Drug Profile

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Levofloxacin in the
treatment of community-
acquired pneumonia
Expert Rev. Anti Infect. Ther. 8(5), 505–514 (2010)

Ayman M Noreddin†1 Levofloxacin is a fluoroquinolone that has a broad spectrum of activity against several causative
and Walid F Elkhatib2,3 bacterial pathogens of community-acquired pneumonia (CAP). The efficacy and tolerability of
1
Department of Pharmacy Practice,
levofloxacin 500 mg once daily for 10 days in patients with CAP are well established. Furthermore,
School of Pharmacy, Hampton a high-dose (750 mg), short-course (5 days) of once-daily levofloxacin has been approved for
University, Hampton, VA 23668, USA use in the USA in the treatment of CAP, acute bacterial sinusitis, acute pyelonephritis and
2
Department of Pharmacy Practice and complicated urinary tract infections. Levofloxacin can be used as a monotherapy in patients
Pharmaceutical Sciences, College of
Pharmacy, University of Minnesota with CAP, however, levofloxacin combination therapy with anti-pseudomonal b-lactam (or
Duluth, 1110 Kirby Dr. Life Science aminoglycoside) should be considered if Pseudomonas aeruginosa is the causative pathogen of
232, Duluth, MN 55812, USA the respiratory infection. The high-dose, short-course levofloxacin regimen maximizes its
3
Department of Microbiology and concentration-dependent antibacterial activity, decreases the potential for drug resistance and
Immunology, Faculty of Pharmacy,
Ain-Shams University, African Union has better patient compliance. Oral levofloxacin is rapidly absorbed and is bioequivalent to the
Organization, Abbassia, Cairo intravenous formulation and the patients can switch between these formulations, which results
P.O.B.: 11566, Egypt in more options with respect to the therapeutic regimens. Furthermore, levofloxacin is generally
†
Author for correspondence: well tolerated, has good tissue penetration and adequate concentrations can be maintained at
Tel.: +1 757 728 6690
Fax: +1 757 727 5840 the site of infections.
[email protected]
Keywords : community-acquired pneumonia • fluoroquinolones • levofloxacin • pharmacodynamics
• pharmacokinetics • therapeutic use • tolerability

Community-acquired pneumonia (CAP) is one Epidemiologic studies have revealed that

of the leading causes of morbidity and mortality pathogenic organisms were not isolated or
in adult populations [1–4] . The severity and inci- identified in over 50% of patients exhibiting
dence of CAP are significant, especially in the clinical signs and symptoms of CAP. Therefore,
elderly and immunocompromised patients [5–7] . antibiotic treatment of CAP is usually empiri-
CAP affects 6 million people in the USA annu- cally determined for both hospitalized and
ally [8] . Approximately 20% (1.1–1.3 million) of outpatient settings [9,23,25] . The guidelines from
these patients are hospitalized [9] with an esti- the Infectious Diseases Society of America/
mated cost of approximately US$25,000 per American Thoracic Society recommend a res-
hospitalization [10] or over US$30 billion annual piratory f luoroquinolone (e.g., levof loxacin
cost in the USA alone, and 12% of hospital- 750 mg, moxifloxacin or gemifloxicin) or a
ized patients die [9] . In patients with severe CAP b-lactam in combination with a macrolide for
requiring admission to the intensive care unit the treatment of CAP. The use of fluoroquino­
(ICU), mortality increases to up to 30% [11–14] . lones is considered to be the primary treatment
The most common cause of CAP is Streptococcus in infections caused by penicil­lin-susceptible
pneumoniae [15–18] . Other bacterial causes include S. pneumoniae, penicillin-resis­tant S. pneumo­
Haemophilus influenzae, Moraxella catarrhalis, niae, Legionella, H. influenzae, M. pneumoniae
Klebsiella pneumoniae, and the ‘atypical’ CAP and C. pneumoniae. Levofloxacin combina-
pathogens that include Chlamydia pneumoniae, tion therapy with anti-pseudomonal b-lac­tam
Mycoplasma pneumoniae and Legionella pneumo­ (or aminoglycoside) should be considered if
phila [2,17,19–22] . Staphylococcus aureus and Gram- Pseudomonas aeruginosa is the causative patho-
negative bacilli have been isolated from patients gen of the respiratory infection [24] . Resistance
with severe CAP who generally require admission to antibacterial drugs in S.  pneumoniae has
to the ICU for management [13,23–25] . become a major problem in the USA and

www.expert-reviews.com 10.1586/ERI.10.35 © 2010 Expert Reviews Ltd ISSN 1478-7210 505

 Drug Profile Noreddin & Elkhatib

worldwide for more than a decade [26] . Furthermore, increasing Pharmacodynamic properties
rates of antibiotic resistance (most notably, penicillin, cepha- Spectrum of activity
losporin and macrolide resistance) observed in bacteria that Levofloxacin is the l-isomer of the racemic fluoroquinolone
commonly cause CAP have resulted in increased treatment ofloxacin [39,41] . Topoisomerase IV is the main target for levo-
failures and inferior clinical outcomes for many patients with floxacin in Gram-positive bacteria and DNA gyrase (topoisomer-
CAP [14,15,27–30] . Although there are reports of the emergence of ase II) is the target for Gram-negative bacteria [42] . Levofloxacin
resistance to some fluoroquinolones among S. pneumoniae [26] , has a broad spectrum of antibacterial activity that involves several
the incidence of levofloxacin-resistant organisms has remained Gram-positive and Gram-negative aerobes and atypical bacteria.
steady with levofloxacin resistance rates in S. pneumoniae of The MIC of levofloxacin required to inhibit the growth of 90%
approximately less than 1% worldwide [31–35] . of clinical isolates (MIC90) is used to assess the in vitro activity of
The chemical name of levofloxacin is S-9-fluoro-2,3-dihydro- levofloxacin. The levofloxacin MIC breakpoints for S. pneumoniae
3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1, 2, tested were obtained from the Clinical and Laboratory Standards
3-de]-1, 4-benzoxazine-6-carboxylic acid hemihydrate with the Institute and they were 2 mg/l or less (susceptible), 4 mg/l (inter-
empirical formula C18H20FN3O4 ·½ H2O (Figure 1) . Levofloxacin mediate) and 8 mg/l or more (resistant) [41,43] . It generally also has
is a light yellowish-white crystal or crystalline powder and its high in vitro activity against S. pneumoniae (including penicillin-
molecular weight is 370.38. It interferes with critical processes susceptible, -intermediate and -resistant strains), which are com-
in the bacterial cell, such as DNA replication, transcription, monly causative in CAP. However, the activity of levofloxacin
repair and recombination, by inhibiting type II topoisomerases. is variable against S. aureus and Enterococcus faecalis [41] . The
Human cells lack these topoisomerases, but they are essential for levofloxacin MIC90 for penicillin-susceptible, -intermediate and
bacterial DNA replication, thereby allowing these agents to be -resistant isolates of S. pneumoniae was 1 mg/l in different studies
specific for bacterial cells. DNA topoisomerases are responsible and greater than 97% of the tested isolates were susceptible to the
for separating the strands of duplex bacterial DNA, inserting drug [31–34,38,44] . Furthermore, levofloxacin generally appears to
another strand of DNA through the break, and then resealing the retain its activity against strains of S. pneumoniae that are resistant
originally separated strands [36,37] . Levofloxacin is active against to penicillin plus macrolides [32] .
a broad range of Gram-positive, Gram-negative and atypical Levofloxacin has variable activity against S. aureus. Depending
bacteria that may be causative pathogens in community-acquired on methicillin susceptibility, levofloxacin had MIC90 values of
and nosocomial infections. Levofloxacin is a well-established 0.25–4.0 mg/l against methicillin-susceptible S. aureus (MSSA)
treatment option for respiratory and urinary tract infections isolates, whereas methicillin-resistant S. aureus isolates exhibited
(UTIs), particularly since levofloxacin is active against some levofloxacin resistance with MIC90 values of greater than 4 to
penicillin- and macrolide-resistant species, such as S. pneumoniae 64 mg/l or more [38,44–46] . The in vitro activity of levofloxacin
(the most common causative pathogen for community-acquired against E. faecalis was limited (MIC90 of 8 to 32 mg/l or more in
respiratory infections) [31–34,38,39] , and the incidence of penicil- vancomycin-susceptible and -resistant strains). Although levo-
lin- and macrolide-resistance in many species is both high and floxacin has limited activity against coagulase-negative staphy-
widespread [40] . In the USA, a high-dose, short-course regimen lococci (>4 mg/l; 54.1%) [45] , it has demonstrated good in vitro
of levofloxacin (750 mg once daily for 5 days) is approved for the activity against a range of other Gram-positive bacteria, such as
treatment of adults with CAP, acute bacterial sinusitis (ABS), Streptococcus pyogenes (1 mg/l; 99.9%) [32,33] and b-hemolytic
complicated UTI and acute pyelonephritis (AP). The use of levo- streptococci (0.5–1 mg/l; 99.1–100%) [47] .
floxacin, including some data on the high-dose, short-course Generally, levofloxacin has good in  vitro activity against
treatment regimen, has been reviewed previously [39] . This review Gram-negative bacteria including the common respiratory tract
focuses on the pharmacology of levofloxacin in the treatment pathogens H. influenzae [31–35,38,44,48–50] , H. parainfluenzae [50]
of CAP. and M. catarrhalis [31,35,44,48–50] , as well as different urinary
tract pathogens (K. pneumoniae [38,44,51] , Enterobacter cloacae
O [38,44,51–53] and Proteus mirabilis [38,45,48]). The MIC90 values for
levofloxacin against isolates of H. influenzae, H. parainfluenzae
F COOH and M. catarrhalis were 0.06 mg/l or less and it had approximately
100% susceptibility rates. Levofloxacin was also highly active
• ½H2O against b-lactamase-negative and -positive isolates of H. influ­
N N enzae [31–34,38] and M. catarrhalis [31,44,48–50,54,55] . On the other
hand, the activity of levofloxacin is variable against the urinary
N O CH3 tract pathogen Escher­ichia coli and P. aeruginosa. The MIC90 of
H3C
levofloxacin against E. coli ranged from 0.06 mg/l or less (suscep-
H tible) to greater than 8 mg/l (resistant) [38,44,45,51,56] . Levofloxacin
showed a lower level of activity against isolates of P. aeruginosa,
with MIC90 values ranging from 0.5 to 64 mg/l and the suscepti-
Figure 1. Levofloxacin.
bility rates were 71–94% [38,44,45,48,51] . It also had limited activity

