Levofloxacin in the Treatment of Pneumonia Caused by Streptococcus pneumoniae, Including Multidrug-Resistant Strains

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1 Levofloxcin in the Tretment of Pneumoni Cused by Streptococcus pneumonie, Including Multidrug-Resistnt Strins Review Jnet Peterson, PhD Ortho-McNeil Jnssen Scientific Affirs, LLC; Rritn, New Jersey, USA Streptococcus pneumonie (S. pneumonie) is the most frequently isolted bcteril pthogen in dults with community-cquired pneumoni (CAP) (1,). Becuse the identity of the custive pthogen is frequently unknown t the time of dignosis, initil ntimicrobil therpy for CAP is usully empiric(1) nd trgeted t the most common bcteril cuses of CAP, including S. pneumonie. However, the growing problem of drug-resistnt S. pneumonie hs undermined the effectiveness of empiric therpy, prticulrly for the most commonly used orl ntibcteril gents. A pooled nlysis ws conducted on dt from 1 clinicl studies evluting levofloxcin in the tretment of pneumoni cused by S. pneumonie, including multidrug resistnt S. pneumonie (MDRSP) strins. The high clinicl cure rtes nd microbiologic erdiction rtes for MDRSP pthogens observed with levofloxcin support its effectiveness in treting ptients who present with CAP. Drug resistnce in Streptococcus pneumonie Mcrolides nd β-lctms re mong the ntimicrobils recommended for the tretment of community-cquired pneumoni (CAP) (). However, resistnce of S. pneumonie to these commonly used ntimicrobils is incresing, with rtes of high-level penicillin nd mcrolide resistnce of 15.7% nd.%, respectively, in the United Sttes in 7 8 (). Furthermore, pneumococci re often resistnt to more thn one clss of ntimicrobils; 4% of S. pneumonie hve been reported to disply multidrug resistnt S. pneumonie (MDRSP), with prevlence tht vries mrkedly from country to country (4). The most commonly observed phenotype, occurring in more thn 9% of MDRSP isoltes, is resistnt to penicillin, zithromycin, nd trimethoprim/sulfmethoxzole (). As result, ny of these gents my select for MDR strins. Given the high rtes of resistnce, it cn be nticipted tht mny currently vilble gents re becoming less effective for the tretment of pneumoni cused by S. pneumonie. Few new ntimicrobils potentilly effective for S. pneumonie, in prticulr orl gents, re in development. As result, there is need to evlute the efficcy of currently vilble tretment options for pneumoni cused by S. pneumonie to identify those gents tht remin effective ginst this pthogen nd tht re still pproprite for the empiric therpy of pneumoni. At the sme time, strtegies to preserve the effectiveness of these gents by minimizing conditions tht might select for resistnt orgnisms should be explored. Pooled nlysis of levofloxcin studies The respirtory fluoroquinolones re recommended in selected ptients with CAP (). Longitudinl surveillnce dt (1998 through 7) show tht the prevlence of levofloxcin-resistnt S. pneumonie remins t 1% or less in the United Sttes (), with 96% to 99% of MDRSP strins lso currently susceptible to levofloxcin; therefore, it my be nticipted tht levofloxcin remins effective for the tretment of CAP cused by S. pneumonie. To collect informtion on the clinicl nd microbiologic efficcy of levofloxcin in sufficient number of ptients with pneumoni cused by MDRSP nd non-mdrsp, n nlysis of dt pooled from 1 previously completed levofloxcin trils ws conducted nd published recently by Peterson nd collegues(5). Clinicl success nd microbiologic erdiction rtes were determined in microbiologiclly evluble (ME) subjects with pneumoni cused by S. pneumonie, including MDRSP (5). The 1 studies, which were conducted from 199 through, represent the totl experience of levofloxcin in pneumoni in the Ortho-McNeil dtbse Address for correspondence Jnet Peterson, PhD Ortho-McNeil Jnssen Scientific Affirs, LLC 1 Route Rritn, New Jersey 8869, USA Phone: Fx: E-mil: Jpeter1@its.jnj.com 9

