Macrolide-Resistant Streptococcus pneumoniae in Community-Acquired Pneumonia: Clinical and Microbiological Outcomes for Patients Treated with ...
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SUPPLEMENT ARTICLE
Macrolide-Resistant Streptococcus pneumoniae
in Community-Acquired Pneumonia:
Clinical and Microbiological Outcomes
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for Patients Treated with Levofloxacin
J. B. Kahn, B. A. Wiesinger, and J. Xiang
Ortho-McNeil Pharmaceutical, Raritan, New Jersey
The rapid emergence and increasing prevalence of antimicrobial resistance in Streptococcus pneumoniae have
greatly complicated the choice of empirical treatment for community-acquired pneumonia (CAP). The newer
macrolides, azithromycin and clarithromycin, have been popular choices for empirical therapy because of their
activity against the common pathogens responsible for CAP and their improved tolerability, compared with
that of erythromycin. Unfortunately, rates of resistance of S. pneumoniae to the macrolide class of antimi-
crobials have increased steadily during the past decade and have reached 40% in certain areas of the United
States. Although the clinical relevance of macrolide-resistant strains of S. pneumoniae has been questioned,
breakthrough bacteremias and clinical failures have been reported among patients receiving macrolide therapy.
We reviewed the levofloxacin clinical database to determine the clinical and microbiological outcomes for
patients with CAP infected with macrolide-resistant S. pneumoniae. Levofloxacin, including the 750-mg short-
course regimen currently under investigation, produced a successful clinical response in 96.9% of patients
with CAP due to macrolide-resistant S. pneumoniae, compared with 95.1% of all patients.
Bacterial lower respiratory tract infections, including being the most frequently isolated pathogen, S. pneu-
community-acquired pneumonia (CAP), continue to moniae has also been identified as the pathogen most
pose a significant global health challenge, despite the commonly associated with morbidity and mortality
wide spectrum of potent antimicrobials available for among patients with CAP [1–3, 8, 9]. S. pneumoniae
treatment. In addition to their associated high inci- therefore should be considered the benchmark for de-
dence, these infections constitute a major cause of death termining empirical treatment of pneumonia in the
worldwide and are the major cause of death due to community [1–3, 6].
infections in the United States [1]. Streptococcus pneu- Until the early 1990s, the selection of empirical ther-
moniae is the most frequently identified etiologic cause apy for CAP was relatively straightforward. Patients
of bacterial pneumonia [1–7], with an estimated two- with lower respiratory tract infections generally re-
sponded to b-lactam antibiotics quite readily, with mac-
thirds of CAPs caused by this organism. In addition to
rolides reserved for patients with penicillin allergies or
for cases that featured “atypical” presentations. Increas-
ing awareness of the significance of “atypical” patho-
Financial support: Statistical and other analyses were done by Ortho-McNeil gens has led to adjustments in the approach to empirical
Pharmaceutical. The present study was supported by funding from Ortho-McNeil
Pharmaceutical. therapy, with the macrolides gaining favor as first-line
therapy for outpatients with a diagnosis of CAP [1, 4,
Reprints or correspondence: Dr. James B. Kahn, Ortho-McNeil Pharmaceutical,
1000 Rte. 202 S, Raritan, NJ 08869 (jkahn@ompus.jnj.com). 6, 8, 10, 11]. The popularity of the macrolides was
Clinical Infectious Diseases 2004; 38(Suppl 1):S24–33 further enhanced by the availability of the newer class
2004 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2004/3801S1-0004$15.00
S24 • CID 2004:38 (Suppl 1) • Kahn et al.members, azithromycin and clarithromycin, as of late 1991. Levofloxacin is a fluoroquinolone antimicrobial that inhibits
Azithromycin and clarithromycin are characterized by an ex- bacterial DNA synthesis specifically and rapidly [31, 32]. Levo-
tended elimination half-life, which allows for a more conven- floxacin, 500 mg iv or po once daily for 7–14 days, is well
ient once- or twice-daily dosing schedule, and by improved established as a safe and effective treatment for CAP [31, 33,
gastrointestinal tolerance, compared with those associated with 34]. More recently, a short-course (5-day), high-dose (750 mg
the older macrolides (e.g., erythromycin) [12]. iv or po once daily) regimen of levofloxacin has been inves-
Coincident with the changing focus of empirical therapy for tigated and has been proven to be at least as safe and effective
CAP, resistance to macrolides among isolates of S. pneumoniae as the standard regimen of levofloxacin for the treatment of
has been increasing throughout the world. In 1988, only 0.2% CAP. This new 750-mg short-course therapy provides maxi-