506 Expert Rev. Anti Infect. Ther. 8(5), (2010)

 Levofloxacin in the treatment of community-acquired pneumonia Drug Profile

against extended-spectrum b-lactamase-producing K. pneumo­ aforementioned report appeared to be related to an AUC:MIC

niae (MIC90 : >8–32 mg/l) [45] . Levofloxacin has good activity ratio of 256 or less; this indicates that to prevent levofloxacin
against the atypi­cal organisms Chlamydophila pneumoniae [57–60] , resistance from being acquired in isolates with a first-step parC
L. pneumophila [38,44,48,57,61,62] and M. pneumoniae [48,57,63–65] with mutation, the AUC:MIC ratio target should be 250 or more [71] .
MIC90 values of 2 mg/l or less. When the range of free AUCs (fAUCs) of levofloxacin and other
fluoroquinolones were simulated, the results demonstrated that
Bactericidal activity fAUC:MIC ratios of 82 or less and 86 or less for levofloxacin
The bactericidal activity of levofloxacin is concentration depend- were associated with a first-step parC mutation and second-step
ent [66] , and the minimum bacterici­dal concentration (MBC) of gyrA mutation in S. pneumoniae and these resistance breakpoints
levofloxacin was less than or equal to four-times the MIC against for levofloxacin were signifi­cantly higher (p ≤ 0.001) than those
the majority of isolates for a num­ber of causative pathogens of res- for other tested fluoroquinolones (gatiflox­acin, gemifloxacin and
piratory tract infec­tions [59,60,64,65,67] . The MBC90 of levofloxacin moxifloxacin) using post hoc ana­lysis. Furthermore, the higher
was one- to four-times the MIC against the majority of M. pneu­ the fAUC:MIC ratio for each fluoroquino­lone, the greater the
moniae isolates (MBC: ≤0.5–1.0 mg/l) as reported by different delay in the development of first- or second-step mutations [72] .
authors [59,60,63–65,67] . The MBC of levofloxacin was one-to-two In the SENTRY (worldwide, 1997–2004) [47] , PROTEKT
times the MIC (≤0.06–4 mg/l) against K. pneumoniae, P. aerugi­ (USA and Canada, 1999–2002) [32–34] and TRUST (USA,
nosa, E. coli and E. cloacae [51] . Levofloxacin has a post-antibiotic 1998–2002) [35] surveillance programs, the overall levofloxacin-
effect (PAE) of 2.0–4.5 h depending on the pathogen [39] . The resistance rate in S. pneumoniae isolates was 1% or less; in peni-
PAE of levofloxacin against S. pneumoniae was up to 4.5 h at cillin-resistant isolates, the overall rate of levoflox­acin resistance
10-times the MIC. Furthermore, levofloxacin has shown PAEs was 0.9–2.7% [31,34,35] . In the TRUST surveillance program from
against MSSA, K. pneumoniae, L. pneu­mophila and anaerobes [39] , 2001 to 2005, the rate of S. pneumoniae resistance to levofloxacin
as well as against erythromycin-resistant and -susceptible strains increased from 0.0 to 0.5%. On the other hand, the resistance
of L. pneumophila [61] . of these isolates to penicillin, amoxicillin/clavulanic acid and
clindamycin increased from 27.4 to 28.9%, 6.5 to 12.9% and
Resistance 12.1 to 18.6%, respectively [73] . A levofloxacin 750 mg dose was
Resistance to antibacterial drugs in S. pneumoniae has been a compared with imipenem–cilastatin in the treatment of noso-
major problem in the USA for more than a decade [26] . The pri- comial pneumonia. The average age of the patients was 55 years
mary cause of reduced susceptibility of bacteria (particularly and 438 patients were randomized. A total of 42% of patients in
S. pneumoniae) to fluoro­quinolones is at least one mutation in the levofloxacin arm were 65 years of age or older. The clinical
the parC and parE genes that code for DNA topoisomerase IV success rate in the intention-to-treat population was 66.2% in
and/or gyrA and gyrB genes that code for DNA gyrase [68,69] . the levofloxacin arm versus 69.4% in the imipenem arm. In the
Another fluoroquinolone resistance mechanism involves active clinically evaluable population, the success rates were 59.3 and
drug efflux through mutation in the efflux regulatory genes mexR 62.5% for levofloxacin and imipenem, respectively [74] . Other
and nfxB [68,70] . data from 1998 and 2005 revealed that the levofloxacin-resistant
Nevertheless, although there are reports of the emergence of isolates of H. influenzae or M. catarrhalis could not be identified in
fluoroquinolone resistance among S. pneumoniae, [26] the inci- large worldwide surveillance studies [32–34,49,54,55] . However, sur-
dence of levofloxacin-resistant organisms has remained stable to veillance studies have demonstrated resistance to levofloxacin in
date, with the level of levofloxacin resis­tance in S. pneumoniae methicillin-susceptible and -resistant strains of S. aureus (MSSA:
remaining 1% or less worldwide [31–35] . 3.4–10.1% and methicillin-resistant S. aureus: 76.6–79.2%) and
In the worldwide PROTEKT surveillance pro­gram between P. aeruginosa (24.7%) [45,46,56] .
1999 and 2000, levofloxacin-resistant isolates of S. pneumoniae
were identified and 94% of these isolates had a muta­tion in one Pharmacokinetics & metabolism
each of the genes coding for topoisomer­ase IV and DNA gyrase Levofloxacin is rapidly absorbed after oral administration and
[69] . On the other hand, in the SENTRY surveillance program shows linear pharmaco­k inetics over the single- and multiple-dose
(1997–2004), fluoroquinolone-resistant isolates of b-hemolytic (once daily) range for approved regimens. The oral solution and
Streptococcus spp. demonstrated significant mutations in the parC tablet formulations are bioequivalent to the intravenous formu-
and/or gyrA gene and a mutation in parC was the only one iden- lation [41] . The mean pharmacokinetic parameters obtained in
tified in the strains with lower MIC values [47] . A report of an different studies of intravenous and oral levofloxacin in healthy
in vitro pharmacodynamic model simulating the concentration adults [75,76] are comparable to those reported in the manufac-
of levofloxacin in the epithelial lining fluid (ELF) after once-daily turer’s US prescribing infor­mation [41] . The peak plasma con-
administration of 500 mg revealed that all five isolates of S. pneu­ centration (Cmax) after single 750 mg doses of levofloxacin given
moniae contain­ing the first-step parC mutation had levoflox­acin to healthy volunteers was 11.3 [75] and 12.1 mg/l for intravenous
resistance within 48 h (≥16-fold increase in MIC) and four of administration, and 7.1 [76] and 9.3 mg/l [41] for oral administra-
the isolates acquired a second-step mutation (gyrA mutations in tion. On the other hand, levofloxacin multiple doses had Cmax
these cases) [71] . The acquisition of a second-step mutation in the values of 12.1 and 12.4 mg/l for intravenous administration and