2 Review (5). Nine of the studies were conducted in ptients with CAP (6-1), nd 1 ws conducted in ptients with nosocomil pneumoni (1). S. pneumonie resistnce ws chrcterized by in vitro testing of clinicl isoltes obtined from prticipnts prior to tretment. Drugs from 5 ntimicrobil clsses were used in the tests: tetrcyclines (tetrcycline, doxycycline); sulfonmides (trimethoprim/sulfmethoxzole); second-genertion cephlosporins (cefuroxime, cefoxitin); penicillins (moxicillin, moxicillin-clvulnte); nd mcrolides (zithromycin, clrithromycin, erythromycin). Isoltes resistnt to or more drug clsses, or those resistnt to 1 drug clss, nd with intermedite resistnce to t lest 1 other drug clss, were clssified s MDRSP. Isoltes tht were susceptible nd/or intermeditely susceptible to ll ntimicrobil clsses, or were resistnt to 1 clss nd fully susceptible to ll others, were clssified s non-mdrsp (5). Clinicl response (cure, improvement, filure), bsed on the investigtor s ssessment t the post-therpy visit (test of cure) for levofloxcintreted ME subjects, ws the primry endpoint of the nlysis. Microbiologic efficcy (erdicted versus persisted) for S. pneumonie ws lso ssessed fter the conclusion of therpy (5). Efficcy of levofloxcin in pneumoni cused by MDRSP nd non-mdrsp A totl of 4 S. pneumonie isoltes collected from 419 levofloxcin-treted ME subjects were vilble for nlysis. Tble 1 summrizes the design, dosing regimens, nd number of subjects with S. pneumonie in ech of the studies. Five studies were comprtive nd 5 were noncomprtive. Tble lists the demogrphic chrcteristics of levofloxcin-treted subjects included in the nlysis, ccording to S. pneumonie clssifiction. A totl of 54 isoltes were clssified s MDRSP nd 66 were clssified s non-mdrsp (5). Tble shows the distribution of levofloxcin minimum inhibitory concentrtion (MIC) vlues for S. pneumonie isoltes ccording to vrious ntimicrobil clsses. Only 1 isolte ws chrcterized s being resistnt to levofloxcin; this isolte ws lso resistnt to ll mcrolides nd doxycycline. Resistnce to 1 or more ntimicrobil drug clsses ws observed in 18.9% (79/4) of S. pneumonie isoltes (5). Clinicl responses were recorded for 54 subjects with n MDRSP isolte nd for 65 subjects with non-mdrsp isolte (Tble 4). Clinicl success (cured or improved) ws observed in 5/54 (96.%) levofloxcin-treted subjects with MDRSP nd in 47/65 (95.1%) non-mdrsp subjects (95% confidence intervl [CI]: ). Microbiologic success rtes re shown in Tble 4. S. pneumonie ws erdicted in 5/54 (96.%) of isoltes from MDRSP ptients versus 5/66 (95.6%) of isoltes from non-mdrsp subjects (95% CI: ). High rtes of S. pneumonie erdiction were chieved with levofloxcin, nd the effect did not pper to be influenced by the resistnce of isoltes to other ntimicrobil clsses (5). Tble 5 shows the clinicl nd microbiologic success rtes of ME subjects with S. pneumonie isoltes resistnt to other ntimicrobils. Dt re shown ccording to the specific clss to which n isolte demonstrted resistnce. Clinicl filure ws observed in subjects with MDRSP who were treted with levofloxcin. Both subjects hd serious comorbidities in ddition to pneumoni. One subject, who ws treted with levofloxcin 75 mg PO for 4 dys, hd lung bscess, chronic obstructive pulmonry