Levofloxacin in the Treatment of Streptococcus , Including Multidrug-Resistant Strains

Levofloxacin in the Treatment of
Pneumonia Caused by Streptococcus
pneumoniae, Including Multidrug-Resistant
Strains
Review
Janet Peterson, PhD
Ortho-McNeil Janssen Scientific Affairs, LLC;
Raritan, New Jersey, USA
Streptococcus pneumoniae (S. pneumoniae) is the most frequently isolated
bacterial pathogen in adults with community-acquired pneumonia (CAP)
(1,2). Because the identity of the causative pathogen is frequently unknown at
the time of diagnosis, initial antimicrobial therapy for CAP is usually empiric(1) and targeted at the most common bacterial causes of CAP, including
S. pneumoniae. However, the growing problem of drug-resistant S. pneumoniae has undermined the effectiveness of empiric therapy, particularly for the most commonly used
oral antibacterial agents. A pooled analysis was conducted on data from 10 clinical studies evaluating
levofloxacin in the treatment of pneumonia caused by S. pneumoniae, including multidrug resistant S.
pneumoniae (MDRSP) strains. The high clinical cure rates and microbiologic eradication rates for MDRSP
pathogens observed with levofloxacin support its effectiveness in treating patients who present with CAP.
Drug resistance in Streptococcus pneumoniae
Macrolides and β-lactams are among the antimicrobials recommended for the treatment of community-acquired pneumonia (CAP) (2). However,
resistance of S. pneumoniae to these commonly
used antimicrobials is increasing, with rates of
high-level penicillin and macrolide resistance of
15.7% and 33.0%, respectively, in the United
States in 2007–2008 (3). Furthermore, pneumococci are often resistant to more than one class of
antimicrobials; 40% of S. pneumoniae have been reported to display multidrug resistant S. pneumoniae
(MDRSP), with a prevalence that varies markedly
from country to country (4). The most commonly
observed phenotype, occurring in more than 90%
of MDRSP isolates, is resistant to penicillin,
azithromycin, and trimethoprim/sulfamethoxazole (3). As a result, any of these agents may select
for MDR strains. Given the high rates of resistance, it can be anticipated that many currently
available agents are becoming less effective for the
treatment of pneumonia caused by S. pneumoniae.
Few new antimicrobials potentially effective
for S. pneumoniae, in particular oral agents, are in
development. As a result, there is a need to evaluate the efficacy of currently available treatment
options for pneumonia caused by S. pneumoniae to
identify those agents that remain effective against
this pathogen and that are still appropriate for the
empiric therapy of pneumonia. At the same time,
strategies to preserve the effectiveness of these
agents by minimizing conditions that might select
for resistant organisms should be explored.
Pooled analysis of levofloxacin studies
The respiratory fluoroquinolones are recommended in selected patients with CAP (2). Longitudinal surveillance data (1998 through 2007)
show that the prevalence of levofloxacin-resistant
S. pneumoniae remains at 1% or less in the United
States (3), with 96% to 99% of MDRSP strains
also currently susceptible to levofloxacin; therefore, it may be anticipated that levofloxacin remains effective for the treatment of CAP caused
by S. pneumoniae. To collect information on the
clinical and microbiologic efficacy of levofloxacin
in a sufficient number of patients with pneumonia caused by MDRSP and non-MDRSP, an
analysis of data pooled from 10 previously completed levofloxacin trials was conducted and published recently by Peterson and colleagues(5).
Clinical success and microbiologic eradication
rates were determined in microbiologically evaluable (ME) subjects with pneumonia caused by S.
pneumoniae, including MDRSP (5). The 10 studies, which were conducted from 1992 through
2002, represent the total experience of levofloxacin in pneumonia in the Ortho-McNeil database
Address for correspondence
Janet Peterson, PhD
Ortho-McNeil Janssen
Scientific Affairs, LLC
1000 Route 202
Raritan, New Jersey 08869,
USA
Phone: 908-927-2054
Fax: 908-218-1286
E-mail: Jpeter13@its.jnj.com
39
Review
(5). Nine of the studies were conducted in patients with CAP (6-12), and 1 was conducted in
patients with nosocomial pneumonia (13).