www.expert-reviews.com 507
 Drug Profile Noreddin & Elkhatib

8.6 mg/l for oral administration [41,76] , and levofloxacin steady- in patients with impaired renal function (creati­nine clearance
state conditions were reached within 48 h of initiating once-daily [CLCR] 50 ml/min), therefore dosage adjustment is required to
intravenous or oral 750 mg doses [41] . After oral administration, avoid drug accumulation as shown in Table 1 [41] . Furthermore,
the Tmax of levofloxacin is reached within 1–2 h, and the absolute levofloxacin is not cleared effec­tively by hemodialysis or con-
bioavailability of oral levofloxacin 500 and 750 mg is approximately tinuous ambulatory peritoneal dialysis [39,41] . The pharmacoki-
99% [41,75,76] . Systemic exposure to levofloxacin was similar for the netic properties of levofloxacin are not influenced by age, gender
intravenous and oral formulations upon administering equal doses or race, and they do not show noticeable differences between
of levofloxacin [41] and the AUC24 was 103  [75] and 90.7 mg/h/l healthy adults and patients with HIV [39] , or patients with seri-
[76] at steady state after intravenous or oral adminis­t ration of ous community-acquired bacterial infections [41] . Levofloxacin
­levofloxacin 750 mg once daily, respectively. pharmacokinetics in hepati­cally impaired patients have not been
The in vitro studies revealed that 24–38% of levofloxacin was investigated; however, because of the limited hepatic metabolism
bound to plasma proteins (mainly to serum albumin in humans) of levofloxacin, hepatic impairment may not have a prominent
and the binding was independent of levofloxacin concentration effect on the drug pharmacokinetics [41] .
[41] . The volumes of distribution ob­tained in the pharmacokinetic
studies are within the range of 74–112 l after single or multiple Clinical efficacy
doses of levofloxacin 500 or 750 mg [75,76] . Levoflox­acin is dis- The efficacy of levoflox­acin 750 mg once daily (intravenous and
tributed extensively in tissues and fluids throughout the body oral) for 5 days in adults with CAP [66] , ABS [85] and compli­
and accumulates in phago­c ytic cells [39] . Furthermore, the mean cated UTI [86,87] has been assessed in a number of randomized,
concentrations of levofloxacin in tis­sues and fluids in the lungs, double-blind, multicentre, noninferi­ority trials [66,85–87] . The end
ELF, alveolar macrophages, polymorphonuclear leukocytes, points were the clinical success rate (proportion of patients show-
paranasal sinus muco­sa and urine surpass the concentration of ing either a clinical cure or improvement with no need for further
levofloxacin in the plas­ma [39,77–83] . It has been reported that the antimicrobial therapies in both situations) 1–2 weeks after the end
paranasal sinuses mucosa:plasma concentration ratio was 2.56 of treatment [66] or at 2–3 weeks of the study [85] , or the micro-
at Tmax after a single 500 mg oral dose of levofloxacin and the biological eradication rate (all patho­gens identified in samples at
concentration of levofloxacin in the paranasal sinuses mucosa the study entry were eradi­cated) at 2–3 weeks of the study [86,87] .
was generally higher than the MIC90 of the common causa­tive Levofloxacin indications and dosing for patients with normal
pathogens for upper respiratory tract infec­tions (0.008–2.0 mg/l), renal function are summarized in Table 2 .
including penicillin-suscepti­ble, -intermediate and -resistant iso- Patients enrolled in the noninferi­ority trial in CAP were aged
lates of S. pneumoniae [82] . In healthy volunteers, oral levofloxacin 18 years or over and were diagnosed with mild-to-severe CAP.
(500 or 750 mg) had a mean ELF:plasma concentration ratio at Other inclusion criteria involved one or more signs or symp-
steady state of 1.16 using popu­lation pharmacokinetic modeling toms including fever, a white blood cell count of greater than
and 3.18 using Monte Carlo simulation [82] . With a lower dosage 10,000 cells/mm3, or hypothermia. The exclusion criteria involved
of levofloxacin (500 mg once daily for 3 days), Cmax and AUC24 patients without a confirmed diagnosis of CAP, patients who had
values for the drug were significantly higher (p < 0.01) in the no follow-up visit, patients who increased (>120%) or reduced
polymorphonuclear leukocytes than in plasma [84] . On the other
hand, the concentrations of levofloxacin in the ELFs and alveolar Table 1. Dosing in patients with diminished
macrophages were 1.5–6-fold higher than that in the plasma at renal function.
steady state after receiv­ing levofloxacin 500 mg once daily for
5 days in older patients undergoing diagnostic bron­choscopy with Renal status Initial dose (mg) Subsequent
dose
a mean age of 62 years [80] .
Levofloxacin is mainly eliminated through the kid­neys, with CLCR ≥50 ml/min 500  500 mg q24h
75–87% of the dose excreted unchanged in the urine within CLCR 20–49 ml/min 500  250 mg q24h
48–72  h of administering oral levofloxacin 500 or 750  mg,
CLCR 10–19 ml/min 500  250 mg q48h
and less than 4% is excreted in the feces [41,75,76] . After a sin-
gle dose of levofloxacin 750 mg, the mean drug concentration Hemodialysis 500  250 mg q48h
in the urine was 475  mg/l at 4  h and 186  mg/l at 24  h [77] , CAPD 500  250 mg q48h
and less than 5% of the dose is excreted in the urine as inactive
CLCR ≥50 ml/min 750  750 mg q24h
metabolites of levofloxacin [41] . The mean total body clearance
(CL) of levofloxacin in healthy volunteers was 8–9.4 l/h [75,76] CLCR 20–49 ml/min 750  750 mg q48h
and approximately 8.6–13.6 l/h [41] . Levofloxacin also appears CLCR 10–19 ml/min 750  500 mg q48h
to undergo glomerular filtration as well as tubular secretion [41] .
Hemodialysis 750  500 mg q48h
After single or multiple doses of oral or intravenous levofloxacin
750 mg, the mean terminal plasma elimination half-life (t1/2b) CAPD 750  500 mg q48h
is 7.5–8.8 h in the pharmacokinetic studies [75,76] . On the other CAPD: Chronic ambulatory peritoneal dialysis; CLCR : Creatinine clearance;
q24h: Every 24 h; q48h: Every 48 h.
hand, the t1/2b of levofloxacin is increased and the CL reduced