of S. pneumoniae isolates in the United States were resistant to mum plasma concentrations that are well in excess of the phar-
macrolides [13]. In 1991–1992, just before the introduction of macodynamic parameter that best correlates with clinical suc-
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clarithromycin and azithromycin, large national surveillance cess for fluoroquinolones (the ratio of the area under the plasma
studies indicated that the prevalence of erythromycin resistance concentration-time curve (AUC) or the maximum plasma con-
had increased to 3.7% in children !2 years old and to 2.2% in centration [Cmax] to MIC) [34–36]. The safety of the 750-mg
children ⭓4 years old [14]. Rates of resistance have continued short-course regimen has also been established [37–39]. A com-
to increase in subsequent years. In a national surveillance study prehensive review of the safety data from phase III clinical trials
of 30 centers, Doern et al. [15] compared antimicrobial resis- that enrolled 1400 patients who received levofloxacin, 750 mg
tance rates among clinical isolates of S. pneumoniae obtained daily for 5 days, demonstrated tolerability similar to that seen
between 1994–1995 and 1999–2000. During 1994–1995, 10.3% with the standard regimens [40], a finding that confirms the
of 1527 S. pneumoniae isolates that were tested in vitro were high safety profile of levofloxacin.
resistant to macrolides. By 1999–2000, the prevalence of mac- The evidence presented above highlights the growing concern
rolide resistance had more than doubled, to 26.2% of the 1531 regarding the role of MRSP in CAP. Applying the basic premise
isolates of S. pneumoniae. Although the patterns of resistance that empirical antimicrobial therapy should rapidly eradicate
(and the prevalence of particular clones) vary among geo- the most likely etiologic pathogens, we undertook a review of
graphic locations, other national and international surveillance the levofloxacin clinical trials database to determine clinical
studies report similar dramatic increases in the prevalence of and microbiological outcomes for patients with CAP infected
macrolide resistance among S. pneumoniae isolates during the with MRSP.
past decade [16–19].
Although the clinical relevance of macrolide-resistant S.
METHODS
pneumoniae (MRSP) has been questioned [1, 3, 8], a number
of treatment failures linked to MRSP have been reported [20– Integrated data from 7 phase III and phase IV clinical trials for
25]. Data supporting the clinical relevance of MRSP infections the treatment of CAP, all of which were conducted in North
come from other sources as well, including retrospective analy- America, were evaluated in this investigation. Data from 4 of
ses of patients hospitalized with bacteremic pneumonia [26, these clinical trials were previously reported elsewhere [41]. All
27] and a matched case-control study [28]. These accumulating patients enrolled in the studies provided written informed con-
data verify that macrolide resistance is clinically relevant and sent, and the study protocol and related study material were
should be a consideration in the determination of appropriate approved by the participating center’s institutional review
therapy for CAP. board before study initiation. The designs and patient char-
The rapid increase in the prevalence of S. pneumoniae isolates acteristics of the individual studies are summarized in table 1.
resistant to multiple antibiotics not only has brought into ques- Four of the studies were open-label, uncontrolled investigations
tion the role of macrolides for the empirical management of evaluating the efficacy and safety of levofloxacin as monother-
CAP but, also, adds a new concern regarding the potential CAP apy for CAP. The other 3 studies were open-label or blinded,
etiologies. This is especially true in areas where penicillin-re- randomized, active treatment–controlled monotherapy CAP
sistant S. pneumoniae or MRSP are endemic [29]. The Infec- studies; the nonlevofloxacin comparators included oral cefu-
tious Diseases Society of America now recommends the em- roxime and parenteral ceftriaxone plus erythromycin, followed
pirical use of a b-lactam in combination with a macrolide by oral clarithromycin plus amoxicillin-clavulanate. The levo-
antibiotic, or monotherapy with a respiratory fluoroquinolone floxacin dose used in 6 studies was 500 mg po or iv for 7–14
(e.g., levofloxacin), for patients with serious CAP infections days; 1 study compared this standard levofloxacin regimen to
[1]. A new class of antimicrobials that has activity against MRSP, the 750-mg short-course regimen (750 mg daily for 5 days).
the ketolides, is also being suggested as alternative therapy for One additional study tested the 750-mg short-course regimen
MRSP infections [30]. of levofloxacin exclusively.
