.
8. Denis A, Bretin F, Fromentin C, et al. Beta-keto-esterchemistry and ketolides. Synthesis and antibacterialactivity of 2-halogeno, 2-methyl and 2,3 enol-etherketolides. 2000;10:2019-2022.
Staphylococcusaureus
CurrMicrobiol.
9. Champney WS, Tober CL. Inhibition of translationand 50S ribosomal subunit formation in cells by 11 different ketolide antibiotics. 1998;37:418-425.
Mol Microbiol.
10. Hansen LH, Mauvais P, Douthwaite S. Themacrolide-ketolide antibiotic binding site is formed bystructures in domains II and V of 23S ribosomal RNA. 1999;31:623-631.
Mol Microbiol.
11. Douthwaite S, Hansen LH, Mauvais P. Macrolideketolideinhibition of MLS-resistant ribosomes isimproved by alternative drug interaction with domain IIof 23S rRNA. 2000;36:183-193.
Mol Microbiol.
12. Xiong L, Shah S, Mauvais P, et al. A ketolide resistancemutation in domain II of 23S rRNA reveals theproximity of hairpin 35 to the peptidyl transferase centre. 1999;31:633-639.
Mayo Clin Proc.
13. Clark JP, Langston E. Ketolides: a new class of antibacterialagents for treatment of community-acquiredrespiratory tract infections in a primary care setting. 2003;78:1113-1124.
Antimicrob Agents Chemother.
14. Weisblum B. Erythromycin resistance by ribosomemodification. 1995;39:577-585.
Streptococcuspneumoniae.
Antimicrob Agents Chemother.
15. Capobianco JO, Cao Z, Shortridge VD, et al.Studies of the novel ketolide ABT-773: transport, bindingto ribosomes, and inhibition of protein synthesis in 2000;44:1562-1567.
Streptococcus pyogenes:
Antimicrob Agents Chemother.
16. Bemer-Melchior P, Juvin ME, Tassin S, et al. Invitro activity of the new ketolide telithromycin comparedwith those of macrolides against influences of resistance mechanisms and methodologicalfactors. 2000;44:2999-3002.
J AntimicrobChemother.
17. Hamilton-Miller JM, Shah S. Patterns of phenotypicresistance to the macrolide-lincosamide-ketolide-streptogramingroup of antibiotics in staphylococci. 2000;46:941-949.
Ann Pharmacother.
18. Shain CS, Amsden GW. Telithromycin: the first ofthe ketolides. 2002;36:452-464.
19. Aventis Pharmaceuticals. Ketek (telithromycin)tablets: prescribing information. Kansas City, Mo. 2004.
J AntimicrobChemother.
20. Ackermann G, Rodloff AC. Drugs of the 21st century:telithromycin (HMR 3647)—the first ketolide. 2003;51:497-511.
Clin MicrobiolInfect.
21. Felmingham D. Microbiological profile of telithromycin,the first ketolide antimicrobial. 2001;7(suppl 3):2-10.
Eur J ClinMicrobiol Infect Dis.
22. Barry AL, Fuchs PC, Brown SD. Relative potency oftelithromycin, azithromycin and erythromycin againstrecent clinical isolates of gram-positive cocci. 2001;20:494-497.
Antimicrob Agents Chemother.
23. Pankuch GA, Visalli MA, Jacobs MR, et al.Susceptibilities of penicillin- and erythromycin-susceptibleand -resistant pneumococci to HMR 3647 (RU66647), a new ketolide, compared with susceptibilitiesto 17 other agents. 1998;42:624-630.
Antimicrob Agents Chemother.
24. Shortridge VD, Zhong P, Cao Z, et al. Comparisonof in vitro activities of ABT-773 and telithromycinagainst macrolide-susceptible and -resistant streptococciand staphylococci. 2002;46:783-786.
Streptococcus pneumoniae
J AntimicrobChemother.
25. Fuchs PC, Barry AL, Brown SD. In vitro activity oftelithromycin against resistantto other antibiotics, including cefotaxime. 2002;49:399-401.
Antimicrob Agents Chemother.
26. Goldstein EJ, Citron DM, Merriam CV, et al. Invitro activities of telithromycin and 10 oral agentsagainst aerobic and anaerobic pathogens isolated fromantral puncture specimens from patients with sinusitis. 2003;47:1963-1967.
Streptococcus pneumoniae
J Antimicrob Chemother.
27. Felmingham D, Reinert RR, Hirakata Y, et al.Increasing prevalence of antimicrobial resistance amongisolates of from the PROTEKTsurveillance study, and comparative in vitro activity ofthe ketolide, telithromycin. 2002;50(suppl S1):25-37.
Streptococcus pyogenes
Streptococcus pneumoniae
J Antimicrob Chemother.