508 Expert Rev. Anti Infect. Ther. 8(5), (2010)

 Levofloxacin in the treatment of community-acquired pneumonia Drug Profile

(<80%) the scheduled doses, and patients who had combination versus 85.7% and 100 versus 90%, respectively [66] . Retrospective
therapy with levofloxacin [66] . Patients with mild-to-severe CAP
ana­lysis revealed that the clinical success rates in the patients with
received levofloxacin 750 mg (intravenous or oral) once daily for
CAP caused by the typical pathogens H. influenzae, H. parainflu­
5 days or 500 mg once daily for 10 days and those receiving the enzae or S. pneumoniae were also similar between the levofloxacin
higher dosage of levofloxacin were given a placebo for the last 750 and 500 mg treat­ment groups (92.3 vs 92.9%, 100 vs 90%
5 days of the 10-day treatment regimen [66] . Susceptibility test-
and 90.9 vs 90%, respectively) [66] .
ing of the causative pathogens to levofloxacin was carried out but The efficacy of the high-dose, short-course of levofloxacin in
initial treatment was empirical. The noninferiority of levofloxacin
achieving early resolution of symp­toms has been studied [90] ,
750 mg once daily for 5 days to levofloxacin 500 mg once daily and the results revealed that the resolution of purulent sputum,
for 10 days was established if the upper limit of the two-sided shortness of breath, chills and cough were 40.6 versus 30.7%,
95% confidence interval for the between-group difference in the 35.1 versus 27.7%, 54.8 versus 54.2% and 10 versus 10.1% of
clinical success rate was less than 15% (if both treatment groups
patients who received the levoflox­acin 750 or 500 mg regimen,
had a clinical success rate of 80–90%) or less than 10% (if bothrespectively. Furthermore, 99.4% of the 158 pathogens isolated
treatment groups had a clinical success rate of ≥90%) [66] . Theat study entry were susceptible to levofloxacin and there was no
results revealed that levofloxacin 750 mg once daily for 5 days significant difference between treatment groups in the time of
was at least as effective as 500 mg once daily for 10 days in the
switching from the intravenous administration of levofloxacin
treatment of mild-to-severe CAP in the over­all patient population
to the oral administration of the drug [90] . The high-dose, short-
[66] , as well as in patients with CAP caused by atypical organ-course of levofloxacin (750 mg once daily for 5 days) also had
isms (C. pneumoniae and/or M. pneumoniae) [88] , and for elderlygood efficacy in the subgroup of patients with severe CAP with
patients aged 65 years or older [89] . high clinical success rates of more than 85%. Moreover, high
In patients receiving either the levofloxacin 750 or 500 mg regi-
microbiological response rates (≥87.5%) were observed in the
men, the baseline characteristics were similar overall microbi­o­
subgroup of microbiolog­ically evaluable patients receiving lev-
logical eradication rates in both groups receiving levofloxacin [66] .
ofloxacin regardless of the treatment regimen [91] . In the same
The eradication rates were high in subgroups of microbiologically
study, the microbiological eradication was observed in 88.2% of
evaluable patients infected with aerobic Gram-positive (82.8 vs typical pathogens identified from respira­tory cultures and 90% of
85.3%) and Gram-negative (96.2 vs 90.7%) pathogens, as well atypical pathogens identified by serological methods [91] .
as other pathogens (93.8 vs 96.2%), when patients received levo- It has been reported that levofloxacin 750 mg once daily for
floxacin 750 mg once daily for 5 days or levofloxacin 500 mg 5 days had good efficacy in patients with CAP caused by atypical
once daily for 10 days. Similar results were obtained with atypi­
organisms [88] . The overall clinical success rate 1–2 weeks after
cal patho­gens and typical pathogens, where eradication rates treating patients with CAP caused by only one atypical path­
for S. pneumoniae, H. influenzae and H. parainfluenzae in the ogen with levofloxacin was more than 95% and the noninferiority
­corresponding post-therapy visit were 86.4 versus 85%, 92.3 of levofloxacin 750 mg once daily for 5 days as compared with
the 10‑day regimen was also established in
Table 2. Levofloxacin indications and dosing for patients with normal this study. The overall clinical success rate
renal function†. was 94.8% for patients with CAP caused
Type of infection Dose (mg) Duration (days) by atypical pathogens receiving the levo-
floxacin 750 mg regimen as compared with
Community-acquired pneumonia 500 7–14 
96.5% for those receiving the levofloxacin
Community-acquired pneumonia 750  5  500  mg regimen [88] . Furthermore, the
Nosocomial pneumonia 750  7–14  clinical success rates at 1–2 weeks post-
treatment for patients with C. pneumoniae,
Acute bacterial exacerbation of chronic bronchitis 500  7–14
L. pneumophila and M. pneumoniae were
Acute bacterial sinusitis 500 10–14 comparable between the groups receiving
Acute bacterial sinusitis 750  5 the levofloxacin 750 and 500 mg dosing
regimen (90.9 vs 100%, 100 vs 100% and
Complicated skin and skin-structure infection 750  7–14 
95.3 vs 94.4%, respectively) [88] .
Uncomplicated skin and skin-structure infection 500  7–10 
Chronic bacterial prostatitis 500  28  Post-marketing surveillance
Acute pyelonephritis 250  10 
Post-marketing data have demonstrated
that simultaneous levofloxacin admin-
Complicated urinary tract infection 250  10  istration with warfarin may increase the
Uncomplicated urinary tract infection 250  3  prothrombin time. Therefore, anticoagu-
Inhalation anthrax (postexposure) 500 60  lation and bleeding should be monitored
in pa­tients receiving the two drugs con-
†
Frequency of dose: every 24 h.
comitantly [41] . Owing to the incidence of