Macrolide-Resistant S. pneumoniae in CAP • CID 2004:38 (Suppl 1) • S25Table 1. Study designs of 7 phase III and phase IV clinical trials of levofloxacin treatment for community-acquired pneumonia (CAP)
that were conducted in North America, as reviewed for the integrated CAP database.
Protocol
[reference] Study design Patient characteristics Treatment regimen
PCAP-001 MC, open-label 655 Adults (18–96 years old) with CAP, inclu- Lvfx, 500 mg po or iv q.d. for 7–14 days
ding infections due to PRSP and MRSP
K90-071 [33] MC, open-label, 590 Adults (18–93 years old) with mild Lvfx, 500 mg po or iv q.d. for 7–14 days; cefur-
Ran, AC to severe CAP oxime axetil, 500 mg po b.i.d. for 7–14 days; or
Ctri, 1 g iv b.i.d. or 2 g iv q.d. for 7–14 days
M92-075 [42] MC, open-label 264 Adults (18–93 years old) with mild Lvfx, 500 mg po or iv q.d. for 7–14 days
to severe CAP
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MULT-01 [36] MC, open-label 313 Adults (17–100 years old) with mixed Lvfx, 250 mg (for patients with UTI) or 500 mg iv
infections, including CAP q.d. for ⭓3 days, followed by po administration
for a total of 5–14 days, depending on
indication
CAPSS-018 MC, open-label, 269 Adults with serious CAP Lvfx, 500 mg iv on day 1, then 500 mg po or iv
Ran, AC q.d. for 7–14 days; or Ctri, 1–2 g iv or im q.d.,
and erythromycin, 500–1000 mg iv q6h, fol-
lowed by clarithromycin, 500 mg po b.i.d., and
amoxicillin/clavulanate, 875 mg po b.i.d., for a
total of 7–14 days
CAPSS-150 MC, DB, Ran, AC 528 Adults (18–89 years old) with mild Lvfx, 750 mg po or iv q.d. for 5 days; or Lvfx,
to severe CAP 500 mg po or iv q.d. for 10 days
CAPSS-171 MC, open-label 124 Adults (22–93 years old) with mild Lvfx, 750 mg po or iv q.d. for 5 days
to severe CAP
NOTE. AC, active control; Ctri, ceftriaxone; DB, double blind; Lvfx, levofloxacin; MC, multicenter; MRSP, macrolide-resistant Streptococcus pneumoniae;
PRSP, penicillin-resistant S. pneumoniae; Ran, randomized; UTI, urinary tract infection.
Pathogens identified in respiratory and blood samples ob- For this investigation, the intent-to-treat population was de-
tained at admission were classified by use of National Com- fined as all patients in the integrated database who had S.
mittee for Clinical Laboratory Standards definitions and were pneumoniae isolated from ⭓1 respiratory or blood sample at
tested for in vitro susceptibility to erythromycin and levoflox- admission. The clinically evaluable population included all en-
acin. The in vitro MIC break points used to determine sus- rolled patients with S. pneumoniae isolated at admission who
ceptibility of S. pneumoniae are provided in table 2 [43]. For had a confirmed diagnosis of CAP; who had received a sufficient
all patients, clinical and microbiological outcomes were eval- course of therapy; who had not received any concomitant or
uated at a posttherapy visit conducted 2–14 days after the last posttherapy treatment with another effective, systemic anti-
dose of therapy; in 6 of the studies, efficacy was also evaluated microbial agent; and who returned for an appropriate postth-
at a poststudy visit 14–33 days after completion of levofloxacin erapy evaluation. The microbiologically evaluable population
treatment. Clinical response to therapy was assessed as “cure” was defined as those patients who were evaluable for clinical
(resolution of clinical signs and symptoms), “improvement” efficacy, who had an appropriate admission respiratory or blood
(partial resolution of clinical signs and symptoms so that no culture done, and who had culture performed at the postther-
additional antibiotic therapy was required), “failure” (inade- apy visit (patients were required to have a blood specimen
quate response to therapy so that additional antibiotic therapy obtained for culture if the admission culture result was positive;
for the original infections was required), or “unable to evaluate”
(patient lost to follow-up). Microbiological response was cat- Table 2. In vitro break points for macro-
egorized as “eradication” (admission pathogen eradicated or lide and levofloxacin susceptibility of Strep-
tococcus pneumoniae.
