Community Acquired Pneumonia[1] - Canadian Society of …cshpontario.ca/_CMS/files/Community Acquired Pneu… ·  · 2014-11-25Objectives To give a brief description of the pathophysiology

Community Acquired Community Acquired Pneumonia: An Update Pneumonia: An Update

on Guidelineson GuidelinesClaudia Summa, Claudia Summa, BScPhmBScPhm

Pharmacy ResidentPharmacy Resident

September 12, 2006September 12, 2006

ObjectivesObjectivesTo give a brief description of the To give a brief description of the pathophysiologypathophysiology of of community acquired pneumonia (CAP)community acquired pneumonia (CAP)To discuss the various organisms that cause CAPTo discuss the various organisms that cause CAPTo discuss the clinical settings with increased risk of To discuss the clinical settings with increased risk of pathogenspathogensTo show which drugs treat CAP bugsTo show which drugs treat CAP bugsTo compare the old MSH guidelines to the new MSH To compare the old MSH guidelines to the new MSH guidelinesguidelinesTo show evidence supporting these changesTo show evidence supporting these changesTo compare side effects, drug interactions, convenience, To compare side effects, drug interactions, convenience, and cost of the various antibiotics used to treat CAPand cost of the various antibiotics used to treat CAP

PathophysiologyPathophysiologyOrganisms can gain access to the lower respiratory tract via:Organisms can gain access to the lower respiratory tract via:

oo inhalation, inhalation, oo bloodstream bloodstream oo aspirationaspiration

Changes in the pulmonary defence may increase the likelihood of Changes in the pulmonary defence may increase the likelihood of infection:infection:

Cough reflex can be impaired by stroke, neuromuscular disease, sCough reflex can be impaired by stroke, neuromuscular disease, sedatives, or edatives, or poor nutritionpoor nutrition

MucociliaryMucociliary transport is depressed with the aging process, tobacco smoking,transport is depressed with the aging process, tobacco smoking,dehydration, morphine, atropine, prior infection with influenza dehydration, morphine, atropine, prior infection with influenza virus, and virus, and chronic bronchitis. chronic bronchitis.

Anatomic changes such as emphysema, Anatomic changes such as emphysema, bronchiectasisbronchiectasis, and obstructive mass , and obstructive mass lesions prevent clearance of microbes. lesions prevent clearance of microbes.

Organisms Causing CAPOrganisms Causing CAPStreptococcus Streptococcus PneumoniaePneumoniaeHaemophilusHaemophilus influenzaeinfluenzaeMycoplasmaMycoplasma pneumoniaepneumoniaeChlamydia Chlamydia pneumoniaepneumoniae

Other agents include: Other agents include: S. S. aureusaureus, group A , group A streptococci, streptococci, MoraxellaMoraxella catarrhaliscatarrhalis, , LegionellaLegionellaspecies, Gram negative bacilli, anaerobes, and species, Gram negative bacilli, anaerobes, and viruses, including respiratory viruses, including respiratory syncytialsyncytial virus, virus, influenza virus, and influenza virus, and parainfluenzaparainfluenza virus.virus.

Clinical Settings with Increased Clinical Settings with Increased Risk of PathogensRisk of Pathogens

AlcoholismAlcoholism –– anaerobes, gramanaerobes, gram--negative bacillinegative bacilliCOPD/smokerCOPD/smoker –– H. H. influenzaeinfluenzae, , M. M. catarrhaliscatarrhalisIncreased age/coIncreased age/co--morbid medical conditionsmorbid medical conditions–– Gram negative bacilliGram negative bacilliRecent hospitalizationsRecent hospitalizations –– Gram negative Gram negative bacilli, bacilli, S. S. aureusaureus, , LegionellaLegionella species, anaerobesspecies, anaerobesNursing homeNursing home –– Gram negative bacilli, Gram negative bacilli, H. H. influenzaeinfluenzae, , S. S. aureusaureus, , C. C. pneumoniaepneumoniae, , anaerobesanaerobes

DRUGS that fight CAP BUGSDRUGS that fight CAP BUGSMacrolidesMacrolides –– S. S. pneumoniaepneumoniae, , MycoplasmaMycoplasma pneumoniaepneumoniae, , Chlamydia Chlamydia pneumoniaepneumoniae, , LegionellaLegionella species (species (azithromycinazithromycin and and clarithromycinclarithromycin), ), H. H. influenzaeinfluenzae ((azithromycinazithromycin and and clarithromycinclarithromycin))