www.expert-reviews.com 509
 Drug Profile Noreddin & Elkhatib

musculo­skeletal disorders, levofloxacin should not be adminis- Levofloxacin 750 mg once daily for 5 days is a well tolerated
tered to pediatric patients aged less than 18 years [41] . Like other fluoroquinolone for patients with CAP or UTIs [86,87,92] . In a
fluoroquinolones, levofloxacin decreases theophylline metabo- pooled ana­lysis of patients with respiratory infections receiving
lism and dosage adjustment for theophylline may be essential for the levofloxacin 750 or 500 mg regimen, the results revealed that
concurrent administration of both drugs. On the other hand, 45.5 and 49% of patients, respectively, had adverse effects during
concomitant fluoroquinolone admin­istration with ciclosporin has the therapy. The adverse effects in both dosage regi­mens included
shown elevated serum concentrations of ciclosporin but these nausea, vomiting, diarrhea, dys­pepsia, constipation, abdomi-
alterations were not clinically signif­icant [41] . nal pain, headache, insom­nia and dizziness. The incidence of
levofloxacin-associated adverse effects was similar between both
Safety & tolerability ­treat­ment regimens (8 vs 7.6%) [92] .
Levofloxacin 750 mg once daily (intravenous and/or oral) for Photosensitivity reactions might be associated with the use
5 days is currently approved for the treat­ment of different infec- of fluoroquino­lones after exposure to the sun or UV light [41] .
tions including CAP (caused by S. pneumoniae, H. influenzae, Fluoroquinolones can potentially prolong the QT interval but
H. parainfluenzae, M. pneumoniae and C. pneumoniae), ABS there were no cases of torsade de pointes in any clinical or post-
(caused by S. pneumoniae, H. influenzae and M. catarrhalis), marketing trials [41,92] . As with most other antibacterial agents,
complicated UTI (caused by E. coli, K. pneumoniae and Proteus levofloxacin was associated in some cases with C. difficile-related
mirabilis) and AP (caused by E. coli) in patients with normal diarrhea, which varied in severity from mild diarrhea to pseudo­
renal function (CLCR : ≥50 ml/min) [41] . Depending on the membranous colitis [41] . Patients receiving levofloxacin and other
dose, intravenous levofloxacin must be administered slowly as quinolones may undergo tendon effects, including ruptures of
an infusion over a minimum period of 60–90 min. Levoflox­ the hand, Achilles tendon and shoulder [41] . The incidence of
acin tablets or oral solution are generally prescribed at a dosage drug-related adverse effects in patients with CAP or ABS was
of 250, 500 or 750 mg once daily and the tablet formulation of also similar between the levofloxacin 750 and 500 mg dosing
levofloxacin can be taken with or without food; however, the regimens [92] .
oral solution should be taken 1 h prior to or 2 h after meals.
In pa­tients receiving levofloxacin, sufficient hydration should Regulatory affairs
be maintained to prevent highly concentrated urine from being Levofloxacin is approved for use in the USA, Canada and world-
formed. Levofloxacin should be administered at least 2 h apart wide in the treatment of CAP, ABS, complicated UTIs and AP.
from agents such as magnesi­um- or aluminium-containing ant- Surveillance programs undertaken in the USA, Canada and
acids, sucralfate, metal cations, zinc-containing multivitamins worldwide reveal that the rates of S. pneumoniae resistance to
or didanosine. Levofloxacin dosing of 750 mg once daily for levofloxacin was 1% or less. On the other hand, the rate of resist-
5 days in patients with impaired renal function requires the fol- ance to levofloxacin was 2.7% or less in penicillin-resistant iso-
lowing dosage adjustments: CLCR : 20–49 ml/min, 750 mg every lates of S. pneumoniae. Some reports have shown that the rate of
48 h; CLCR: 10–19 ml/min or patients on hemodialysis or chronic levofloxacin resistance in S. pneumoniae in the USA has decreased
ambulatory peritoneal dialysis, 750 mg initial dose then 500 mg between 2000 and 2006 [31,33,35,38,49] .
every 48 h. Owing to the limited metabolism of levofloxacin,
dosage ad­justment is expected to be unnecessary in patients with Conclusion
reduced hepatic function [41] . The respiratory fluoroquinolones are considered as a substantial
Data from patients aged 65 years or over (Phase III clinical component of the anti-infective armamentarium for the man-
trials) demonstrated no differ­ence between elderly and younger agement of respiratory infections. Levofloxacin is active against
patients with re­gard to the safety or effectiveness of levofloxacin, most respiratory pathogens and has a good clinical success rate.
although elderly patients may be more sensitive to levofloxacin, The favorable pharmacodynamic, safety, efficacy and tolerability
mainly due to the effect of the drug on the QT interval. Thus, profile, in addition to in vitro activity against the common respira-
caution is required with the simultaneous administration of levo- tory pathogens, make levofloxacin among the first-line agents for
floxacin with drugs that prolong the QT interval such as class IA the treatment of CAP.
or class III antiarrhythmics in this particular group. Furthermore,
caution is necessary with the use of levofloxacin in the elderly Expert commentary
due to the increased risk of severe tendon disorders in this group The guidelines from the Infectious Diseases Society of America/
of patients, particularly if they are receiving corticosteroids [41] . Ameri­c an Thoracic Society recommend a respira­tory fluo-
Blood glucose monitoring is recommended in patients with roquinolone (e.g., levofloxacin 750 mg) or a b-lactam plus a
diabetes mellitus receiving simultaneous hypoglycemic agents macrolide for the treatment of CAP. The use of fluoroquino­
and/or insulin because symptomatic hyperglycemia and hypogly- lones is considered to be the primary therapy in the infections
cemia have been reported with levofloxacin administration [41] . caused by penicil­lin-susceptible S. pneumoniae, penicillin-resis­
Concomitant administration of fluoroquinolones (including levo- tant S. pneumoniae, Legionella, H. influenzae, M. pneumoniae
floxacin) with NSAID may increase the risk of CNS stimulation and C.  pneumoniae. Levofloxacin combination therapy with
and convulsive seizures [41] . anti-pseudomonal b-lac­t am (or aminoglycoside) should be

510 Expert Rev. Anti Infect. Ther. 8(5), (2010)

 Levofloxacin in the treatment of community-acquired pneumonia Drug Profile

considered if P. aeruginosa is the causative pathogen of the respi- Five-year view

ratory infection. Resistance to antibacterial drugs in S. pneumo­ In the last 5 years, the rate of resistance of S. pneumoniae to amoxi-
niae has become a major problem in the USA and worldwide for cillin/clavulanic acid, azithro­mycin and tetracycline appears to
more than a decade. Although there are reports of the emergence have amplified but the levofloxacin resistance rate of S. pneumoniae
of resistance to some fluoroquinolones among S. pneumoniae, remains 1% or less worldwide [93] . High-dose, short-term therapy
the incidence of levofloxacin-resistant organisms has remained (levofloxacin 750 mg once daily for 5 days) will globally be the stand-
steady, with levofloxacin resistance rates in S. pneumoniae of ard dosing regimen for levofloxacin in the treatment of CAP. Due to
approximately less than 1% worldwide. In general, levofloxacin increased availability of pneumococcal vaccination programs, it is
shows good in vitro activity against clinically-relevant Gram- expected that the incidence and severity of pneumococcal infections
positive, Gram-negative and atypical organisms. Levofloxacin will be on the decline. Other problematic infections with resistant
is active against the Gram-positive penicillin-susceptible and bacteria will be the main focus of research in the next 5 years.
-resistant strains of S. pneumoniae, the Gram-negative species
E. cloacae and P. mirabilis, and the atypical organisms C. pneu­ Information resources
moniae, L. pneumophila and M. pneumoniae, with MIC90 val- Medical literature published in any language since 1980 on levo-
ues of 2 mg/l or less. Levofloxacin is highly active against the floxacin was identified using PubMed, MEDLINE and Embase.
Gram-negative species H. influenzae, H.  parainfluenzae and Additional references were identified from the reference lists of
M. catarrhalis (MIC90 : ≤0.06 mg/l), including b-lactamase-posi- published articles. Bibliographical information, including contrib-
tive strains of H. influenzae and M. catarrhalis. As the activity of utory unpublished data, was also obtained from Ortho-McNeil
levofloxacin is concentration dependent, the most common pre- Janssen Scientific Affairs, LLC (NJ, USA).
dictor of microbiological and clinical efficacy is the AUC:MIC
ratio. A ratio of greater than 30 was used in some studies to Financial & competing interests disclosure
predict in vivo activity, particularly against S. pneumoniae, but a The authors have no relevant affiliations or financial involvement with any
higher ratio (>100) is suggested to be predictive of a bactericidal organization or entity with a financial interest in or financial conflict with
effect and thus reduces the potential of first-step mutations. The the subject matter or materials discussed in the manuscript. This includes
availability of pneumococcal vaccines is definitely helping to employment, consultancies, honoraria, stock ownership or options, expert
reduce the spread of pneumococcal infections and decrease the testimony, grants or patents received or pending, or royalties.
spread of resistant S. pneumoniae. No writing assistance was utilized in the production of this manuscript.

Key issues
• Community-acquired pneumonia (CAP) is one of the leading causes of death and ranks sixth in the overall cause of deaths in the USA.
• Levofloxacin is a valuable antimicrobial agent that has activity against a wide range of bacterial pathogens causing CAP.
• The efficacy of the high-dose (750 mg), short-course (once daily for 5 days) of levofloxacin in achieving early resolution of CAP
symp­toms has been shown.
• The levels of levofloxacin-resistant organisms has remained steady with resistance rates less than 1% worldwide for
Streptococcus pneumoniae.
• Levofloxacin activity is concentration dependent and the common predictor of microbiological and clinical outcome is the
AUC:MIC ratio.
• Levofloxacin is distributed throughout the body and the concentration in other tissues can exceed that in the plasma from 2–4 h after
administration and its pharmacokinetics are not affected by age, gender or race.
• Levofloxacin is generally well tolerated in patients with respiratory or urinary tract infections and no clinically significant adverse events
that occurred were deemed to be drug related.