presumed eradicated; the pathogen was presumed to have been
eradicated if no appropriate specimen was obtained and if the
MIC, mg/mL
patient exhibited clinical cure or improvement), “persistence”
Susceptibility Erythromycin Levofloxacin
(continued presence or presumed presence of the admission
pathogen; the pathogen was presumed to have persisted if the Susceptible ⭐0.25 ⭐2.0
patient exhibited clinical failure but no posttherapy culture was Intermediate 0.5 4.0
available), and “unknown” (lost to follow-up; no appropriate Resistant ⭓1.0 ⭓8.0
posttherapy culture was available). NOTE. Data are from [43].
S26 • CID 2004:38 (Suppl 1) • Kahn et al.Table 3. Patient populations from 7 phase III and admission isolates of S. pneumoniae (of 325 strains tested) were
phase IV studies of levofloxacin to treat commu- resistant to levofloxacin.
nity-acquired pneumonia in patients who had
Table 4 summarizes the demographic characteristics of the
Streptococcus pneumoniae isolated at admission.
intent-to-treat population, according to the erythromycin sus-
Patient population, isolate susceptibility, No. of ceptibility of the admission S. pneumoniae pathogen. There
a
and sample patients were no apparent risk factors for macrolide resistance on the
Intent-to-treat 378 basis of baseline demographic features. Approximately 10% of
Clinically evaluable 311 patients with pneumococcal pneumonia in both of the age
Macrolide susceptible groups (!65 years of age and ⭓65 years of age) were infected
Respiratory or blood sample 229 with MRSP.
Blood sample only 44 Table 5 summarizes the clinical outcomes, based on mac-
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Macrolide intermediate rolide susceptibility and the source of the sample yielding a
Respiratory or blood sample 1 positive result (either respiratory or blood), for the microbi-
Blood sample only 0 ologically evaluable patients. Thirty-one (96.9%) of the 32 pa-
Macrolide resistant tients with MRSP present at admission either were clinically
Respiratory or blood sample 32 cured or showed improvement at the posttherapy assessment
Blood sample only 6 following treatment with levofloxacin. Clinical failure occurred
Microbiologically evaluable 309 in a 72-year-old woman who had severe pneumonia at ad-
Macrolide susceptible mission. The MICs of erythromycin and levofloxacin for this
Respiratory or blood sample 228 strain of S. pneumoniae isolated at admission were 4.0 mg/mL
Blood sample only 43 and 1.0 mg/mL, respectively; the microbiological outcome for
Macrolide intermediate this patient was presumed persistence. This posttherapy clinical
Respiratory or blood sample 1 success rate in patients with MRSP was comparable to the
Blood sample only 0 results for patients infected with a macrolide-susceptible strain
Macrolide resistant of S. pneumoniae (294 [95.1%] of 309 patients). All 6 levo-
Respiratory or blood sample 32 floxacin-treated patients with MRSP bacteremia were found to
Blood sample only 6 have clinical success at both the posttherapy and the poststudy
a
Macrolide susceptibility data are not available for all pa-
assessments.
tients; data from 49 and 50 patients, respectively, are missing Microbiological outcomes were determined for patients who
for the clinically and microbiologically evaluable populations.
were deemed to have achieved clinical success at the posttherapy
and poststudy visits; these results are presented in table 6. At
the poststudy assessment, MRSP isolated from admission res-
patients who were no longer producing sputum were recorded
piratory or blood samples was eradicated in 31 (96.9%) of the
as such at the posttherapy visit). The primary efficacy variable
32 levofloxacin-treated patients; the 72-year-old woman with
was clinical response after therapy in the microbiologically ev-
presumed persistent MRSP infection is described in the pre-
aluable patients who had MRSP infections.
vious paragraph. Eradication rates for levofloxacin-treated pa-
tients with MRSP were comparable to those for patients with
RESULTS macrolide-susceptible S. pneumoniae (289 [93.5%] of 309 pa-
tients). MRSP was eradicated from the blood of all 6 bacteremic
The numbers of intent-to-treat, clinically evaluable, and mi-
patients (100%) treated with levofloxacin.