S. pneumoniae resistance was characterized by
in vitro testing of clinical isolates obtained from
participants prior to treatment. Drugs from 5 antimicrobial classes were used in the tests: tetracyclines (tetracycline, doxycycline); sulfonamides
(trimethoprim/sulfamethoxazole); second-generation cephalosporins (cefuroxime, cefoxitin); penicillins (amoxicillin, amoxicillin-clavulanate); and
macrolides (azithromycin, clarithromycin, erythromycin). Isolates resistant to 2 or more drug
classes, or those resistant to 1 drug class, and with
intermediate resistance to at least 1 other drug
class, were classified as MDRSP. Isolates that were
susceptible and/or intermediately susceptible to
all antimicrobial classes, or were resistant to 1 class
and fully susceptible to all others, were classified
as non-MDRSP (5).
Clinical response (cure, improvement, failure), based on the investigator’s assessment at the
post-therapy visit (test of cure) for levofloxacintreated ME subjects, was the primary endpoint of
the analysis. Microbiologic efficacy (eradicated
versus persisted) for S. pneumoniae was also assessed after the conclusion of therapy (5).
Efficacy of levofloxacin in pneumonia
caused by MDRSP and non-MDRSP
A total of 420 S. pneumoniae isolates collected
from 419 levofloxacin-treated ME subjects were
available for analysis. Table 1 summarizes the design, dosing regimens, and number of subjects
with S. pneumoniae in each of the studies. Five
studies were comparative and 5 were noncomparative. Table 2 lists the demographic characteristics
of levofloxacin-treated subjects included in the
analysis, according to S. pneumoniae classification.
A total of 54 isolates were classified as MDRSP
and 366 were classified as non-MDRSP (5).
Table 3 shows the distribution of levofloxacin minimum inhibitory concentration (MIC)
values for S. pneumoniae isolates according to various antimicrobial classes. Only 1 isolate was characterized as being resistant to levofloxacin; this
isolate was also resistant to all 3 macrolides and
doxycycline. Resistance to 1 or more antimicrobial drug classes was observed in 18.9% (79/420)
of S. pneumoniae isolates (5).
Clinical responses were recorded for 54 subjects with an MDRSP isolate and for 365 subjects
with a non-MDRSP isolate (Table 4). Clinical success (cured or improved) was observed in 52/54
(96.3%) levofloxacin-treated subjects with MDRSP
and in 347/365 (95.1%) non-MDRSP subjects
(95% confidence interval [CI]: –6.7–4.3).
40
Microbiologic success rates are shown in Table 4. S. pneumoniae was eradicated in 52/54
(96.3%) of isolates from MDRSP patients versus
350/366 (95.6%) of isolates from non-MDRSP
subjects (95% CI: –6.1–4.8). High rates of S. pneumoniae eradication were achieved with levofloxacin, and the effect did not appear to be influenced
by the resistance of isolates to other antimicrobial
classes (5).
Table 5 shows the clinical and microbiologic
success rates of ME subjects with S. pneumoniae
isolates resistant to other antimicrobials. Data are
shown according to the specific class to which an
isolate demonstrated resistance.
Clinical failure was observed in 2 subjects
with MDRSP who were treated with levofloxacin.
Both subjects had serious comorbidities in addition to pneumonia. One subject, who was treated
with levofloxacin 750 mg PO for 4 days, had a
lung abscess, chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), diabetes, obesity, and renal failure. S. pneumoniae resistant to penicillin, cephalosporin, and sulfonamide
classes was found in blood cultures from this patient; the isolate was susceptible to levofloxacin.
This subject was discontinued from the study, but
was treated again, this time successfully, with levofloxacin 500 mg, followed by clarithromycin (5).