FluoroquinolonesFluoroquinolones –– S. S. pneumoniaepneumoniae, , LegionellaLegionella species, species, H. H. influenzaeinfluenzae

Amoxicillin, Amoxicillin/Amoxicillin, Amoxicillin/ClavulanicClavulanic acid acid –– S. S. pneumoniaepneumoniae, , MoraxellaMoraxellacatarrhaliscatarrhalis or or H. H. influenzaeinfluenzae

22ndnd or 3or 3rdrd generation generation cephalosporinscephalosporins –– S. S. pneumoniaepneumoniae, aerobic gram , aerobic gram negative bacilli, negative bacilli, H. H. influenzaeinfluenzae

ClindamycinClindamycin –– S. S. pneumoniaepneumoniae, , anaerobesanaerobes

MetronidazoleMetronidazole –– anaerobesanaerobes

* = Non* = Non--formularyformulary

Outpatient Therapy Outpatient Therapy –– Without Without Modifying FactorsModifying Factors

AzithromycinAzithromycin 500mg PO on day 1, then 500mg PO on day 1, then 250mg PO 250mg PO odod f4df4dORORClarithromycinClarithromycin 500mg PO q12h500mg PO q12hORORClarithromycinClarithromycin XL 1000mg PO XL 1000mg PO odod * *

Alternative:Alternative:DoxycyclineDoxycycline 100mg PO q12h100mg PO q12hORORMoxifloxacinMoxifloxacin 400mg PO 400mg PO ododORORLevofloxacinLevofloxacin 500 500 –– 750mg PO 750mg PO odod

Erythromycin 500mg PO q6hErythromycin 500mg PO q6hORORAzithromycinAzithromycin 500mg PO on day 1, then 500mg PO on day 1, then 250mg PO 250mg PO odod f4df4dORORClarithromycinClarithromycin 500mg PO q12h500mg PO q12h

Alternative:Alternative:DoxycyclineDoxycycline 100mg PO q12h100mg PO q12h

NEW GUIDELINESNEW GUIDELINESOLD GUIDELINESOLD GUIDELINES

Outpatient Therapy Outpatient Therapy –– With Modifying FactorsWith Modifying Factors

Amoxicillin/Amoxicillin/clavulanicclavulanic acid 875mg/125mg PO acid 875mg/125mg PO q12h *q12h *ORORAmoxicillin/Amoxicillin/clavulanicclavulanic acid 500mg/125mg PO acid 500mg/125mg PO q8hq8hORORAmoxicillin 1000mg PO q8hAmoxicillin 1000mg PO q8h

One of the above plus:One of the above plus:AzithromycinAzithromycin 500mg PO on day 1, then 250mg 500mg PO on day 1, then 250mg PO PO odod f4df4dORORClarithromycinClarithromycin 500mg PO q12h500mg PO q12hORORClarithromycinClarithromycin XL 1000mg PO daily *XL 1000mg PO daily *

OR Single Therapy:OR Single Therapy:LevofloxacinLevofloxacin 500500--750mg 750mg PO PO ododORORMoxifloxacinMoxifloxacin 400mg PO 400mg PO odod

Amoxicillin/Amoxicillin/clavulanicclavulanic acid 500mg/125mg PO acid 500mg/125mg PO q8hq8hORORCefuroximeCefuroxime 500mg PO q12h500mg PO q12hORORCefprozilCefprozil 500mg PO q12h500mg PO q12h

One of the above plus:One of the above plus:AzithromycinAzithromycin 500mg PO on day 1, then 250mg 500mg PO on day 1, then 250mg PO PO odod f4df4dORORClarithromycinClarithromycin 500mg PO q12h500mg PO q12h

OR Single Therapy:OR Single Therapy:LevofloxacinLevofloxacin 500mg PO 500mg PO ododORORMoxifloxacinMoxifloxacin 400mg PO 400mg PO odod

NEW GUIDELINESNEW GUIDELINESOLD GUIDELINESOLD GUIDELINES

Inpatient Therapy Inpatient Therapy –– Admission to a Hospital WardAdmission to a Hospital Ward

INTRAVENOUSINTRAVENOUSCeftriaxoneCeftriaxone 1g IV q24h plus 1g IV q24h plus AzithromycinAzithromycin500mg IV 500mg IV odod f5df5dORORMoxifloxacinMoxifloxacin 400mg IV 400mg IV odod