3 Loh LC, Khoo SK, Quah SY et al. 5 Gutierrez F, Masia M, Mirete C et al. The
References
Adult community-acquired pneumonia influence of age and gender on the
1 Almirall J, Bolibar I, Vidal J et al. in Malaysia: prediction of mortality population-based incidence of community-
Epidemiology of community-acquired from severity assessment on acquired pneumonia caused by different
pneumonia in adults: a population-based admission. Respirology 9(3), 379–386 microbial pathogens. J. Infect. 53(3),
study. Eur. Respir. J. 15(4), 757–763 (2004). 166–174 (2006).
(2000).
4 O’Meara ES, White M, Siscovick DS, 6 Kaplan V, Angus DC. Community-
2 Gutierrez F, Masia M, Rodriguez JC et al. Lyles MF, Kuller LH. Hospitalization for acquired pneumonia in the elderly.
Epidemiology of community-acquired pneumonia in the cardiovascular Health Crit. Care Clin. 19(4), 729–748 (2003).
pneumonia in adult patients at the dawn of Study: incidence, mortality, and 7 Viegi G, Pistelli R, Cazzola M et al.
the 21st century: a prospective study on the influence on longer-term survival. J. Am. Epidemiological survey on incidence and
Mediterranean coast of Spain. Clin. Geriatr. Soc. 53(7), 1108–1116 treatment of community acquired pneumonia
Microbiol. Infect. 11(10), 788–800 (2005). (2005). in Italy. Respir. Med. 100(1), 46–55 (2006).

www.expert-reviews.com 511
 Drug Profile Noreddin & Elkhatib

8 Colice GL, Morley MA, Asche C, 19 Huang HH, Zhang YY, Xiu QY et al. 30 Reinert RR, Reinert S, van der Linden M,
Birnbaum HG. Treatment costs of Community-acquired pneumonia in Cil MY, Al-Lahham A, Appelbaum P.
community-acquired pneumonia in an Shanghai, China: microbial etiology and Antimicrobial susceptibility of Streptococcus
employed population. Chest 125(6), implications for empirical therapy in a pneumoniae in eight European countries
2140–2145 (2004). prospective study of 389 patients. Eur. J. from 2001 to 2003. Antimicrob. Agents
9 Niederman MS, Mandell LA, Anzueto A Clin. Microbiol. Infect. Dis. 25(6), 369–374 Chemother. 49(7), 2903–2913 (2005).
et al. Guidelines for the management of (2006). 31 Jones RN, Fritsche TR, Sader HS, Stilwell
adults with community-acquired 20 Saito A, Kohno S, Matsushima T et al. MG. Activity of garenoxacin, an
pneumonia. Diagnosis, assessment of Prospective multicenter study of the investigational des-F(6)-quinolone, tested
severity, antimicrobial therapy, and causative organisms of community- against pathogens from community-
prevention. Am. J. Respir. Crit. Care Med. acquired pneumonia in adults in Japan. acquired respiratory tract infections,
163(7), 1730–1754 (2001). J. Infect. Chemother. 12(2), 63–69 (2006). including those with elevated or resistant-
10 Kollef MH, Shorr A, Tabak YP, Gupta V, 21 Thibodeau KP, Viera AJ. Atypical level fluoroquinolone MIC values. Diagn.
Liu LZ, Johannes RS. Epidemiology and pathogens and challenges in community- Microbiol. Infect. Dis. 58(1), 9–17 (2007).
outcomes of health-care-associated acquired pneumonia. Am. Fam. Physician 32 Brown SD, Rybak MJ. Antimicrobial
pneumonia: results from a large US 69(7), 1699–1706 (2004). susceptibility of Streptococcus pneumoniae,
database of culture-positive pneumonia. 22 Woodhead M. Community-acquired Streptococcus pyogenes and Haemophilus
Chest 128(6), 3854–3862 (2005). pneumonia in Europe: causative pathogens influenzae collected from patients across the
11 Bodi M, Rodriguez A, Sole-Violan J et al. and resistance patterns. Eur. Respir. J. USA, in 2001–2002, as part of the
Antibiotic prescription for community- Suppl. 36, S20–S27 (2002). PROTEKT US study. J. Antimicrob.
acquired pneumonia in the intensive care Chemother. 54(Suppl. 1), i7–i15 (2004).
23 File TM Jr, Garau J, Blasi F et al.
unit: impact of adherence to Infectious Guidelines for empiric antimicrobial 33 Doern GV, Brown SD. Antimicrobial
Diseases Society of America guidelines on prescribing in community-acquired susceptibility among community-acquired
survival. Clin. Infect. Dis. 41(12), pneumonia. Chest 125(5), 1888–1901 respiratory tract pathogens in the USA:
1709–1716 (2005). (2004). data from PROTEKT US 2000–2001.
12 Tejerina E, Frutos-Vivar F, Restrepo MI J. Infect. 48(1), 56–65 (2004).
24 Mandell LA, Wunderink RG, Anzueto A
et al. Prognosis factors and outcome of et al. Infectious Diseases Society of 34 Hoban D, Waites K, Felmingham D.
community-acquired pneumonia needing America/American Thoracic Society Antimicrobial susceptibility of community-
mechanical ventilation. J. Crit. Care 20(3), consensus guidelines on the management acquired respiratory tract pathogens in North
230–238 (2005). of community-acquired pneumonia in America in 1999–2000: findings of the
13 Wilson PA, Ferguson J. Severe community- adults. Clin. Infect. Dis. 44(Suppl. 2), PROTEKT surveillance study. Diagn.
acquired pneumonia: an Australian S27–S72 (2007). Microbiol. Infect. Dis. 45(4), 251–259 (2003).
perspective. Intern. Med. J. 35(12), 25 Woodhead M, Blasi F, Ewig S et al. 35 Karlowsky JA, Thornsberry C, Jones ME
699–705 (2005). Guidelines for the management of adult et al. Factors associated with relative rates
14 Woodhead M, Welch CA, Harrison DA, lower respiratory tract infections. Eur. of antimicrobial resistance among
Bellingan G, Ayres JG. Community- Respir. J. 26(6), 1138–1180 (2005). Streptococcus pneumoniae in the United
acquired pneumonia on the intensive care States: results from the TRUST
26 Doern GV, Richter SS, Miller A et al.
unit: secondary analysis of 17,869 cases in Surveillance Program (1998–2002). Clin.
Antimicrobial resistance among
the ICNARC case Mix Programme Infect. Dis. 36(8), 963–970 (2003).
Streptococcus pneumoniae in the United
Database. Crit. Care. 10(Suppl. 2), S1 States: have we begun to turn the corner on 36 Wang JC. DNA topoisomerases. Annu.
(2006). resistance to certain antimicrobial classes? Rev. Biochem. 65, 635–692 (1996).
15 File TM Jr. Clinical implications and Clin. Infect. Dis. 41(2), 139–148 (2005). 37 Wang JC. A journey in the world of DNA
treatment of multiresistant Streptococcus 27 Bonofiglio L, Ojeda MI, de Mier C et al. rings and beyond. Annu. Rev. Biochem. 78,
pneumoniae pneumonia. Clin. Microbiol. Phenotypic and genotypic characterization 31–54 (2009).
Infect. 12(Suppl. 3), 31–41 (2006). of macrolide resistant Streptococcus 38 Huband MD, Cohen MA, Zurack M et al.
16 Lauderdale TL, Chang FY, Ben RJ et al. pneumoniae recovered from adult patients In vitro and in vivo activities of PD 0305970
Etiology of community acquired with community-acquired pneumonia in and PD 0326448, new bacterial gyrase/
pneumonia among adult patients requiring an Argentinian teaching hospital. Int. J. topoisomerase inhibitors with potent
hospitalization in Taiwan. Respir. Med. Antimicrob. Agents 25(3), 260–263 antibacterial activities versus multidrug-
99(9), 1079–1086 (2005). (2005). resistant Gram-positive and fastidious
17 Leesik H, Ani U, Juhani A, Altraja A. 28 Felmingham D. Comparative organism groups. Antimicrob. Agents
Microbial pathogens of adult community- antimicrobial susceptibility of respiratory Chemother. 51(4), 1191–1201 (2007).
acquired pneumonia in Southern Estonia. tract pathogens. Chemotherapy. 39 Croom KF, Goa KL. Levofloxacin: a review
Medicina (Kaunas) 42(5), 384–394 (2006). 50(Suppl. 1), 3–10 (2004). of its use in the treatment of bacterial
18 Luna CM, Famiglietti A, Absi R et al. 29 Fuller JD, McGeer A, Low DE. Drug- infections in the United States. Drugs
Community-acquired pneumonia: etiology, resistant pneumococcal pneumonia: 63(24), 2769–2802 (2003).
epidemiology, and outcome at a teaching clinical relevance and approach to 40 Keating GM, Scott LJ. Moxifloxacin: a
hospital in Argentina. Chest 118(5), management. Eur. J. Clin. Microbiol. Infect. review of its use in the management of
1344–1354 (2000). Dis. 24(12), 780–788 (2005). bacterial infections. Drugs 64(20),
2347–2377 (2004).

