Levofloxacin in the Treatment of Pneumonia Caused by ...

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: [email protected]

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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).

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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

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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

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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

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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)