A second clinical failure was observed in a
subject hospitalized with severe pneumonia,
chronic bronchitis, and CHF. After treatment with
levofloxacin 500 mg IV for 14 days, S. pneumoniae
isolated from sputum samples was resistant to
macrolides and sulfonamide, but was susceptible
to levofloxacin. The subject died of respiratory
distress 21 days after the start of treatment(5).
Strategies for preserving susceptibility of
S. pneumoniae to levofloxacin
The continued efficacy of levofloxacin is predicted, in part, by surveillance data that demonstrate
>99% of strains remain susceptible to levofloxacin in the United States. However, rare isolates of
fluoroquinolone-resistant S. pneumoniae have
been reported, particularly in regions of the
world where levofloxacin is administered for long
periods (eg, for the treatment of tuberculosis) or
at low doses (14,15).
Because prolonged drug exposure is an important driver of antimicrobial resistance, shortduration therapy may minimize selective pressure
for resistant S. pneumoniae. Nord and colleagues
conducted an open-label study designed to test
the hypothesis that limiting exposure to levofloxacin by using high-dose, short-course therapy minimizes selective pressure for resistant organisms
(16). They compared the risk of colonization with
Levofloxacin in pneumococcal pneumonia
Table 1. Overview of clinical studies to support the efficacy of levofloxacin for the treatment of MDRSP in pneumonia
Protocol No.
Investigator(s)
(Country[s])
Start date
End date
Study description/design
No. subjects evaluated
Gender (M/F)a,b
Race (C/B/O)a,b
Mean age (yr)a (range)
Treatment regimen(s)
Total duration
S. pneumoniae isolates
MDRSP
Non-MDRSP
Total
Comparative studies
CAPSS-018
Multicenter (US)
02 December 1997
28 March 2000
Multiple-dose, multicenter, randomized, open-label, active-controlled,
parallel-group study to show that
LVFX was at least as efficacious as
CEFT and ERYTH followed by CLAR
and AMX/CL in the treatment of
serious CAP in adults
LVFX: 132
G: 65% / 35%
R: 64% / 32% / 4%
A: 62 (24–94)
CEFT and ERYTH f/b
CLAR and AMX/CL: 137
G: 71% / 29%
R: 69% / 26% / 5%
A: 60 (18–94)
LVFX 500 mg q.d.
CEFT 1–2 g IV or IM q.d.
ERYTH 0.5–1 g IV q6h
CLAR 500 mg PO b.i.d.
AMX/CL 875 mg PO b.i.d.
LVFX = 7–14 days
CEFT and ERYTH f/b
CLAR and AMX/CL = 7–14 days
Post-therapy: 3–12 days
2
11
13
CAPSS-056
Multicenter (US)
15 December 1997
07 June 1999
Multiple-dose, multicenter, randomized, open-label, active-controlled,
parallel-group study to show that
LVFX was comparable to AZITH in the
treatment of moderate to severe CAP
in adults
LVFX: 115
G: 67% / 33%
R: 77% / 11% / 12%
A: 66 (26–94)
AZITH: 121
G: 75% / 25%
R: 74% / 13% / 13%
A: 67 (37–91)
LVFX 500 mg q.d.
AZITH 500 mg q.d.
CEFT 1 g IV q.d.
LVFX = 10–14 days
AZITH (IV)/CEFT (min. 2 days) f/b
AZITH (PO) = min. 10 days.
Post-therapy: 2–16 days
3
11
14
CAPSS-117
Multicenter (Canada, US)
12 December 1997
07 June 2001
Multiple-dose, multicenter, randomized, open-label, active-controlled,
parallel-group study to compare the
safety and efficacy of LVFX with that
of IMIP/CIL in the treatment of
nosocomial pneumonia in adults
LVFX: 220
G: 73% / 27%
R: 78% / 11% / 11%
A: 56 (19–93)
IMIP/CIL: 218
G: 71% / 29%
R: 74% / 13% / 13%
A: 57 (18–93)
LVFX 750 mg q.d.