crobiologically evaluable patients infected with S. pneumoniae
are presented, in table 3, according to the erythromycin sus-
ceptibility of the pneumococci isolated at admission. A total
DISCUSSION
of 378 patients with culture-proven pneumococcal pneumonia
were enrolled in the combined studies. Of these 378 intent-to- An awareness of current patterns of antibacterial resistance is
treat patients, 311 were evaluable for clinical outcomes and 309 essential for prudent prescribing of therapy for CAP to ensure
were evaluated for microbiological outcomes. For 32 of the clinical success and bacterial eradication. Unfortunately, during
patients, the result of culture of a respiratory or blood sample the past decade, there has been a steady decline in antimicrobial
obtained at admission was positive for an MRSP isolate (eryth- activity against S. pneumoniae, which is the most clinically rel-
romycin MIC, ⭓1 mg/mL); 6 of the patients had bacteremia evant CAP pathogen. Of particular concern is the precipitous
due to MRSP. One additional patient tested positive for a res- increase in strains of S. pneumoniae that are resistant to b-
piratory isolate with intermediate resistance to macrolides. Two lactams and the macrolides. On the basis of results from na-
Macrolide-Resistant S. pneumoniae in CAP • CID 2004:38 (Suppl 1) • S27Table 4. Demographic characteristics of levofloxacin-treated patients with pneumococ-
cal pneumonia.
a
Erythromycin susceptibility
Susceptible Intermediate Resistant Unknown Total
Characteristic (n p 281) (n p 1) (n p 38) (n p 58) (n p 378)
Sex
Male 177 (76.9) 0 19 (8.3) 34 (14.8) 230
Female 104 (70.3) 1 (0.7) 19 (12.8) 24 (16.2) 148
Race
White 185 (74.6) 1 (0.4) 29 (11.7) 33 (13.3) 248
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Black 87 (73.7) 0 7 (5.9) 24 (20.3) 118
Asian 1 (50.0) 0 1 (50.0) 0 2
Hispanic 5 (71.4) 0 1 (14.3) 1 (14.3) 7
Other 3 (100.0) 0 0 0 3
Age, years
!65 185 (73.4) 0 24 (9.5) 43 (17.1) 252
⭓65 96 (76.2) 1 (0.8) 14 (11.1) 15 (11.9) 126
Mean SD 55.2 17.1 69.0 57.5 16.6 54.0 16.3 55.3 16.9
Range 18–93 69–69 25–94 23–85 18–94
NOTE. Unless indicated otherwise, data are no. of patients with the characteristic (% of total patients
with that characteristic).
a
Worst case, by patient.
tional surveillance studies, ∼30% of pneumococci in the United S. pneumoniae is ⭐0.25 mg/mL [43]. The maximum plasma
States are now nonsusceptible to penicillin, and ∼25% of pneu- concentration of azithromycin achieved with the recommended
mococcal strains are resistant to macrolides [18, 44, 45]. The dosage schedule for CAP (500 mg on day 1, followed by 250
close correlation between b-lactam and macrolide resistance mg/day for days 2–5) ranges from 0.24 to 0.41 mg/mL and
limits the selection of empirical therapy even further. The in- decreases to a minimum level of 0.05 mg/mL during the dosing
cidence of macrolide resistance is much higher among pneu- interval [12, 53]. Although the Cmax for clarithromycin is higher
mococcal strains exhibiting high-level penicillin resistance (1.0–2.1 mg/mL), concentrations still decrease rapidly (elimi-
(MIC, ⭓2 mg/mL; 25%–70% of strains) than among penicillin- nation half-life, ∼4 h) during the 12-h dosing interval [12, 54].