INTRAVENOUSINTRAVENOUSCeftriaxoneCeftriaxone 1g IV q24h plus 1g IV q24h plus AzithromycinAzithromycin500mg IV 500mg IV odod f5df5dORORLevofloxacinLevofloxacin 500mg IV 500mg IV odod

ORALORALAmoxicillin/Amoxicillin/clavulanicclavulanic acid 875mg/125mg PO acid 875mg/125mg PO q12h *q12h *ORORAmoxicillin/Amoxicillin/clavulanicclavulanic acid 500mg/125mg PO acid 500mg/125mg PO q8hq8hORORAmoxicillin 1000mg PO q8hAmoxicillin 1000mg PO q8hPlusPlusAzithromycinAzithromycin 500mg PO on day 1, then 250mg 500mg PO on day 1, then 250mg PO PO odod f4df4dORORClarithromycinClarithromycin 500mg PO q12h500mg PO q12hORORClarithromycinClarithromycin XL 1000mg PO XL 1000mg PO odod * *

OR Single Therapy:OR Single Therapy:MoxifloxacinMoxifloxacin 400mg PO 400mg PO odod

ORALORALAmoxicillin/Amoxicillin/clavulanicclavulanic acid 500mg125mg PO acid 500mg125mg PO q8hq8hPlusPlusAzithromycinAzithromycin 500mg PO on day 1, then 250mg 500mg PO on day 1, then 250mg PO PO odod f4df4dORORClarithromycinClarithromycin 500mg PO q12h500mg PO q12h

OR Single Therapy:OR Single Therapy:LevofloxacinLevofloxacin 500mg PO 500mg PO odod

NEW GUIDELINESNEW GUIDELINESOLD GUIDELINESOLD GUIDELINES

Inpatient TherapyInpatient Therapy–– MacroMacro--AspirationAspiration

INTRAVENOUSINTRAVENOUSCeftriaxoneCeftriaxone 1g IV q24h 1g IV q24h with with MetronidazoleMetronidazole 500mg 500mg IV q12hIV q12h

INTRAVENOUSINTRAVENOUSCeftriaxoneCeftriaxone 1g IV q24h 1g IV q24h with with MetronidazoleMetronidazole 500mg 500mg IV q12hIV q12h

ORALORALAmoxicillin/Amoxicillin/clavulanicclavulanic acid acid 875mg/125mg PO q12h *875mg/125mg PO q12h *ORORAmoxicillin/Amoxicillin/clavulanicclavulanic acid acid 500mg/125mg PO q8h500mg/125mg PO q8h

ORALORALAmoxicillin/Amoxicillin/clavulanicclavulanic acid acid 500mg/125mg PO q8h500mg/125mg PO q8h

NEW GUIDELINESNEW GUIDELINESOLD GUIDELINESOLD GUIDELINES

Inpatient Therapy: Admission to Inpatient Therapy: Admission to an ICUan ICU

CeftriaxoneCeftriaxone 1g IV q24h 1g IV q24h with with AzithromycinAzithromycin500mg IV 500mg IV odod

Alternative:Alternative:CeftriaxoneCeftriaxone 1g IV q24h 1g IV q24h with with MoxifloxacinMoxifloxacin400mg IV/PO 400mg IV/PO odod

CeftriaxoneCeftriaxone 1g IV q24h 1g IV q24h with with AzithromycinAzithromycin500mg IV 500mg IV odod

Alternative:Alternative:CeftriaxoneCeftriaxone 1g IV q24h 1g IV q24h with with LevofloxacinLevofloxacin 500mg 500mg IV/PO IV/PO odod

NEW GUIDELINESNEW GUIDELINESOLD GUIDELINESOLD GUIDELINES

Inpatient Therapy Inpatient Therapy –– Admission to Admission to an ICU (Modifying Factors)an ICU (Modifying Factors)

BronchiectasisBronchiectasisPiperacillin/TazobactamPiperacillin/Tazobactam 4.5g IV 4.5g IV q8h with q8h with Ciprofloxacin 400mg Ciprofloxacin 400mg IV/750mg PO q12hIV/750mg PO q12h