IMIP/CL 0.5–1 g IV q6–8h
LVFX = 7–15 days
IMIP/CL = 7–15 days
Post-therapy: 3–15 days
0
2
2
K90-071
Multicenter (Canada, US)
11 November 1992
25 January 1995
Multiple-dose, multicenter, randomized, open-label, active-controlled,
parallel-group study to compare the
safety and efficacy of LVFX with that
of CEFT or CEFUR in the treatment of
CAP in adults
LVFX: 295
G: 55% / 45%
R: 63% / 34% / 2%
A: 49 (18–87)
CEFT/CEFUR: 295
G: 55% / 45%
R: 64% / 34% / 2%
A: 50 (18–96)
LVFX 500 mg. q.d.
CEFT 1–2 g IV q.d.
CEFUR 500 mg PO b.i.d.
LVFX = 7–14 days
CEFT/CEFUR = 7–14 days
Post-therapy: 1–10 days
3
21
24
CAPSS-150
Multicenter (US)
05 March 2001
07 June 2002
Multiple-dose, multicenter, randomized, double-blind, active-controlled,
parallel-group study to show that a 5day course of LVFX 750 mg q.d. was
at least as effective as a 10-day
course of LVFX 500 mg q.d. in the
treatment of mild to severe CAP in
adults
LVFX 750 mg: 256
G: 58% / 42%
R: 70% / 20% / 10%
A: 53 (18–86)
LVFX 500 mg: 272
G: 60% / 40%
R: 67% / 24% / 9%
A: 55 (18–89)
LVFX 750 mg q.d. = 5 days;
LVFX 500 mg q.d. = 10 days
Post-therapy: 7–14 days
7
36
43
41
Review
Protocol No.
Investigator(s)
(Country[s])
Start date
End date
Study description/design
No. subjects evaluated
Gender (M/F)a,b
Race (C/B/O)a,b
Mean age (yr)a (range)
Treatment regimen(s)
Total duration
S. pneumoniae isolates
MDRSP
Non-MDRSP
Total
Noncomparative studies
CAPSS-171
Multicenter (US)
31 January 2001
21 May 2002
Multiple-dose, multicenter, noncomparative, open-label study to
investigate the clinical efficacy and
safety of a 5-day course of LVFX 750
mg q.d. in the treatment of mild to
severe CAP in adults
LVFX: 123
G: 58% / 42%
R: 65% / 27% / 8%
A: 60 (22–93)
LVFX 750 mg. q.d.
LVFX = 5 days
Post-therapy: 7–14 days
1
8
9
LOFBIV-PCAP-001E
Multicenter (Canada, US)
27 October 1996
21 July 1998
Multiple-dose, multicenter, noncomparative, open-label study to
investigate the efficacy and safety of
LVFX in the treatment of CAP caused
by penicillin- or macrolide-resistant
LVFX: 655
G: 59% / 41%
R: 69% / 26% / 5%
A: 55 (18–96)
LVFX 500 mg q.d.
LVFX = 7–14 days
Post-therapy: 2–10 days
20
106
126
strains of S. pneumoniae in adults
LOFBIV-MULT-001
Multicenter (US)
12 September 1994
25 February 1995
Multiple-dose, multicenter, noncomparative, open-label study to evaluate
the safety of LVFX in the treatment of
bacterial infections of the respiratory
tract, skin infections, and UTI in adults
LVFX: 313
(97 with CAP)
G: 57% / 43%
R: 58% / 28% / 13%
A: 48 (17–100)
LVFX 500 mg q.d.
LVFX = 7–14 days
Post-therapy: 5–7 days
0
18
18
M92-075
364023:1
Multicenter (US)
30 September 1993
20 July 1994
Multiple-dose, multicenter, noncomparative, open-label study to evaluate
the safety and efficacy of LVFX in the
treatment of CAP in adults
LVFX: 264
G: 55% / 45%
R: 83% / 15% / 2%
A: 52 (18–93)
LVFX 500 mg q.d.