susceptible strains (MIC, ⭐0.06 mg/mL; ∼5% of strains) [15– Jacobs et al. [55] applied pharmacodynamic parameters to
18, 29]. Macrolide resistance is not limited to penicillin-resis- interpret in vitro susceptibility data in a more clinically mean-
tant strains of S. pneumoniae, however. In the Tracking ingful manner. National Committee for Clinical Laboratory
Resistance in the United States Today (TRUST) national sur- Standards break points were used to test the susceptibilities of
veillance study, ∼10% of pneumococcal strains in 1999–2000 1476 clinical isolates of S. pneumoniae against 10 oral anti-
were resistant to macrolides alone [18]. microbial agents, including azithromycin, clarithromycin, and
Various hypotheses have been offered for the precipitous ciprofloxacin. The previously derived key pharmacodynamic
increase in the prevalence of MRSP. Some investigators have parameters pertinent to clinical outcomes for each agent tested
found positive correlations between macrolide use and the (time above the MIC, for the macrolides, and the ratio of AUC
emergence of resistance [17, 46, 47], with cross-resistance al- to the MIC, for azalides and fluoroquinolones), in conjunction
most invariably found among the older (erythromycin) and with the MIC data, were used to determine susceptibility under
newer (azithromycin and clarithromycin) macrolides [48, 49]. clinical conditions. By use of these criteria, only 69% of the S.
Also, substantial data indicate that suboptimal antibiotic reg- pneumoniae strains were susceptible to azithromycin and clar-
imens can enhance the development of resistance. With this ithromycin. The primary factor responsible for the lack of mac-
background, the relatively long elimination half-lives of azith- rolide susceptibility was the very low plasma concentrations
romycin and clarithromycin, in combination with serum con- achieved with azithromycin and clarithromycin, which were
centrations that fall below the MIC90 for S. pneumoniae during below the MIC90 for S. pneumoniae for most of the dosing
much of the dosing interval, have been proposed as key factors interval.
in the selection of MRSP [29, 50–52]. The in vitro susceptibility Two principal mechanisms of macrolide resistance are known
break point for both azithromycin and clarithromycin against to exist among isolates of S. pneumoniae: target site modifi-
S28 • CID 2004:38 (Suppl 1) • Kahn et al.Table 5. Clinical response of microbiologically evaluable, levofloxacin-
treated patients with pneumococcal pneumonia.
Source yielding Streptococcus pneumoniae
Respiratory
or blood sample Blood sample only
Time point, clinical All All
response S. pneumoniae MRSP S. pneumoniae MRSP
After therapy
Successa 294 (95.1) 31 (96.9) 60 (89.6) 6 (100.0)
Failure 15 (4.9) 1 (3.1) 7 (10.4) 0
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Unable to evaluate 0 0 0 0
Total 309 32 67 6
After study
Successa 236 (76.4) 28 (87.5) 45 (67.2) 6 (100.0)
Failure 4 (1.3) 0 1 (1.5) 0
Unable to evaluate 69 (22.3) 4 (12.5) 21 (31.3) 0
Total 309 32 67 6
NOTE. Data are no. (%) of patients. MRSP, macrolide-resistant S. pneumoniae.
a
Includes cure and improved condition.
cation and active drug efflux [29, 49, 56, 57]. Target site mod- resistance to macrolides (MIC, 14 mg/mL). Initially, it was
ification results from mutations in the ermB gene [56]. The thought that concentrations of the macrolide achieved at the
ermB mutation, also referred to as the MLSB phenotype, pro- site of infection would be high enough to overcome the efflux
duces very high-level resistance (erythromycin and azithro- pump mechanism [3]. However, reports of therapeutic failures
mycin MIC, ⭓64 mg/mL). The second mechanism of resistance associated with MRSP infections include strains with both types
results from mutations in the mefE gene (also referred to as of resistance genes present [20, 26, 28].
the M phenotype) [57], which encodes a macrolide efflux pump Although the clinical relevance of macrolide resistance was
and produces a lower level of resistance (erythromycin and questioned initially, case reports and case series associating
azithromycin MICs, 2–32 mg/mL). Pneumococcal strains that macrolide use with clinical failure in patients with MRSP pneu-
are resistant to erythromycin by either mechanism are also monia or bacteremia are increasing [20–28]. In a retrospective
resistant to azithromycin and clarithromycin, although clin- assessment of 41 patients hospitalized with bacteremic pneu-
damycin is unaffected by the efflux phenotype [29, 58, 59]. monia, 7 patients had previously received antimicrobial therapy
The relative prevalence of the 2 erythromycin resistance before admission [26]. Four of the 7 patients with treatment
mechanisms varies both geographically and temporally [29, 49, failure had breakthrough pneumococcal bacteremias caused by
56]. In Europe, most macrolide resistance is related to the MLSB low-level macrolide-resistant strains (MIC, 8–16 mg/mL) after
phenotype, whereas increased drug efflux is the more common treatment with azithromycin or clarithromycin for 3–5 days.