512 Expert Rev. Anti Infect. Ther. 8(5), (2010)

 Levofloxacin in the treatment of community-acquired pneumonia Drug Profile

41 Levaquin® (Levofloxacin tablets, oral 50 Soriano F, Granizo JJ, Coronel P et al. 58 Roblin PM, Reznik T, Kutlin A,
solution, injection): US prescribing Antimicrobial susceptibility of Haemophilus Hammerschlag MR. In vitro activities of
information. Ortho-McNeil Pharmaceutical, influenzae, Haemophilus parainfluenzae and rifamycin derivatives ABI-1648 (Rifalazil,
Inc., Raritan, NJ, USA (2009). Moraxella catarrhalis isolated from adult KRM-1648), ABI-1657, and ABI-1131
42 Hurst M, Lamb HM, Scott LJ, Figgitt DP. patients with respiratory tract infections in against Chlamydia trachomatis and recent
Levofloxacin: an updated review of its use four southern European countries. The clinical isolates of Chlamydia pneumoniae.
in the treatment of bacterial infections. ARISE project. Int. J. Antimicrob. Agents. Antimicrob. Agents Chemother. 47(3),
Drugs 62(14), 2127–2167 (2002). 23(3), 296–299 (2004). 1135–1136 (2003).
43 Clinical and Laboratory Standards 51 Hansen GT, Blondeau JM. Comparison of 59 Kohlhoff SA, Roblin PM, Reznik T,
Institute. Methods for dilution antimicrobial the minimum inhibitory, mutant Hawser S, Islam K, Hammerschlag MR.
susceptibility tests for bacteria that grow prevention and minimum bactericidal In vitro activity of a novel
aerobically. Approved standard – seventh concentrations of ciprofloxacin, diaminopyrimidine compound, iclaprim,
edition. Clinical and Laboratory Standards levofloxacin and garenoxacin against against Chlamydia trachomatis and
Institute Document M7-A7. Clinical and enteric Gram-negative urinary tract C. pneumoniae. Antimicrob. Agents
Laboratory Standards Institute, Wayne, infection pathogens. J. Chemother. 17(5), Chemother. 48(5), 1885–1886 (2004).
PA, USA (2006). 484–492 (2005). 60 Hammerschlag MR, Roblin PM. The
44 Gordon KA, Sader HS, Jones RN. 52 Deshpande LM, Diekema DJ, Jones RN. in vitro activity of a new fluoroquinolone,
Contemporary re-evaluation of the activity Comparative activity of clinafloxacin and ABT-492, against recent clinical isolates of
and spectrum of grepafloxacin tested nine other compounds tested against 2000 Chlamydia pneumoniae. J. Antimicrob.
against isolates in the United States. Diagn. contemporary clinical isolates from patients Chemother. 54(1), 281–282 (2004).
Microbiol. Infect. Dis. 47(1), 377–383 in United States hospitals. Diagn. 61 Dubois J, St-Pierre C. Comparative in vitro
(2003). Microbiol. Infect. Dis. 35(1), 81–88 (1999). activity and post-antibiotic effect of
45 Fritsche TR, Sader HS, Jones RN. Potency 53 Rolston KV, Frisbee-Hume S, LeBlanc BM, gemifloxacin against Legionella spp.
and spectrum of garenoxacin tested against Streeter H, Ho DH. Antimicrobial activity J. Antimicrob. Chemother. 45(Suppl. 1),
an international collection of skin and soft of a novel des-fluoro (6) quinolone, 41–46 (2000).
tissue infection pathogens: report from the garenoxacin (BMS-284756), compared to 62 Stout JE, Sens K, Mietzner S, Obman A,
SENTRY antimicrobial surveillance other quinolones, against clinical isolates Yu VL. Comparative activity of quinolones,
program (1999–2004). Diagn. Microbiol. from cancer patients. Diagn. Microbiol. macrolides and ketolides against Legionella
Infect. Dis. 58(1), 19–26 (2007). Infect. Dis. 44(2), 187–194 (2002). species using in vitro broth dilution and
46 Goff DA, Dowzicky MJ. Prevalence and 54 Thornsberry C, Sahm DF, Kelly LJ et al. intracellular susceptibility testing. Int. J.
regional variation in meticillin-resistant Regional trends in antimicrobial resistance Antimicrob. Agents. 25(4), 302–307 (2005).
Staphylococcus aureus (MRSA) in the USA among clinical isolates of Streptococcus 63 Waites KB, Crabb DM, Bing X, Duffy LB.
and comparative in vitro activity of pneumoniae, Haemophilus influenzae, and In vitro susceptibilities to and bactericidal
tigecycline, a glycylcycline antimicrobial. Moraxella catarrhalis in the United States: activities of garenoxacin (BMS-284756)
J. Med. Microbiol. 56(Pt 9), 1189–1193 results from the TRUST Surveillance and other antimicrobial agents against
(2007). Program, 1999–2000. Clin. Infect. Dis. human mycoplasmas and ureaplasmas.
34(Suppl. 1), S4–S16 (2002). Antimicrob. Agents Chemother. 47(1),
47 Biedenbach DJ, Toleman MA, Walsh TR,
Jones RN. Characterization of 55 Karlowsky JA, Thornsberry C, Critchley 161–165 (2003).
fluoroquinolone-resistant b-hemolytic IA et al. Susceptibilities to levofloxacin in 64 Waites KB, Crabb DM, Duffy LB.
Streptococcus spp. isolated in North Streptococcus pneumoniae, Haemophilus Comparative in vitro activities of the
America and Europe including the first influenzae, and Moraxella catarrhalis investigational fluoroquinolone DC-159a
report of fluoroquinolone-resistant clinical isolates from children: results from and other antimicrobial agents against
Streptococcus dysgalactiae subspecies 2000–2001 and 2001–2002 TRUST human mycoplasmas and ureaplasmas.
equisimilis: report from the SENTRY studies in the United States. Antimicrob. Antimicrob. Agents Chemother. 52(10),
Antimicrobial Surveillance Program Agents Chemother. 47(6), 1790–1797 3776–3778 (2008).
(1997–2004). Diagn. Microbiol. Infect. Dis. (2003).
65 Duffy LB, Crabb DM, Bing X, Waites
55(2), 119–127 (2006). 56 Zhanel GG, Hisanaga TL, Laing NM et al. KB. Bactericidal activity of levofloxacin
48 Nilius AM, Shen LL, Hensey-Rudloff D Antibiotic resistance in Escherichia coli against Mycoplasma pneumoniae. J.
et al. In vitro antibacterial potency and outpatient urinary isolates: final results Antimicrob. Chemother. 52(3), 527–528
spectrum of ABT-492, a new from the North American Urinary Tract (2003).
fluoroquinolone. Antimicrob. Agents Infection Collaborative Alliance
66 Dunbar LM, Wunderink RG, Habib MP
Chemother. 47(10), 3260–3269 (2003). (NAUTICA). Int. J. Antimicrob. Agents.
et al. High-dose, short-course levofloxacin
27(6), 468–475 (2006).
49 Jacobs MR, Felmingham D, Appelbaum for community-acquired pneumonia: a new
PC, Gruneberg RN, Alexander Project 57 Critchley IA, Jones ME, Heinze PD et al. treatment paradigm. Clin. Infect. Dis.
Group. The Alexander Project 1998–2000: In vitro activity of levofloxacin against 37(6), 752–760 (2003).
susceptibility of pathogens isolated from contemporary clinical isolates of Legionella
67 Waites KB, Crabb DM, Duffy LB.
community-acquired respiratory tract pneumophila, Mycoplasma pneumoniae and
Comparative in vitro susceptibilities and
infection to commonly used antimicrobial Chlamydia pneumoniae from North
bactericidal activities of investigational
agents. J. Antimicrob. Chemother. 52(2), America and Europe. Clin. Microbiol.
fluoroquinolone ABT-492 and other
229–246 (2003). Infect. 8(4), 214–221 (2002).
antimicrobial agents against human