LVFX: 7–14 days
Post-therapy: 1–10 days
3
35
38
CAPSS-043
EDMS-USRA-7877610
Multicenter (US)
23 October 1997
May 2000
Multiple-dose, multicenter, noncomparative, open-label study to evaluate
the bacteriologic and clinical efficacy
and safety of LVFX in the treatment of
CAP in adults
LVFX: 1,730
G: 54% / 46%c
R: 86% / 11% / 2%c
A: 55c (18–93)c
LVFX: 500 mg q.d.
LVFX: 10–14 days
Post-therapy: 2–7 days
15
118
133
54
366
420
Total subjects with S. pneumoniae isolates
From intention-to-treat (ITT) population.
Percentages may not add up to 100% due to rounding or data not available.
c
From clinically evaluable population.
Abbreviations: N
o. = number, G = gender, R = race, A = mean age, C = Caucasian, B = Black, O = other, F = female, M = male, f/b = followed by, yr = years, MDRSP =
multidrug resistant Streptococcus pneumoniae, LVFX = levofloxacin, CEFT = ceftriaxone, ERYTH = erythromycin, CLAR = clarithromycin, AMX/CL =
amoxicillin/clavulanic acid, CAP = community-acquired pneumonia, AZITH = azithromycin, IMIP/CIL = imipenem/cilastatin, CEFUR = cefuroxime axetil,
UTI = urinary tract infection, q.d. = once daily, b.i.d. = twice a day, IV = intravenous, IM = intramuscular, PO = oral.
Adapted from reference (5).
a
b
fluoroquinolone-resistant or macrolide-resistant
bacteria in the oral microflora of healthy adults. A
total of 143 healthy adults without antibacterial
exposure during the previous 90 days were randomized to receive either levofloxacin 750 mg
once daily for 5 days or the macrolide azithromycin 500 mg once daily on day 1 and 250 mg once
42
daily on days 2 through 5 (16). The resistance of
streptococci in oropharyngeal cultures to levofloxacin and azithromycin was assessed before,
during, and after treatment.
Levofloxacin treatment was found to be associated with a lower rate of microbial resistance
than was azithromycin (16). In the group exposed
Levofloxacin in pneumococcal pneumonia
Table 2. Baseline demographic characteristics of levofloxacin-treated subjects by Streptococcus pneumoniae
resistance group from pooled pneumonia studies (microbiologically evaluable population)
Age (years)
<65, n (%)
≥65, n (%)
Unknown
Range
Gender
Male, n (%)
Female, n (%)
Race
White, n (%)
Black, n (%)
Hispanic, n (%)
Asian, n (%)
Other, n (%)
MDRSP
(n = 54)
Non-MDRSP
(n = 366)a
35 (66.0)
19 (35.2)
0
25-80
240 (65.6)
124 (34.0)
1
18-93
27 (50.0)
27 (51.0)
223 (61.1)
142 (38.8)
41 (75.9)
8 (15.1)
0 (0.0)
2 (3.8)
3 (5.7)
259 (71.0)
94 (25.7)
7 (1.9)
3 (0.8)
2 (0.5)
One subject yielded 2 S. pneumoniae isolates, 1 MDRSP and 1 non-MDRSP and is included in each group.
Abbreviation: MDRSP = multidrug-resistant Streptococcus pneumoniae.
Adapted from reference (5).
a
Table 3. Distribution of levofloxacin MIC values (μg/ml) for Streptococcus pneumoniae classified by number of resistant drug classes (microbiologically evaluable population)
Number of resistant drug classesa
Levofloxacin MIC (μg/ml)
N
0b (susceptible to all classes)
0b (susceptible and/or intermediate)
1b (resistant to 1, susceptible to all other classes)
1c (intermediate to 1 or more other classes)
2c
3c
4c
294
49
24
22
18
11
4
<0.25
0.25
0.50
1.0
2.0
9
50
15
4
10
1
4
3
209
29
16
11
14
7
1
26
3
3
2
1
1
2
4.0
8.0
16
1
Number of drug classes to which all isolates of Streptococcus pneumoniae were resistant at admission.