mechanism for MRSP in the United States. In a survey of This study not only documented clinical failures associated with
invasive S. pneumoniae isolates in metropolitan Atlanta, Geor- macrolide resistance but, also, countered the prediction that
gia, the overall incidence of macrolide resistance increased from resistance due to the M phenotype was not clinically relevant
16% to 31% during the 6 years from 1994 through 1999 [60]. because the high concentrations of macrolide achieved at the
The frequency of pneumococcal isolates with the MLSB phe- infection site would be sufficient to overcome the efflux pump
notype remained stable during the surveillance period, whereas and eradicate the pathogens. Similar findings were reported in
the percentage of all S. pneumoniae isolates exhibiting the efflux a more recent retrospective analysis from Belgium [27]. Medical
mutation increased significantly, from 9% in 1994 to 26% in records from 136 patients hospitalized with pneumococcal bac-
1999 (P ! .001). Of even greater concern was the parallel in- teremia were reviewed to identify outpatient treatment failure.
crease in erythromycin MICs for the isolates containing efflux. Twelve patients had received antimicrobial therapy (4 had re-
In 1995, 21% of the efflux-positive isolates had an MIC90 of ceived clarithromycin, and 8 had received b-lactams) for ⭓48
⭓8 mg/mL; by 1999, the percentage had increased to 94% h before admission. The S. pneumoniae isolates recovered from
(P ! .001). Of note, Peric et al. [61] recently demonstrated that all 4 patients who had failure of clarithromycin therapy were
198% of Haemophilus influenzae strains have a macrolide efflux highly resistant to macrolides.
mechanism, with ∼1.3% of these strains showing high-level In a more rigorously designed matched case-control study,
Macrolide-Resistant S. pneumoniae in CAP • CID 2004:38 (Suppl 1) • S29Table 6. Microbiological response of microbiologically evaluable, lev-
ofloxacin-treated patients with pneumococcal pneumonia.
Source yielding Streptococcus pneumoniae
Respiratory
or blood sample Blood sample only
Time point,
microbiological All All
response S. pneumoniae MRSP S. pneumoniae MRSP
After therapy
Eradicateda 289 (93.5) 31 (96.9) 58 (86.6) 6 (100.0)
b
Persisted 17 (5.5) 1 (3.1) 6 (9.0) 0
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Unknown 3 (1.0) 0 3 (4.5) 0
Total 309 32 67 6
After study
Eradicateda 243 (78.6) 30 (93.8) 45 (67.2) 6 (100.0)
Persistedb 1 (0.3) 0 0 0
c
Relapsed 4 (1.3) 0 2 (3.0) 0
Unknown 61 (19.7) 2 (6.2) 20 (29.9) 0
Total 309 32 67 6
NOTE. Data are no. (%) of patients. MRSP, macrolide-resistant S. pneumoniae.
a
Includes eradicated plus presumed eradicated.
b
Includes persisted plus presumed persisted.
c
Includes relapsed plus presumed relapsed.
Lonks et al. [28] compared the rates of breakthrough pneu- structure at C-3 with a keto group [30]. The ketolides were
mococcal bacteremia among patients infected with macrolide- specifically designed to address the growing problem of peni-
resistant isolates with those among patients infected with mac- cillin-resistant or macrolide-resistant pneumococci. Telithro-
rolide-susceptible isolates. Eighteen (24%) of 76 case patients mycin is the first member of the class to undergo clinical as-
with macrolide-resistant pneumococcal bacteremia were taking sessment and is awaiting final approval of the United States
a macrolide when blood was obtained for culture, compared Food and Drug Administration (Rockville, MD) [30].