Suspected or confirmed Suspected or confirmed Pseudomonas Pseudomonas aeruginosaaeruginosa::Piperacillin/TazobactamPiperacillin/Tazobactam 4.5g IV 4.5g IV q8h with q8h with TobramycinTobramycin 5mg/kg IV 5mg/kg IV ododPLUSPLUSAzithromycinAzithromycin 500mg IV 500mg IV odod or or MoxifloxacinMoxifloxacin 400mg IV/PO 400mg IV/PO odod

BronchiectasisBronchiectasisPiperacillin/TazobactamPiperacillin/Tazobactam 4.5g IV 4.5g IV q8h with q8h with TobramycinTobramycin 5mg/kg IV 5mg/kg IV odod

Suspected or confirmed Suspected or confirmed Pseudomonas Pseudomonas aeruginosaaeruginosa::Piperacillin/TazobactamPiperacillin/Tazobactam 4.5g IV 4.5g IV q8h with q8h with TobramycinTobramycin 5mg/kg IV 5mg/kg IV ododPLUSPLUSAzithromycinAzithromycin 500mg IV 500mg IV odod or or LevofloxacinLevofloxacin 500mg IV 500mg IV odod

NEW GUIDELINESNEW GUIDELINESOLD GUIDELINESOLD GUIDELINES

Evidence For Addition of High Evidence For Addition of High Dose AmoxicillinDose Amoxicillin

AubierAubier M, M, VersterVerster C, C, RegameyRegamey P, et al. OnceP, et al. Once--Daily Daily SparfloxacinSparfloxacinVersus High Dosage Amoxicillin in the Treatment of Versus High Dosage Amoxicillin in the Treatment of CommunityCommunity--Acquired, Suspected Acquired, Suspected PneumococcalPneumococcal Pneumonia in Pneumonia in AdultsAdults. Clinical Infectious Disease.. Clinical Infectious Disease. 1998; 26: 13121998; 26: 1312--20.20.

One year, multiOne year, multi--center, randomized, doublecenter, randomized, double--blind trial comparing the efficacy and safety of blind trial comparing the efficacy and safety of onceonce--daily daily sparfloxacinsparfloxacin and a 1and a 1--g g tidtid dosage of dosage of amoxicillinamoxicillin

Out of 329 enrolled patients, 159 were Out of 329 enrolled patients, 159 were randomized to receive randomized to receive sparfloxacinsparfloxacin and 170 to and 170 to receive amoxicillinreceive amoxicillin

Evidence for Addition of High Dose Evidence for Addition of High Dose Amoxicillin /2Amoxicillin /2

RESULTS:RESULTS:

Average duration was 10.8 days Average duration was 10.8 days

Both drugs were effective in the intentBoth drugs were effective in the intent--toto--treat and treat and evaluableevaluable population at both endpointspopulation at both endpoints

Overall rates of success among Overall rates of success among evaluableevaluable patients patients were equivalent between drugs, both at the end of were equivalent between drugs, both at the end of treatment (treatment (sparfloxacinsparfloxacin, 92%; amoxicillin, 87%) and , 92%; amoxicillin, 87%) and at followat follow--up (up (sparfloxacinsparfloxacin, 89%; amoxicillin, 84%), 89%; amoxicillin, 84%)

SparfloxacinSparfloxacin was well tolerated and produced fewer was well tolerated and produced fewer gastrointestinal side effects than amoxicillingastrointestinal side effects than amoxicillin

Resistance of Resistance of FluoroquinolonesFluoroquinolonesEmergence of Emergence of S. S. pneumoniaepneumoniae with reduced susceptibility to the with reduced susceptibility to the fluoroquinolonesfluoroquinolones (FQ) has been described in Canada, Spain, (FQ) has been described in Canada, Spain, Hong Kong, eastern and central Europe and to a lesser extent, Hong Kong, eastern and central Europe and to a lesser extent, the United Statesthe United States

Resistance is primarily due to mutations in the genes encoding Resistance is primarily due to mutations in the genes encoding the target the target topoisomerasetopoisomerase enzymesenzymes

In Canada, Chen et al found that ciprofloxacinIn Canada, Chen et al found that ciprofloxacin--resistant resistant pneumococcipneumococci increased from 0% in 1993 to 1.7% in 1997increased from 0% in 1993 to 1.7% in 1997--1998. 1998. In adults the prevalence was 0% in 1993 to 3.7% in 1998In adults the prevalence was 0% in 1993 to 3.7% in 1998