Non-MDRSP: Susceptible or intermediately resistant to all drug classes for which susceptibility testing was conducted at admission or resistant to 1 class and susceptible to all others.
c
MDRSP: Includes subjects with Streptococcus pneumoniae resistant to at least 2 drug classes or resistant to 1 class and intermediately resistant to at least 1 other drug class at admission.
Abbreviation: MIC = minimum inhibitory concentration.
Adapted from reference (5).
a
b
to azithromycin, the proportion of subjects with
macrolide-resistant streptococcal isolates increased
at the end of the dosing period, and resistant isolates still were observed throughout the 6-week
post-treatment period. For subjects exposed to levofloxacin, a small number of levofloxacin-resistant streptococci were observed at the end of the
dosing period. However, by week 2 post-treatment, the number of subjects with levofloxacinresistant isolates decreased, and this decline continued throughout the 6-week evaluation period
(16). It is noteworthy that this study also demonstrated that 69.4% of subjects had 1 or more bac-
teria resistant to azithromycin at study entry, and
it was postulated that this finding may reflect the
current high rates of macrolide resistance.
Strategies for treating CAP in an era of
MDRSP
The increase in antimicrobial resistance has
changed empiric treatment strategies for patients
with CAP. The 2007 Infectious Disease Society
of America/American Thoracic Society guidelines recommend use of a macrolide only in previously healthy patients with no risk factors for
drug-resistant S. pneumoniae infection (eg, recent
43
Review
Table 4. Post-therapy clinical success rates and microbiologic eradication rates of levofloxacin-treated subjects
with MDRSP isolates versus subjects with non-MDRSP isolates from pooled pneumonia studies (microbiologically evaluable population)
Clinical success
MDRSP
Success
Non–MDRSPc
Failure
Unknown
n/N (%)
N/N (%)
n/N (%)
Difference in
success rates
(95% CI)
347/365
(95.1)
18/365 (4.9)
0
–1.2% (–6.7–4.3)
Unknown
Failure
Unknown
n/N (%)
n/N (%)
n/N (%)
52/54 (96.3)
2/54 (3.7)
0
Unknown
Eradicated
a
Success
Microbiologic eradicationb
MDRSP
Non–MDRSP
n/N (%)
n/N (%)
n/N (%)
n/N (%)
n/N (%)
n/N (%)
Difference in
eradication rates
(95% CI)
52/54 (96.3)
2/54 (3.7)
0/54 (0)
350/366
(95.6)
13/366 (3.6)
3/366 (0.8)
–0.7% (–6.1–4.8)
Eradicatedb
Persisted
Persisted
Clinical success includes the clinical responses of cured and improved (as defined in the individual studies from which this pooled
sample was obtained).
b
Includes eradicated if documented eradication and presumed eradicated based on clinical success.
c
For clinical outcome, 1 subject with both MDRSP and non-MDRSP isolates was included in the MDRSP group only.
Abbreviations:MDRSP = multidrug-resistant Streptococcus pneumoniae, CI = confidence interval.
Adapted from reference (5).
a
Table 5. Clinical and microbiologic success rates of levofloxacin-treated subjects with resistant Streptococcus
pneumoniae by class of resistance (microbiologically evaluable population)
Antimicrobial classa
PEN
CSP
MAC
SUL
TET
MDRSP
Non–MDRSP
Clinical
n/N (%)
Microbiologic
n/N (%)
Clinical
n/N (%)
Microbiologic
n/N (%)
15/16 (93.8)
22/23 (95.7)
36/37 (97.3)
22/24 (91.7)
4/4 (100)
15/16 (93.8)
22/23 (95.7)
36/37 (97.3)
22/24 (91.7)
4/4 (100)
3/3 (100)
0
14/14 (100)
7/7 (100)
0/1 (0)
3/3 (100)
0
14/14 (100)
6/7 (85.7)
0/1 (0)
Isolates may have been resistant to more than 1 antimicrobial class.
Abbreviations:MDRSP = multidrug-resistant Streptococcus pneumoniae, PEN = penicillins, CSP = second-generation cephalosporins, MAC = macrolides, SUL = sulfonamides, TET = tetracyclines.
Adapted from reference (5).
a
use of antimicrobials) and in areas where highlevel macrolide resistance is less than 25%. With
currently reported high-level resistance rates
greater than 25% in the United States, application of these guidelines should limit use of macrolide monotherapy in the treatment of CAP. A
respiratory fluoroquinolone (levofloxacin, moxifloxacin, gemifloxacin) or combination therapy
with a β-lactam plus a macrolide is recommended in patients at high risk for resistant infection,
such as those with serious comorbid disease or
those who have used antimicrobials during the
previous 3 months (2).
The pooled analysis of data from 10 levofloxacin studies (5) found high rates of clinical
and microbiologic efficacy in subjects with pneumonia caused by S. pneumoniae. The success rates
44
with levofloxacin treatment were similar in patients with MDRSP or non-MDRSP infection.
As the authors of the analysis note, the component studies in the analysis reported clinical success rates ≥90%, suggesting that levofloxacin remains effective for treating pneumococcal
pneumonia. Nevertheless, the analysis has limitations, principally because the data were collected
from studies that differed in their design. In particular, half the studies were comparative and half
were noncomparative. However, the validity of
the pooling of data from these studies was supported by a test for homogeneity of the odds ratios (OR) for clinical success in the comparative
versus noncomparative studies, which found that
the difference was not statistically significant (p =
0.27). The pooling of data from several studies
Levofloxacin in pneumococcal pneumonia
with different designs was a strategy that permitted a sufficient number of S. pneumoniae isolates to
be analyzed (5).
Discussion
A pooled analysis of data from 10 clinical studies
demonstrated the effectiveness of levofloxacin in
treating pneumonia caused by S. pneumoniae, including MDRSP strains. High clinical cure rates
and microbiologic eradication rates for MDRSP
pathogens were observed. These rates were similar
to those observed in subjects with non-MDRSP
pathogens, as would be expected based on current
susceptibility patterns of S. pneumoniae to levofloxacin.
Acknowledgments
The studies used in this analysis were funded and
conducted by Ortho-McNeil Inc. and Johnson &
Johnson Pharmaceutical Research & Development, LLC. The author acknowledges Alan Fisher,
DrPh, for his analytical assistance and insights regarding the original paper and numerous colleagues, who over a decade, planned and conducted the original analysis of S. pneumoniae that
formed the basis for the current analysis. The author also wishes to acknowledge writing and editorial assistance from Ira Mills, PhD and Craig
Ornstein, PhD of Advogent.
REFERENCES
1
Guthrie R. Community-acquired
lower respiratory tract infections:
etiology and treatment. Chest
2001; 120: 2021–34.
2
Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD,
Dean NC, Dowell SF, File TM Jr.,
Musher DM, Niederman MS, Torres
A, Whitney CG. Infectious Diseases
Society of America/American Thoracic Society consensus guidelines
on the management of community-acquired pneumonia in adults.
Clin Infect Dis 2007; 44(Suppl 2):
S27–72.
3
Ortho-McNeil Janssen Pharmaceuticals I. TRUST 12, 2008. Data on
file. Ortho-McNeil Janssen Pharmaceuticals, Inc.; 2008.
4
Van Bambeke F, Reinert RR, Appelbaum PC, Tulkens PM, Peetermans
WE. Multidrug-resistant Streptococcus pneumoniae infections:
current and future therapeutic options. Drugs 2007; 67: 2355–
82.
5
Peterson J, Yektashenas B, Fisher
AC. Levofloxacin for the treatment
of pneumonia caused by Streptococcus pneumoniae including multidrug-resistant strains: pooled
analysis. Curr Med Res Opin 2009;
25: 559–68.
6
Dunbar LM, Wunderink RG, Habib
MP, Smith LG, Tennenberg AM,
Khashab MM, Wiesinger BA, Xiang
JX, Zadeikis N, Kahn JB. Highdose, short-course levofloxacin for
community-acquired pneumonia: a
new treatment paradigm. Clin Infect Dis 2003; 37: 752–60.
7
File TM Jr, Segreti J, Dunbar L,
Player R, Kohler R, Williams RR,
Kojak C, Rubin A. A multicenter,
randomized study comparing the
efficacy and safety of intravenous
and/or oral levofloxacin versus ceftriaxone and/or cefuroxime axetil
in treatment of adults with community-acquired pneumonia. Antimicrob Agents Chemother 1997;
41: 1965–72.
8
Fogarty C, Siami G, Kohler R, File
TM Jr, Tennenberg AM, Olson WH,
Wiesinger BA, Scott Marshall J-A,
Oross M, Kahn JB. Multicenter,
open-label, randomized study to
compare the safety and efficacy of
levofloxacin versus ceftriaxone sodium and erythromycin followed
by clarithromycin and amoxicillinclavulanate in the treatment of serious community-acquired
pneumonia in adults. Clin Infect Dis
2004; 38(Suppl 1): S16–23.
9
Fogarty CM, Sullivan JG, Chattman
MS, Williams RR, Kojak C, Rubin
A. Once a day levofloxacin in the
treatment of mild to moderate and
severe community-acquired pneumonia in adults. Infect Dis Clin
Pract 1998; 7: 400–7.
10
Frank E, Liu J, Kinasewitz G, Moran GJ, Oross MP, Olson WH, Reichl
V, Freitag S, Bahal N, Wiesinger
BA, Tennenberg A, Kahn JB. A multicenter, open-label, randomized
comparison of levofloxacin and
azithromycin plus ceftriaxone in
hospitalized adults with moderate
to severe community-acquired
pneumonia. Clin Ther 2002; 24:
1292–308.
11
Mazar R, Morgan N, Williams RR.
A noncomparative, multicenter
study to evaluate the safety and
efficacy of levofloxacin 500 mg
once daily in the treatment of community-acquired pneumonia in
adults (Protocol LOFBIV-PCAP001). Raritan, NJ: RW Johnson
Pharmaceutical Research Institute
Clinical Study Report; 1999. Report No.: Document No. EDMSUSRA-2572838.
12
Preston SL, Drusano GL, Berman
AL, Fowler CL, Chow AT, Dornseif
B, Reichl V, Natarajan J, Corrado
M. Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials. JAMA 1998; 279:
125–9.
13
West M, Boulanger BR, Fogarty C,
Tennenberg A, Wiesinger B, Oross
M, Wu SC, Fowler C, Morqan N,
Kahn JB. Levofloxacin compared
with imipenem/cilastatin followed
by ciprofloxacin in adult patients
with nosocomial pneumonia: a
multicenter, prospective, randomized, open-label study. Clin Ther
2003; 25: 485–506.
14
von Gottberg A, Klugman KP, Cohen C, Wolter N, de Gouveia L, du
Plessis M, Mpembe R, Quan V,
Whitelaw A, Hoffmann R, Govender N, Meiring S, Smith AM,
Schrag S. Emergence of levofloxacin-nonsusceptible Streptococcus
pneumoniae and treatment for
multidrug-resistant tuberculosis in
children in South Africa: a cohort
observational surveillance study.
Lancet 2008; 371: 1108–13.
15
Felmingham D. Comparative antimicrobial susceptibility of respiratory tract pathogens.
Chemotherapy 2004; 50(Suppl
1): S3–10.
16
Nord CE, Peterson J, Ambruzs M,
Fisher AC. Levofloxacin versus
azithromycin on the oropharyngeal
carriage and selection of antibacterial-resistant streptococci in the microflora of healthy adults. Curr Med
Res Opin 2009; 25: 1461–7.
45