disese (COPD), congestive hert filure (CHF), dibetes, obesity, nd renl filure. S. pneumonie resistnt to penicillin, cephlosporin, nd sulfonmide clsses ws found in blood cultures from this ptient; the isolte ws susceptible to levofloxcin. This subject ws discontinued from the study, but ws treted gin, this time successfully, with levofloxcin 5 mg, followed by clrithromycin (5). A second clinicl filure ws observed in subject hospitlized with severe pneumoni, chronic bronchitis, nd CHF. After tretment with levofloxcin 5 mg IV for 14 dys, S. pneumonie isolted from sputum smples ws resistnt to mcrolides nd sulfonmide, but ws susceptible to levofloxcin. The subject died of respirtory distress 1 dys fter the strt of tretment(5). Strtegies for preserving susceptibility of S. pneumonie to levofloxcin The continued efficcy of levofloxcin is predicted, in prt, by surveillnce dt tht demonstrte >99% of strins remin susceptible to levofloxcin in the United Sttes. However, rre isoltes of fluoroquinolone-resistnt S. pneumonie hve been reported, prticulrly in regions of the world where levofloxcin is dministered for long periods (eg, for the tretment of tuberculosis) or t low doses (14,15). Becuse prolonged drug exposure is n importnt driver of ntimicrobil resistnce, shortdurtion therpy my minimize selective pressure for resistnt S. pneumonie. Nord nd collegues conducted n open-lbel study designed to test the hypothesis tht limiting exposure to levofloxcin by using high-dose, short-course therpy minimizes selective pressure for resistnt orgnisms (16). They compred the risk of coloniztion with 4

3 Levofloxcin in pneumococcl pneumoni Tble 1. Overview of clinicl studies to support the efficcy of levofloxcin for the tretment of MDRSP in pneumoni Protocol No. Investigtor(s) (Country[s]) Strt dte End dte Study description/design No. subjects evluted Gender (M/F),b Rce (C/B/O),b Men ge (yr) (rnge) Tretment regimen(s) Totl durtion S. pneumonie isoltes MDRSP Totl Non-MDRSP Comprtive studies CAPSS-18 December Mrch Multiple-dose, multicenter, rndomized, open-lbel, ctive-controlled, prllel-group study to show tht LVFX ws t lest s efficcious s CEFT nd ERYTH followed by CLAR nd AMX/CL in the tretment of serious CAP in dults LVFX: 1 G: 65% / 5% R: 64% / % / 4% A: 6 (4 94) CEFT nd ERYTH f/b CLAR nd AMX/CL: 17 G: 71% / 9% R: 69% / 6% / 5% A: 6 (18 94) CEFT 1 g IV or IM q.d. ERYTH.5 1 g IV q6h CLAR 5 mg PO b.i.d. AMX/CL 875 mg PO b.i.d. LVFX = 7 14 dys CEFT nd ERYTH f/b CLAR nd AMX/CL = 7 14 dys Post-therpy: 1 dys 1 CAPSS December June 1999 Multiple-dose, multicenter, rndomized, open-lbel, ctive-controlled, prllel-group study to show tht LVFX ws comprble to AZITH in the tretment of moderte to severe CAP in dults LVFX: 5 G: 67% / % R: 77% / % / 1% A: 66 (6 94) AZITH: G: 75% / 5% R: 74% / 1% / 1% A: 67 (7 91) AZITH 5 mg q.d. CEFT 1 g IV q.d. LVFX = 1 14 dys AZITH (IV)/CEFT (min. dys) f/b AZITH (PO) = min. 1 dys. Post-therpy: 16 dys 14 CAPSS-7 Multicenter (Cnd, US) 1 December June 1 Multiple-dose, multicenter, rndomized, open-lbel, ctive-controlled, prllel-group study to compre the sfety nd efficcy of LVFX with tht of IMIP/CIL in the tretment of nosocomil pneumoni in dults LVFX: G: 7% / 7% R: 78% / % / % A: 56 (19 9) IMIP/CIL: 18 G: 71% / 9% R: 74% / 1% / 1% A: 57 (18 9) LVFX 75 mg q.d. IMIP/CL.5 1 g IV q6 8h LVFX = 7 15 dys IMIP/CL = 7 15 dys Post-therpy: 15 dys K9-71 Multicenter (Cnd, US) November Jnury 1995 Multiple-dose, multicenter, rndomized, open-lbel, ctive-controlled, prllel-group study to compre the sfety nd efficcy of LVFX with tht of CEFT or CEFUR