In 2002, the Canadian Bacterial Surveillance Network reported a In 2002, the Canadian Bacterial Surveillance Network reported a prevalence of prevalence of levofloxacinlevofloxacin--resistant resistant pneumococcipneumococci of 4% in of 4% in sputum isolates recovered from patients over 65 years of agesputum isolates recovered from patients over 65 years of age

Evidence for High Dose, Short Evidence for High Dose, Short Course Course LevofloxacinLevofloxacin

Dunbar LM, Dunbar LM, WunderinkWunderink RG, RG, HabibHabib MP, et al. HighMP, et al. High--Dose, ShortDose, Short--Course Course LevofloxacinLevofloxacin for Communityfor Community--Acquired Pneumonia: A Acquired Pneumonia: A New Treatment Paradigm. New Treatment Paradigm. Clinical Infectious Diseases.Clinical Infectious Diseases. 2003; 2003; 37: 75237: 752--760.760.

MultiMulti--center, randomized, doublecenter, randomized, double--blind trial blind trial

Compared Compared levofloxacinlevofloxacin dosages of 750mg/ day for 5 days with dosages of 750mg/ day for 5 days with 500mg/day for 10 days for the treatment of mild to severe CAP500mg/day for 10 days for the treatment of mild to severe CAP

Out of 530 patients enrolled, 256 patients received Out of 530 patients enrolled, 256 patients received levofloxacinlevofloxacin750mg/day IV/PO for 5 days and 272 patients received 750mg/day IV/PO for 5 days and 272 patients received levofloxacinlevofloxacin 500mg/day IV/PO for 10 days500mg/day IV/PO for 10 days

Evidence for High Dose, Short Evidence for High Dose, Short Course Course LevofloxacinLevofloxacin /2/2

Results:Results:

At postAt post--therapy assessment, the clinical success rates in the therapy assessment, the clinical success rates in the clinically clinically evaluableevaluable population were 92.4% for the 750mg group population were 92.4% for the 750mg group and 91.1% for the 500mg groupand 91.1% for the 500mg group

Microbiological eradication rates were 93.2% and 92.4% in the Microbiological eradication rates were 93.2% and 92.4% in the 750mg and 500mg groups, respectively.750mg and 500mg groups, respectively.

Authors concluded that the short course, high dose regimen of Authors concluded that the short course, high dose regimen of levofloxacinlevofloxacin was at least as effective and well tolerated for the was at least as effective and well tolerated for the treatment of mild to severe CAP as 500mg of treatment of mild to severe CAP as 500mg of levofloxacinlevofloxacin per per day for 10 days.day for 10 days.

Side Effects and Drug Interactions of Side Effects and Drug Interactions of the Various Antibioticsthe Various Antibiotics

MacrolidesMacrolidesSide effects include:Side effects include:abdominal cramping, nausea,abdominal cramping, nausea,vomiting, vomiting, diarrheadiarrhea, rash , rash Drug interactions include:Drug interactions include:warfarinwarfarin, , digoxindigoxin, cyclosporine, , cyclosporine, benzodiazepines, benzodiazepines, carbamezapinecarbamezapine

DoxycyclineDoxycyclineSide effects include:Side effects include:nausea, vomiting, photosensitivitynausea, vomiting, photosensitivityDrug interactions include:Drug interactions include:calcium, magnesium, iron, calcium, magnesium, iron, phenytoinphenytoin, , phenobarbitalphenobarbital

Amoxicillin , Amoxicillin/Amoxicillin , Amoxicillin/ClavulanicClavulanicacid acid Side effects include:Side effects include:hypersensitivity reactions, rash, hypersensitivity reactions, rash, nausea, vomitingnausea, vomiting

FluoroquinolonesFluoroquinolonesSide effects include:Side effects include:abdominal pain, headache, abdominal pain, headache, dizziness, photosensitivitydizziness, photosensitivityDrug interactions include:Drug interactions include:calcium, calcium, warfarinwarfarin, , theophyllinetheophylline, , cyclosporinecyclosporine

CeftriaxoneCeftriaxoneSide effects include:Side effects include:hypersensitivity reactions, rash, hypersensitivity reactions, rash, nausea, vomiting, pain at the nausea, vomiting, pain at the injection siteinjection site

MetronidazoleMetronidazoleSide effects include:Side effects include:vertigo, headache, abdominal vertigo, headache, abdominal cramps, cramps, diarrheadiarrhea, vomiting, taste , vomiting, taste alterationsalterationsDrug interactions include:Drug interactions include:ethanol, ethanol, warfarinwarfarin