www.expert-reviews.com 513
 Drug Profile Noreddin & Elkhatib

mycoplasmas and ureaplasmas. Antimicrob. 76 Chien SC, Wong FA, Fowler CL et al. 86 Peterson J, Kaul S, Khashab M, Fisher AC,
Agents Chemother. 47(12), 3973–3975 Double-blind evaluation of the safety and Kahn JB. A double-blind, randomized
(2003). pharmacokinetics of multiple oral comparison of levofloxacin 750 mg
68 Felmingham D, Feldman C, Hryniewicz once-daily 750-milligram and 1-gram doses once-daily for five days with ciprofloxacin
W et al. Surveillance of resistance in of levofloxacin in healthy volunteers. 400/500 mg twice-daily for 10 days for the
bacteria causing community-acquired Antimicrob. Agents Chemother. 42(4), treatment of complicated urinary tract
respiratory tract infections. Clin. Microbiol. 885–888 (1998). infections and acute pyelonephritis. Urology
Infect. 8(Suppl. 2), 12–42 (2002). 77 Stein GE, Schooley SL, Nicolau DP. 71(1), 17–22 (2008).
69 Canton R, Morosini M, Enright MC, Urinary bactericidal activity of single doses 87 Klausner HA, Brown P, Peterson J et al. A
Morrissey I. Worldwide incidence, (250, 500, 750 and 1000 mg) of trial of levofloxacin 750 mg once daily for 5
molecular epidemiology and mutations levofloxacin against fluoroquinolone- days versus ciprofloxacin 400 mg and/or
implicated in fluoroquinolone-resistant resistant strains of Escherichia coli. Int. J. 500 mg twice daily for 10 days in the
Streptococcus pneumoniae: data from the Antimicrob. Agents. 32(4), 320–325 (2008). treatment of acute pyelonephritis. Curr.
global PROTEKT surveillance programme. 78 Gotfried MH, Danziger LH, Rodvold KA. Med. Res. Opin. 23(11), 2637–2645
J. Antimicrob. Chemother. 52(6), 944–952 Steady-state plasma and intrapulmonary (2007).
(2003). concentrations of levofloxacin and 88 Dunbar LM, Khashab MM, Kahn JB,
70 Higgins PG, Fluit AC, Milatovic D, ciprofloxacin in healthy adult subjects. Zadeikis N, Xiang JX, Tennenberg AM.
Verhoef J, Schmitz FJ. Mutations in GyrA, Chest 119(4), 1114–1122 (2001). Efficacy of 750-mg, 5-day levofloxacin in
ParC, MexR and NfxB in clinical isolates of 79 Rodvold KA, Danziger LH, Gotfried MH. the treatment of community-acquired
Pseudomonas aeruginosa. Int. J. Antimicrob. Steady-state plasma and bronchopulmonary pneumonia caused by atypical pathogens.
Agents. 21(5), 409–413 (2003). concentrations of intravenous levofloxacin Curr. Med. Res. Opin. 20(4), 555–563
and azithromycin in healthy adults. (2004).
71 Deryke CA, Du X, Nicolau DP. Evaluation
of bacterial kill when modelling the Antimicrob. Agents Chemother. 47(8), 89 Shorr AF, Zadeikis N, Xiang JX,
bronchopulmonary pharmacokinetic 2450–2457 (2003). Tennenberg AM, Wes Ely E. A multicenter,
profile of moxifloxacin and levofloxacin 80 Capitano B, Mattoes HM, Shore E et al. randomized, double-blind, retrospective
against parC-containing isolates of Steady-state intrapulmonary concentrations comparison of 5- and 10-day regimens of
Streptococcus pneumoniae. J. Antimicrob. of moxifloxacin, levofloxacin, and levofloxacin in a subgroup of patients aged
Chemother. 58(3), 601–609 (2006). azithromycin in older adults. Chest 125(3), > or =65 years with community-acquired
965–973 (2004). pneumonia. Clin. Ther. 27(8), 1251–1259
72 LaPlante KL, Rybak MJ, Tsuji B, Lodise
(2005).
TP, Kaatz GW. Fluoroquinolone resistance 81 Conte JE Jr, Golden JA, McIver M, Little
in Streptococcus pneumoniae: area under the E, Zurlinden E. Intrapulmonary 90 File TM Jr, Milkovich G, Tennenberg AM,
concentration-time curve/MIC ratio and pharmacodynamics of high-dose Xiang JX, Khashab MM, Zadeikis N.
resistance development with gatifloxacin, levofloxacin in subjects with chronic Clinical implications of 750 mg, 5-day
gemifloxacin, levofloxacin, and bronchitis or chronic obstructive levofloxacin for the treatment of
moxifloxacin. Antimicrob. Agents pulmonary disease. Int. J. Antimicrob. community-acquired pneumonia. Curr.
Chemother. 51(4), 1315–1320 (2007). Agents. 30(5), 422–427 (2007). Med. Res. Opin. 20(9), 1473–1481 (2004).
73 Sahm DF, Benninger MS, Evangelista AT, 82 Drusano GL, Preston SL, Gotfried MH, 91 Shorr AF, Khashab MM, Xiang JX,
Yee YC, Thornsberry C, Brown NP. Danziger LH, Rodvold KA. Levofloxacin Tennenberg AM, Kahn JB. Levofloxacin
Antimicrobial resistance trends among penetration into epithelial lining fluid as 750-mg for 5 days for the treatment of
sinus isolates of Streptococcus pneumoniae in determined by population pharmacokinetic hospitalized Fine Risk Class III/IV
the United States (2001–2005). modeling and Monte Carlo simulation. community-acquired pneumonia patients.
Otolaryngol. Head. Neck. Surg. 136(3), Antimicrob. Agents Chemother. 46(2), Respir. Med. 100(12), 2129–2136 (2006).
385–389 (2007). 586–589 (2002). 92 Khashab MM, Xiang J, Kahn JB.
74 West M, Boulanger BR, Fogarty C et al. 83 Pea F, Marioni G, Pavan F et al. Comparison of the adverse event profiles of
Levofloxacin compared with imipenem/ Penetration of levofloxacin into paranasal levofloxacin 500 mg and 750 mg in clinical
cilastatin followed by ciprofloxacin in adult sinuses mucosa of patients with chronic trials for the treatment of respiratory
patients with nosocomial pneumonia: a rhinosinusitis after a single 500 mg oral infections. Curr. Med. Res. Opin. 22(10),
multicenter, prospective, randomized, dose. Pharmacol. Res. 55(1), 38–41 (2007). 1997–2006 (2006).
open-label study. Clin. Ther. 25(2), 84 Garraffo R, Lavrut T, Durant J et al. 93 Yee YC, Evangelista AT, Obot-Tucker M
485–506 (2003). In vivo comparative pharmacokinetics and et al. Five-year surveillance (2003–2007) of
75 Chow AT, Fowler C, Williams RR, pharmacodynamics of moxifloxacin and anti-pneumococcal activity of oral agents
Morgan N, Kaminski S, Natarajan J. levofloxacin in human neutrophils. Clin. recommended for the empirical treatment
Safety and pharmacokinetics of multiple Drug Investig. 25(10), 643–650 (2005). of com­munity-acquired pneumonia (CAP)
750-milligram doses of intravenous in adults. Presented at: 47th Interscience
85 Poole M, Anon J, Paglia M, Xiang J,
levofloxacin in healthy volunteers. Conference on Antimicrobial Agents and
Khashab M, Kahn J. A trial of high-dose,
Antimicrob. Agents Chemother. 45(7), Chemotherapy. Chicago, IL, USA, 17–20
short-course levofloxacin for the treatment
2122–2125 (2001). September (2007).
of acute bacterial sinusitis. Otolaryngol.
Head. Neck. Surg. 134(1), 10–17 (2006).

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