in the tretment of CAP in dults LVFX: 95 G: 55% / 45% R: 6% / 4% / % A: 49 (18 87) CEFT/CEFUR: 95 G: 55% / 45% R: 64% / 4% / % A: 5 (18 96) LVFX 5 mg. q.d. CEFT 1 g IV q.d. CEFUR 5 mg PO b.i.d. LVFX = 7 14 dys CEFT/CEFUR = 7 14 dys Post-therpy: 1 1 dys 1 4 CAPSS-15 5 Mrch 1 7 June Multiple-dose, multicenter, rndomized, double-blind, ctive-controlled, prllel-group study to show tht 5- dy course of LVFX 75 mg q.d. ws t lest s effective s 1-dy course of in the tretment of mild to severe CAP in dults LVFX 75 mg: 56 G: 58% / 4% R: 7% / % / 1% A: 5 (18 86) LVFX 5 mg: 7 G: 6% / 4% R: 67% / 4% / 9% A: 55 (18 89) LVFX 75 mg q.d. = 5 dys; = 1 dys Post-therpy: 7 14 dys

4 Review Protocol No. Investigtor(s) (Country[s]) Strt dte End dte Study description/design No. subjects evluted Gender (M/F),b Rce (C/B/O),b Men ge (yr) (rnge) Noncomprtive studies Tretment regimen(s) Totl durtion S. pneumonie isoltes MDRSP Totl Non-MDRSP CAPSS Jnury 1 1 My open-lbel study to investigte the clinicl efficcy nd sfety of 5-dy course of LVFX 75 mg q.d. in the tretment of mild to severe CAP in dults LVFX: 1 G: 58% / 4% R: 65% / 7% / 8% A: 6 ( 9) LVFX 75 mg. q.d. LVFX = 5 dys Post-therpy: 7 14 dys LOFBIV-PCAP-1E Multicenter (Cnd, US) 7 October July 1998 open-lbel study to investigte the efficcy nd sfety of LVFX in the tretment of CAP cused by penicillin- or mcrolide-resistnt strins of S. pneumonie in dults LVFX: 655 G: 59% / 41% R: 69% / 6% / 5% A: 55 (18 96) LVFX = 7 14 dys Post-therpy: 1 dys LOFBIV-MULT-1 1 September Februry 1995 open-lbel study to evlute the sfety of LVFX in the tretment of bcteril infections of the respirtory trct, skin infections, nd UTI in dults LVFX: 1 (97 with CAP) G: 57% / 4% R: 58% / 8% / 1% A: 48 (17 1) LVFX = 7 14 dys Post-therpy: 5 7 dys M :1 September 199 July 1994 open-lbel study to evlute the sfety nd efficcy of LVFX in the tretment of CAP in dults LVFX: 64 G: 55% / 45% R: 8% / 15% / % A: 5 (18 9) LVFX: 7 14 dys Post-therpy: 1 1 dys 5 8 CAPSS-4 EDMS-USRA October 1997 My open-lbel study to evlute the bcteriologic nd clinicl efficcy nd sfety of LVFX in the tretment of CAP in dults LVFX: 1,7 G: 54% / 46% c R: 86% / % / % c A: 55 c (18 9) c LVFX: 5 mg q.d. LVFX: 1 14 dys Post-therpy: 7 dys Totl subjects with S. pneumonie isoltes From intention-to-tret (ITT) popultion. b Percentges my not dd up to 1% due to rounding or dt not vilble. c From cliniclly evluble popultion. Abbrevitions: No. = number, G = gender, R = rce, A = men ge, C = Cucsin, B = Blck, O = other, F = femle, M = mle, f/b = followed by, yr = yers, MDRSP = multidrug resistnt Streptococcus pneumonie, LVFX = levofloxcin, CEFT = ceftrixone, ERYTH = erythromycin, CLAR = clrithromycin, AMX/CL = moxicillin/clvulnic cid, CAP = community-cquired pneumoni, AZITH = zithromycin, IMIP/CIL = imipenem/cilsttin, CEFUR = cefuroxime xetil, UTI = urinry trct infection, q.d. = once dily, b.i.d. = twice dy, IV = intrvenous, IM = intrmusculr, PO = orl. Adpted from reference (5). fluoroquinolone-resistnt or mcrolide-resistnt bcteri in the orl microflor of helthy dults. A totl of 14 helthy dults without ntibcteril exposure during the previous 9 dys were rndomized to receive either levofloxcin 75 mg once dily for 5 dys or the mcrolide zithromycin 5 mg once dily on dy 1 nd 5 mg once dily on dys through 5 (16). The resistnce of streptococci in orophryngel cultures to levofloxcin nd zithromycin ws ssessed before, during, nd fter tretment. Levofloxcin tretment ws found to be ssocited with lower rte of microbil resistnce thn ws zithromycin (16). In the group exposed 4