28. Giovanetti E, Montanari MP, Marchetti F, et al. Invitro activity of ketolides telithromycin and HMR 3004against Italian isolates of and with different erythromycinsusceptibility. 2000;46:905-908.
Streptococcuspneumoniae
29. Nicolau DP, Jenkins SG. Resistance phenotypes andmulti-drug resistance among isolates of from the US during PROTEKT US year 2(2001-2002) [poster no. 203]. San Diego, Calif. 2003.
Haemophilus influenzae.Antimicrob Agents Chemother.
30. Barry AL, Fuchs PC, Brown SD. In vitro activities ofthe ketolide HMR 3647 against recent gram-positiveclinical isolates and 1998;42:2138-2140.
Diagn Microbiol Infect Dis.
31. Jones RN, Biedenbach DJ. Antimicrobial activity ofRU-66647, a new ketolide. 1997;27:7-12.
J Antimicrob Chemother.
32. Boswell FJ, Andrews JM, Ashby JP, et al. The invitroactivity of HMR 3647, a new ketolide antimicrobialagent. 1998;42:703-709.
Streptococcus pneumoniae, Haemophilus influenzae,
Moraxella catarrhalis. Diagn Microbiol Infect Dis.
33. Hoban DJ, Zhanel GG, Karlowsky JA. In vitro activityof the novel ketolide HMR 3647 and comparativeoral antibiotics against Canadian respiratory tract isolatesof and 1999;35:37-44.
Streptococcus pneumoniae, Streptococcuspyogenes, Haemophilus influenzae
Moraxellacatarrhalis. J Antimicrob Chemother.
34. Schmitz FJ, Schwarz S, Milatovic D, et al. In vitroactivities of the ketolides ABT-773 and telithromycin andof three macrolides against genetically characterizedisolates of and 2002;50:145-148.
Streptococcus pneumoniae,Haemophilus influenzae
Moraxella catarrhalis. Int JAntimicrob Agents.
35. Kucukbasmaci O, Gonullu N, Aktas Z, et al. In vitroactivity of telithromycin compared with macrolides andfluoroquinolones against and 2003;22:497-501.
J Antimicrob Chemother.
36. Khair OA, Andrews JM, Honeybourne D, et al.Lung concentrations of telithromycin after oral dosing. 2001;47:837-840.
C hlamydiapneumoniae. Antimicrob Agents Chemother.
37. Strigl S, Roblin PM, Reznik T, et al. In vitro activityof ABT 773, a new ketolide antibiotic, against 2000;44:1112-1113.
M pneumoniae
Antimicrob Agents Chemother.
38. Kenny GE, Cartwright FD. Susceptibilities ofMycoplasma hominis, , and Ureaplasmaurealyticum to GAR-936, dalfopristin, dirithromycin,evernimicin, gatifloxacin, linezolid, moxifloxacin, quinupristin-dalfopristin, and telithromycin compared to theirsusceptibilities to reference macrolides, tetracyclines,and quinolones. 2001;45:2604-2608.
Antimicrob Agents Chemother.
39. Bebear CM, Renaudin H, Bryskier A, et al.Comparative activities of telithromycin (HMR 3647), levofloxacin,and other antimicrobial agents against humanmycoplasmas. 2000;44:1980-1982.
Mycoplasma pneumoniae
Antimicrob Agents Chemother.
40. Yamaguchi T, Hirakata Y, Izumikawa K, et al. Invitro activity of telithromycin (HMR3647), a newketolide, against clinical isolates of in Japan. 2000;44:1381-1382.
Chlamydiapneumoniae. Antimicrob Agents Chemother.
41. Roblin PM, Hammerschlag MR. In vitro activity of anew ketolide antibiotic, HMR 3647, against 1998;42:1515-1516.
Chemotherapy.
42. Perret C, Lenfant B, Weinling E, et al. Pharmacokineticsand absolute oral bioavailability of an 800-mgoral dose of telithromycin in healthy young and elderlyvolunteers. 2002;48:217-223.
43. Lenfant B, Perret C, Pascual MH. The bioavailabilityof telithromycin (HMR 3647), a new once daily ketolideantimicrobial, is unaffected by food. Proceedings of the5th International Conference on Macrolides, Azalides,Streptogramins, Ketolides, and Oxazolidinones; Selville,Spain; January 26-28, 2000.
Antimicrob Agents Chemother.
44. Namour F, Wessels DH, Pascual MH, et al.Pharmacokinetics of the new ketolide telithromycin(HMR 3647) administered in ascending single and multipledoses. 2001;45:170-175.
AntimicrobAgents Chemother.
45. Kadota J, Ishimatsu Y, Iwashita T, et al. Intrapulmonarypharmacokinetics of telithromycin, a newketolide, in healthy Japanese volunteers. 2002;46:917-921.
Antimicrob AgentsChemother.
46. Muller-Serieys C, Soler P, Cantalloube C, et al.Bronchopulmonary disposition of the ketolidetelithromycin (HMR 3647). 2001;45:3104-3108.
J Antimicrob Chemother.
47. Muller-Serieys C, Andrews J, Vacheron F, et al.Tissue kinetics of telithromycin, the first ketolide antibacterial. 2004;53:149-157.
Antimicrob Agents Chemother.
48. Mandell GL, Coleman E. Uptake, transport, anddelivery of antimicrobial agents by human polymorphonuclearneutrophils. 2001;45:1794-1798.
AntimicrobAgents Chemother.
49. Miossec-Bartoli C, Pilatre L, Peyron P, et al. Thenew ketolide HMR3647 accumulates in the azurophilgranules of human polymorphonuclear cells. 1999;43:2457-2462.
J AntimicrobChemother.
50. Gia HP, Roeder V, Namour F, et al. HMR 3647achieves high and sustained concentrations in whiteblood cells in man (abstract no. P79). 1999;44(suppl A):57-58.
51. Sultan E, Namour F, Mauriac C, et al. Telithromycin(HMR 3647), a new ketolide antimicrobial, is metabolizedand excreted mainly in faeces in man. Proceedingsof the 5th International Conference on Macrolides,Azalides, Streptogramins, Ketolides, and Oxazolidinones;Selville, Spain; January 26-28, 2000.
J Clin Pharmacol.
52. Shi J, Montay G, Chapel S, et al. Pharmacokineticsand safety of the ketolide telithromycin in patients withrenal impairment. 2004;44:234-244.
Antimicrob Agents Chemother.
53. Odenholt I, Lowdin E, Cars O. Pharmacodynamicsof telithromycin in vitro against respiratory tract pathogens. 2001;45:23-29.
Haemophilus influenzae
Haemophilus parainfluenzae. Antimicrob AgentsChemother.
54. Bozdogan B, Clark C, Bryskier A, et al. Activities ofHMR 3787 and RU 64399 compared with those of fourother agents against and 2003;47:405-407.
Helicobacter pylori. Antimicrob AgentsChemother.
55. Gustafsson I, Engstrand L, Cars O. In vitro pharmacodynamicstudies of activities of ketolides HMR 3647(telithromycin) and HMR 3004 against extracellular orintracellular 2001;45:353-355.
56. Lippert C, Leese PT, Sultan E. Effect of gastric pH onthe bioavailability of telithromycin (HMR 3647) (abstractP1269). 11th European Congress of Clinical Microbiologyand Infectious Disease; Istanbul, Turkey; April 1-4, 2001.
57. Shi J, Montay G, Leroy B, et al. Effects of ketoconazoleand itraconazole on the pharmacokinetics of telithromycin,a new ketolide antibiotic (abstract A-1833). 42ndInterscience Conference on Antimicrobial Agents andChemotherapy; San Diego, Calif; September 27-30, 2002.
Drugs.
58. Zhanel GG, Walters M, Noreddin A, et al. Theketolides: a critical review. 2002;62:1771-1804.
Ketek (Telithromycin).Briefing Document for the FDA Anti-Infective Drug ProductsAdvisory Committee Meeting.
59. Aventis Pharmaceuticals. Bridgewater, NJ.2003.
60. Lippert C, Leese PT, Sultan E. Telithromycin (HMR3647) does not interact with the CYP 2D6 substrateparoxetine (abstract P1268). 11th European Congress ofClinical Microbiology and Infectious Disease; Istanbul,Turkey; April 1-4, 2001.
61. Scholtz HE, Pretorius SG, Wessels DH, et al.Telithromycin (HMR 3647), a new ketolide antimicrobial,does not affect the reliability of low-dose, triphasicoral contraceptives (abstract 09.30). 5th InternationalConference on the Macrolides, Azalides, Streptogramins,Ketolides, and Oxazolidinones; Selville, Spain; January26-28, 2000.
Ear Nose Throat J.
62. Luterman M, Tellier G, Lasko B, et al. Efficacy andtolerability of telithromycin for 5 or 10 days vs amoxicillin/clavulanic acid for 10 days in acute maxillarysinusitis. 2003;82:576-584, 586.
AmJ Rhinol.
63. Buchanan PP, Stephens TA, Leroy B. A comparisonof the efficacy of telithromycin versus cefuroxime axetilin the treatment of acute bacterial maxillary sinusitis. 2003;17:369-377.
Chemotherapy.
64. Roos K, Brunswig-Pitschner C, Kostrica R, et al.Efficacy and tolerability of once-daily therapy withtelithromycin for 5 or 10 days for the treatment of acutemaxillary sinusitis. 2002;48:100-108.
65. Mandell L, Chang J, Oster G, et al. Comparison ofhealthcare utilization in patients with acute exacerbationsof chronic bronchitis (ACEB) receiving telithromycin(tel) versus clarithromycin (cla) in a randomized, double-blind,multicenter clinical trial (abstract L-1595). 43rdAnnual Interscience Conference on Antimicrobial Agentsand Chemotherapy; Chicago, Ill; September 14-17, 2003.
Respir Med.
66. Aubier M, Aldons PM, Leak A, et al. Telithromycinis as effective as amoxicillin/clavulanate in acute exacerbationsof chronic bronchitis. 2002;96:862-871.
J Int Med Res.
67. Zervos MJ, Heyder AM, Leroy B. Oral telithromycin800 mg once daily for 5 days versus cefuroxime axetil500 mg twice daily for 10 days in adults with acuteexacerbations of chronic bronchitis. 2003;31:157-169.
Clin Microbiol Infect.
68. Carbon C, Moola S, Velancsics I, et al. Telithromycin800 mg once daily for seven to ten days is an effectiveand well-tolerated treatment for community-acquiredpneumonia. 2003;9:691-703.
Streptococcus pneumoniae
69. Fogarty C, Patel TC, Galbraith H, et al. Efficacy ofthe first ketolide antibacterial, telithromycin, in the treatmentof community acquired pneumonia caused by (abstract L-857). 41st AnnualInterscience Conference on Antimicrobial Agents andChemotherapy; Chicago, Ill; December 16-19, 2001.
Infection.
70. Hagberg L, Torres A, van Rensburg D, et al.Efficacy and tolerability of once-daily telithromycin comparedwith high-dose amoxicillin for treatment of community-acquired pneumonia. 2002;30:378-386.
Clin Ther.
71. Mathers DL, Hassman J, Tellier G. Efficacy and tolerabilityof once-daily oral telithromycin compared withclarithromycin for the treatment of community-acquiredpneumonia in adults. 2004;26:48-62.
Int J Clin Pract.
72. Pullman J, Champlin J, Vrooman PS Jr. Efficacy andtolerability of once-daily oral therapy with telithromycincompared with trovafloxacin for the treatment of community-acquired pneumonia in adults. 2003;57:377-384.
73. Tellier G, Isakov T, Petermann W, et al. Efficacyand safety of telithromycin (800 mg once daily) for 5 or7 days vs clarithromycin (500 mg twice daily) for 10days in the treatment of patients with community-acquiredpneumonia (abstract L-373). 42nd InterscienceConference on Antimicrobial Agents and Chemotherapy;San Diego, Calif; September 27-30, 2002.
Curr Med Res Opin.
74. Van Rensburg DJ, Matthews PA, Leroy B. Efficacyand safety of telithromycin in community-acquiredpneumonia. 2002;18:397-400.
Ann Intern Med.
75. Anthonisen NR, Manfreda J, Warren CP, et al. Antibiotictherapy in exacerbations of chronic obstructivepulmonary disease. 1987;106:196-204.
J Antimicrob Chemother.
76. Tellier G, Niederman MS, Nusrat R, et al. Clinicaland bacteriological efficacy and safety of 5 and 7 dayregimens of telithromycin once daily compared with a10 day regimen of clarithromycin twice daily in patientswith mild to moderate community-acquired pneumonia. 2004;54:515-523.
77. Lorenz J, Roscher K. Telithromycin demonstratesefficacy and safety in the treatment of community-acquiredupper and lower respiratory tract infections inthe usual care setting (abstract SA172). InternationalConference of Chemotherapy; Chicago, Ill; September 14-17, 2003.
J AntimicrobChemother.
78. Reinert RR. Clinical efficacy of ketolides in the treatmentof respiratory tract infections. 2004;53:918-927.
J Gen Intern Med.
79. Metlay JP, Shea JA, Crossette LB, et al. Tensions inantibiotic prescribing: pitting social concerns against theinterests of individual patients. 2002;17:87-94.
Streptococcus pneumoniae
Antimicrob Agents Chemother.
80. Doern GV, Heilmann KP, Huynh HK, et al.Antimicrobial resistance among clinical isolates of in the United States during1999-2000, including a comparison of resistance ratessince 1994-1995. 2001;45:1721-1729.
Streptococcus pneumoniae
Clin Infect Dis.
81. Jacobs MR. In vivo veritas: in vitro macrolide resistancein systemic infectionsdoes result in clinical failure. 2002;35:565-569.
Streptococcuspneumoniae, Haemophilus influenzae
Moraxellacatarrhalis
Clin Infect Dis.
82. Hoban DJ, Doern GV, Fluit AC, et al. Worldwideprevalence of antimicrobial resistance in , and in the SENTRY Antimicrobial SurveillanceProgram, 1997-1999. 2001;32(suppl 2):S81-S93.