Cost in terms of per dayCost in terms of per day

Convenience and Cost of the Convenience and Cost of the Various AntibioticsVarious Antibiotics

MacrolidesMacrolidesDosing:Dosing: QID (E), BID (C), OD (A and QID (E), BID (C), OD (A and C)C)Cost: Cost: E E -- $0.80 $0.80

A A -- $3.52 (PO),$3.52 (PO),$20.50 (IV)$20.50 (IV)

C C -- $5.92 $5.92

DoxycyclineDoxycyclineDosing:Dosing: BIDBIDCost: Cost: $0.56 $0.56

Amoxicillin, Amoxicillin/Amoxicillin, Amoxicillin/ClavulanicClavulanicacidacidDosing:Dosing: BID, TIDBID, TIDCost:Cost: $0.66 (A)$0.66 (A)

$1.56 (A/C)$1.56 (A/C)

FluoroquinolonesFluoroquinolonesDosing:Dosing: BID (C), OD (M, L)BID (C), OD (M, L)Cost:Cost: C C -- $1.22 (PO), $57.02 $1.22 (PO), $57.02

(IV) (IV) M M -- $3.40 (PO), $28.90$3.40 (PO), $28.90

(IV)(IV)L L -- $4.00 (500mg PO),$4.00 (500mg PO),

$7.55 (750mg PO),$7.55 (750mg PO),$34.00 (IV) $34.00 (IV)

CeftriaxoneCeftriaxoneDosing:Dosing: ODODCost:Cost: $34.00$34.00

MetronidazoleMetronidazoleDosing:Dosing: BIDBIDCost:Cost: $0.44 (PO), $2.58 (IV)$0.44 (PO), $2.58 (IV)

ReferencesReferences1.1. MandellMandell LA, Bartlett JG, et al. Update of the Infectious Diseases of SLA, Bartlett JG, et al. Update of the Infectious Diseases of Society of America Guidelines for the ociety of America Guidelines for the

management of communitymanagement of community--acquired pneumonia in acquired pneumonia in immunocompetentimmunocompetent adults. adults. Clinical Infectious DiseasesClinical Infectious Diseases. . 2003; 37: 14052003; 37: 1405--33.33.

2.2. MandellMandell LA, LA, MarrieMarrie TJ, Grossman RF, et al. Canadian guidelines for the initial maTJ, Grossman RF, et al. Canadian guidelines for the initial management of community nagement of community acquired pneumonia: an evidenceacquired pneumonia: an evidence--based update by the Canadian Thoracic Society. The Canadian based update by the Canadian Thoracic Society. The Canadian CommunityCommunity--Acquired Pneumonia Working Group. Acquired Pneumonia Working Group. Clinical Infectious Diseases.Clinical Infectious Diseases. 2000; 31: 3832000; 31: 383--421.421.

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5.5. Chen D, Chen D, McGeerMcGeer A, de A, de AzevedoAzevedo J et al. Decreased susceptibility of J et al. Decreased susceptibility of Streptococcus Streptococcus pneumoniaepneumoniae to to fluoroquinolonesfluoroquinolones in Canada. Canadian Bacterial in Canada. Canadian Bacterial SurveillancSurveillanc Network. Network. New England Journal of MedicineNew England Journal of Medicine. . 1999; 341: 2331999; 341: 233--9.9.

6.6. AubierAubier M, M, VersterVerster R, R, RegameyRegamey C, et al. OnceC, et al. Once--daily daily sparfloxacinsparfloxacin versus high dosage amoxicillin in the versus high dosage amoxicillin in the treatment of communitytreatment of community--acquired, suspected acquired, suspected pneumococcalpneumococcal pneumonia in adults. pneumonia in adults. Clinical Infectious Clinical Infectious DiseasesDiseases. 1998; 26: 1312. 1998; 26: 1312--20. 20.

7.7. Dunbar LM, Dunbar LM, WunderinkWunderink RG, RG, HabibHabib MP, et al. HighMP, et al. High--Dose, ShortDose, Short--Course Course LevofloxacinLevofloxacin for Communityfor Community--Acquired Acquired Pneumonia: A New Treatment Paradigm. Pneumonia: A New Treatment Paradigm. Clinical Infectious Diseases.Clinical Infectious Diseases. 2003; 37: 7522003; 37: 752--760.760.

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