5 Levofloxcin in pneumococcl pneumoni Tble. Bseline demogrphic chrcteristics of levofloxcin-treted subjects by Streptococcus pneumonie resistnce group from pooled pneumoni studies (microbiologiclly evluble popultion) Age (yers) <65, n (%) 65, n (%) Unknown Rnge Gender Mle, n (%) Femle, n (%) Rce White, n (%) Blck, n (%) Hispnic, n (%) Asin, n (%) Other, n (%) MDRSP (n = 54) 5 (66.) 19 (5.) (5.) 7 (51.) 41 (75.9) 8 (15.1) (.) (.8) (5.7) Non-MDRSP (n = 66) 4 (65.6) 14 (4.) (61.1) 14 (8.8) 59 (71.) 94 (5.7) 7 (1.9) (.8) (.5) One subject yielded S. pneumonie isoltes, 1 MDRSP nd 1 non-mdrsp nd is included in ech group. Abbrevition: MDRSP = multidrug-resistnt Streptococcus pneumonie. Adpted from reference (5). Tble. Distribution of levofloxcin MIC vlues (μg/ml) for Streptococcus pneumonie clssified by number of resistnt drug clsses (microbiologiclly evluble popultion) Number of resistnt drug clsses b (susceptible to ll clsses) b (susceptible nd/or intermedite) 1 b (resistnt to 1, susceptible to ll other clsses) 1 c (intermedite to 1 or more other clsses) c c 4 c Levofloxcin MIC (μg/ml) N < Number of drug clsses to which ll isoltes of Streptococcus pneumonie were resistnt t dmission. b Non-MDRSP: Susceptible or intermeditely resistnt to ll drug clsses for which susceptibility testing ws conducted t dmission or resistnt to 1 clss nd susceptible to ll others. c MDRSP: Includes subjects with Streptococcus pneumonie resistnt to t lest drug clsses or resistnt to 1 clss nd intermeditely resistnt to t lest 1 other drug clss t dmission. Abbrevition: MIC = minimum inhibitory concentrtion. Adpted from reference (5). to zithromycin, the proportion of subjects with mcrolide-resistnt streptococcl isoltes incresed t the end of the dosing period, nd resistnt isoltes still were observed throughout the 6-week post-tretment period. For subjects exposed to levofloxcin, smll number of levofloxcin-resistnt streptococci were observed t the end of the dosing period. However, by week post-tretment, the number of subjects with levofloxcinresistnt isoltes decresed, nd this decline continued throughout the 6-week evlution period (16). It is noteworthy tht this study lso demonstrted tht 69.4% of subjects hd 1 or more bcteri resistnt to zithromycin t study entry, nd it ws postulted tht this finding my reflect the current high rtes of mcrolide resistnce. Strtegies for treting CAP in n er of MDRSP The increse in ntimicrobil resistnce hs chnged empiric tretment strtegies for ptients with CAP. The 7 Infectious Disese Society of Americ/Americn Thorcic Society guidelines recommend use of mcrolide only in previously helthy ptients with no risk fctors for drug-resistnt S. pneumonie infection (eg, recent 4

6 Review Tble 4. Post-therpy clinicl success rtes nd microbiologic erdiction rtes of levofloxcin-treted subjects with MDRSP isoltes versus subjects with non-mdrsp isoltes from pooled pneumoni studies (microbiologiclly evluble popultion) Clinicl success MDRSP Non MDRSP c Difference in Success Filure Unknown Success Filure Unknown N/N (%) 5/54 (96.) /54 (.7) 47/65 Microbiologic erdiction b (95.1) success rtes (95% CI) 18/65 (4.9) 1.