with none of the 136 matched controls with macrolide-sus- At this point in time, resistance to the ketolides is uncom-
ceptible isolates (P ! .0001). As found in the retrospective case mon, but reports of such resistance are beginning to appear
series, macrolide treatment failure occurred in association with [30, 44, 62]. When resistance does occur, it appears to be linked
low-level macrolide resistance (M phenotype; MIC, 4 mg/mL). to target site modification, which is one of the main mecha-
These data demonstrate that therapeutic failure during mac- nisms associated with macrolide resistance. In the Prospective
rolide treatment is more likely in patients infected with MRSP Resistant Organism Tracking and Epidemiology for the Ketolide
and that either of the 2 primary macrolide-resistance mecha- Telithromycin (PROTEKT) study, a global surveillance study
nisms can be involved. of the susceptibility of bacteria obtained from patients with
None of these case reports or studies proves a cause-and- community-acquired respiratory tract infections [44], 25
effect relationship between treatment failure and macrolide re- (2.1%) of 1199 isolates of S. pneumoniae required telithromycin
sistance. The existence of a causal relationship can be estab- MICs of 10.5 mg/mL; these isolates were found to harbor the
lished convincingly only in large, prospective, randomized, phenotype MLSB resistance gene. In an in vitro study, Davies
controlled clinical investigations specifically designed to test the et al. [63] found low-level resistance of S. pneumoniae (both
hypothesis that macrolide treatment failures are more likely to macrolide-susceptible and macrolide-resistant strains) to tel-
occur in patients infected with MRSP. For a variety of ethical ithromycin through sequential subcultures in subinhibitory
and logistic considerations, it is unlikely that this type of study concentrations.
will ever be conducted. The accumulating data do indicate, Recent national guidelines for the empirical management of
however, that macrolide resistance can be clinically relevant and CAP reflect the shifting patterns and susceptibilities of the most
should be a consideration in determining appropriate therapy frequently encountered pathogens [1, 6], with the current In-
for CAP. fectious Diseases Society of America guidelines including the
Ketolides are semisynthetic macrolide derivatives created by option of monotherapy with a respiratory fluoroquinolone. In
the replacement of the cladinose component of the macrolide addition, the ketolides have been developed to address the prob-
S30 • CID 2004:38 (Suppl 1) • Kahn et al.lem of MRSP. However, the antimicrobial spectrum of the ke- phase III levofloxacin studies. Of the 27 patients with a mac-
tolides for the management of CAP is not as broad as is that rolide-resistant strain of S. pneumoniae isolated at admission,
of the fluoroquinolones [64], because the ketolides have limited the pathogen was eradicated in 26 patients (96.3%) after treat-
in vitro activity against H. influenzae [30, 65–68] and little or ment with levofloxacin.
no activity against gram-negative rods. Of greatest concern are In the present study, we reviewed the outcomes of 378 pa-
the limited data supporting the use of macrolides for bacteremic tients who were enrolled in the combined studies and who had
pneumococcal pneumonia, especially considering the relatively a diagnosis of pneumococcal pneumonia. For 32 of the 378
low concentrations of the macrolides attained in plasma [6, 29] patients, results of cultures of blood or respiratory samples
and the recent reports of breakthrough bacteremia in patients obtained at admission were positive for an MRSP isolate.
receiving macrolide therapy [26, 27]. Thirty-one (96.9%) of the 32 patients with CAP due to MRSP,
Characteristics of levofloxacin that support its use as effective including all 6 patients with MRSP present on culture of blood
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monotherapy for CAP include broad-spectrum bactericidal ac- samples obtained at admission, had either clinical cure or im-
tivity against the common pathogens implicated in mild to provement after receiving treatment with levofloxacin and re-
severe CAP, including S. pneumoniae (including penicillin-re- quired no further antibiotic therapy. The clinical success rate
sistant strains [penicillin MIC, ⭓2 mg/mL]), H. influenzae, Mor- among patients infected with a macrolide-susceptible strain of
axella catarrhalis, Legionella pneumophila, Chlamydia pneu- S. pneumoniae was comparable (95.1%) to the clinical success
moniae, Mycoplasma pneumoniae, Staphylococcus aureus, and rate among patients with MRSP. Eradication rates in patients
gram-negative rods [31, 69–72]; extensive distribution into pul- with MRSP and macrolide-susceptible S. pneumoniae were
monary tissue, epithelial lining fluid, and alveolar macrophages 96.9% and 93.5%, respectively. These data support levofloxacin
[73–75]; and essentially complete (⭓99%) oral absorption [76]. as an appropriate choice in the treatment of CAP wherever
The spectrum of levofloxacin activity also includes S. pneu- penicillin-resistant S. pneumoniae or MRSP is present in the
moniae isolates that are highly resistant to penicillin [15, 31, community.
70]. An additional feature of levofloxacin is its excellent tol-
erability and favorable safety profile when used alone or in
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