% ( ) MDRSP Non MDRSP Difference in Erdicted b Persisted Unknown Erdicted Persisted Unknown 5/54 (96.) /54 (.7) /54 () 5/66 (95.6) erdiction rtes (95% CI) 1/66 (.6) /66 (.8).7% ( ) Clinicl success includes the clinicl responses of cured nd improved (s defined in the individul studies from which this pooled smple ws obtined). b Includes erdicted if documented erdiction nd presumed erdicted bsed on clinicl success. c For clinicl outcome, 1 subject with both MDRSP nd non-mdrsp isoltes ws included in the MDRSP group only. Abbrevitions: MDRSP = multidrug-resistnt Streptococcus pneumonie, CI = confidence intervl. Adpted from reference (5). Tble 5. Clinicl nd microbiologic success rtes of levofloxcin-treted subjects with resistnt Streptococcus pneumonie by clss of resistnce (microbiologiclly evluble popultion) Antimicrobil clss MDRSP Non MDRSP PEN CSP MAC SUL TET Clinicl 15/16 (9.8) / (95.7) 6/7 (97.) /4 (91.7) 4/4 (1) Microbiologic 15/16 (9.8) / (95.7) 6/7 (97.) /4 (91.7) 4/4 (1) Clinicl / (1) 14/14 (1) 7/7 (1) /1 () Microbiologic / (1) 14/14 (1) 6/7 (85.7) /1 () Isoltes my hve been resistnt to more thn 1 ntimicrobil clss. Abbrevitions: MDRSP = multidrug-resistnt Streptococcus pneumonie, PEN = penicillins, CSP = second-genertion cephlosporins, MAC = mcrolides, SUL = sulfonmides, TET = tetrcyclines. Adpted from reference (5). use of ntimicrobils) nd in res where highlevel mcrolide resistnce is less thn 5%. With currently reported high-level resistnce rtes greter thn 5% in the United Sttes, ppliction of these guidelines should limit use of mcrolide monotherpy in the tretment of CAP. A respirtory fluoroquinolone (levofloxcin, moxifloxcin, gemifloxcin) or combintion therpy with β-lctm plus mcrolide is recommended in ptients t high risk for resistnt infection, such s those with serious comorbid disese or those who hve used ntimicrobils during the previous months (). The pooled nlysis of dt from 1 levofloxcin studies (5) found high rtes of clinicl nd microbiologic efficcy in subjects with pneumoni cused by S. pneumonie. The success rtes with levofloxcin tretment were similr in ptients with MDRSP or non-mdrsp infection. As the uthors of the nlysis note, the component studies in the nlysis reported clinicl success rtes 9%, suggesting tht levofloxcin remins effective for treting pneumococcl pneumoni. Nevertheless, the nlysis hs limittions, principlly becuse the dt were collected from studies tht differed in their design. In prticulr, hlf the studies were comprtive nd hlf were noncomprtive. However, the vlidity of the pooling of dt from these studies ws supported by test for homogeneity of the odds rtios (OR) for clinicl success in the comprtive versus noncomprtive studies, which found tht the difference ws not sttisticlly significnt (p =.7). The pooling of dt from severl studies 44

7 Levofloxcin in pneumococcl pneumoni with different designs ws strtegy tht permitted sufficient number of S. pneumonie isoltes to be nlyzed (5). Discussion A pooled nlysis of dt from 1 clinicl studies demonstrted the effectiveness of levofloxcin in treting pneumoni cused by S. pneumonie, including MDRSP strins. High clinicl cure rtes nd microbiologic erdiction rtes for MDRSP pthogens were observed. These rtes were similr to those observed in subjects with non-mdrsp pthogens, s would be expected bsed on current susceptibility ptterns of S. pneumonie to levofloxcin. Acknowledgments The studies used in this nlysis were funded nd conducted by Ortho-McNeil Inc. nd Johnson & Johnson Phrmceuticl Reserch & Development, LLC. The uthor cknowledges Aln Fisher, DrPh, for his nlyticl ssistnce nd insights regrding the originl pper nd numerous collegues, who over decde, plnned nd conducted the originl nlysis of S. pneumonie tht formed the bsis for the current nlysis. The uthor lso wishes to cknowledge writing nd editoril ssistnce from Ir Mills, PhD nd Crig Ornstein, PhD of Advogent. R E F E R E N C E S 1 Guthrie R. Community-cquired lower respirtory trct infections: etiology nd tretment. Chest 1; 1: 1 4. Mndell LA, Wunderink RG, Anzueto A, Brtlett JG, Cmpbell GD, Den NC, Dowell SF, File TM Jr., Musher DM, Niedermn MS, Torres A, Whitney CG. Infectious Diseses Society of Americ/Americn Thorcic Society consensus guidelines on the mngement of community-cquired pneumoni in dults. Clin Infect Dis 7; 44(Suppl ): S7 7. Ortho-McNeil Jnssen Phrmceuticls I. TRUST 1, 8. Dt on file. Ortho-McNeil Jnssen Phrmceuticls, Inc.; 8. 4 Vn Bmbeke F, Reinert RR, Appelbum PC, Tulkens PM, Peetermns WE. Multidrug-resistnt Streptococcus pneumonie infections: current nd future therpeutic options. Drugs 7; 67: Peterson J, Yektshens B, Fisher AC. Levofloxcin for the tretment of pneumoni cused by Streptococcus pneumonie including multidrug-resistnt strins: pooled nlysis. Curr Med Res Opin 9; 5: Dunbr LM, Wunderink RG, Hbib MP, Smith LG, Tennenberg AM, Khshb MM, Wiesinger BA, Xing JX, Zdeikis N, Khn JB. Highdose, short-course levofloxcin for community-cquired pneumoni: new tretment prdigm. Clin Infect Dis ; 7: File TM Jr, Segreti J, Dunbr L, Plyer R, Kohler R, Willims RR, Kojk C, Rubin A. A multicenter, rndomized study compring the efficcy nd sfety of intrvenous nd/or orl levofloxcin versus ceftrixone nd/or cefuroxime xetil in tretment of dults with community-cquired pneumoni. Antimicrob Agents Chemother 1997; 41: Fogrty C, Simi G, Kohler R, File TM Jr, Tennenberg AM, Olson WH, Wiesinger BA, Scott Mrshll J-A, Oross M, Khn JB. Multicenter, open-lbel, rndomized study to compre the sfety nd efficcy of levofloxcin versus ceftrixone sodium nd erythromycin followed by clrithromycin nd moxicillinclvulnte in the tretment of serious community-cquired pneumoni in dults. Clin Infect Dis 4; 8(Suppl 1): S16. 9 Fogrty CM, Sullivn JG, Chttmn MS, Willims RR, Kojk C, Rubin A. Once dy levofloxcin in the tretment of mild to moderte nd severe community-cquired pneumoni in dults. Infect Dis Clin Prct 1998; 7: Frnk E, Liu J, Kinsewitz G, Morn GJ, Oross MP, Olson WH, Reichl V, Freitg S, Bhl N, Wiesinger BA, Tennenberg A, Khn JB. A multicenter, open-lbel, rndomized comprison of levofloxcin nd zithromycin plus ceftrixone in hospitlized dults with moderte to severe community-cquired pneumoni. Clin Ther ; 4: Mzr R, Morgn N, Willims RR. A noncomprtive, multicenter study to evlute the sfety nd efficcy of levofloxcin 5 mg once dily in the tretment of community-cquired pneumoni in dults (Protocol LOFBIV-PCAP- 1). Rritn, NJ: RW Johnson Phrmceuticl Reserch Institute Clinicl Study Report; Report No.: Document No. EDMS- USRA Preston SL, Drusno GL, Bermn AL, Fowler CL, Chow AT, Dornseif B, Reichl V, Ntrjn J, Corrdo M. Phrmcodynmics of levofloxcin: new prdigm for erly clinicl trils. JAMA 1998; 79: West M, Boulnger BR, Fogrty C, Tennenberg A, Wiesinger B, Oross M, Wu SC, Fowler C, Morqn N, Khn JB. Levofloxcin compred with imipenem/cilsttin followed by ciprofloxcin in dult ptients with nosocomil pneumoni: multicenter, prospective, rndomized, open-lbel study. Clin Ther ; 5: von Gottberg A, Klugmn KP, Cohen C, Wolter N, de Gouvei L, du Plessis M, Mpembe R, Qun V, Whitelw A, Hoffmnn R, Govender N, Meiring S, Smith AM, Schrg S. Emergence of levofloxcin-nonsusceptible Streptococcus pneumonie nd tretment for multidrug-resistnt tuberculosis in children in South Afric: cohort observtionl surveillnce study. Lncet 8; 71: Felminghm D. Comprtive ntimicrobil susceptibility of respirtory trct pthogens. Chemotherpy 4; 5(Suppl 1): S Nord CE, Peterson J, Ambruzs M, Fisher AC. Levofloxcin versus zithromycin on the orophryngel crrige nd selection of ntibcteril-resistnt streptococci in the microflor of helthy dults. Curr Med Res Opin 9; 5: