Levofloxacin 750-mg for 5 days for the treatment of hospitalized Fine Risk Class III/IV community-acquired pneumonia patients

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1 Respiratory Medicine (2006) 100, Levofloxacin 750-mg for 5 days for the treatment of hospitalized Fine Risk Class III/IV community-acquired pneumonia patients Andrew F. Shorr a,, Mohammed M. Khashab b, Jim X. Xiang b, Alan M. Tennenberg c, James B. Kahn b a Department of Medicine, Pulmonary and Critical Care Medicine, Room 2A-38D, Washington Hospital Center, 110 Irving St. NW, Washington, DC 20010, USA b Ortho-McNeil Pharmaceutical, Inc., 1000 Route 202 South, Room 3213 Raritan, NJ , USA c Tibotec, Inc., Therapeutics, 430 Route 22 East, Bridgewater, NJ 08807, USA Received 21 December 2005; accepted 20 March 2006 KEYWORDS Community-acquired pneumonia; Levofloxacin; Antimicrobial; Efficacy; Symptom resolution; Safety Summary Background: The efficacy and safety of 750-mg, 5-day levofloxacin was recently shown to be comparable to 500-mg, 10-day levofloxacin in a randomized, doubleblind, multicentre clinical trial for mild-to-severe community-acquired pneumonia (CAP). This subgroup analysis attempted to compare the safety and efficacy of a short-course levofloxacin regimen with traditional levofloxacin dosing for PSI Class III/IV patients. Methods: This retrospective, subgroup analysis focused on Pneumonia Severity Index Class III and IV patients enrolled in the study. Measurements included clinical and microbiological success rates, adverse events, and symptom resolution by day 3 of therapy. Results: Of the 528 patients in the ITT population, 219 (41.5%) were categorized as PSI Class III/IV and included in this analysis. Among the clinically evaluable patients, 90.8% (69/76) of patients treated with the 750-mg regimen achieved clinical success, compared with 85.5% (71/83) treated with 500-mg levofloxacin (95% CI, 15.9 to 5.4). Eradication rates in the microbiologically evaluable population were comparable for the 750- and 500-mg regimens (88.9% vs 87.5%, respectively; 95% CI, 18.3 to 15.6). Both regimens were well tolerated and had comparable safety profiles. A greater proportion of patients in the 750-mg treatment group experienced resolution of fever (48.4% vs 34.0%; P ¼.046) and purulent sputum (48.4% vs 27.5%; P ¼.007) by day 3 of therapy. Corresponding author. Tel.: ; fax: address: afshorr@dnamail.com (A.F. Shorr) /$ - see front matter & 2006 Elsevier Ltd. All rights reserved. doi: /j.rmed

2 2130 A.F. Shorr et al. Conclusions: The 750-mg, 5-day levofloxacin course achieved comparable clinical and microbiologic efficacy to the 500-mg, 10-day regimen. By day 3 of therapy, a greater proportion of patients in the 750-mg group had objective and subjective resolution of fever. Further research is needed to determine the economic significance of short-course levofloxacin therapy. & 2006 Elsevier Ltd. All rights reserved. Introduction Community-acquired pneumonia (CAP) accounts for approximately 1 million hospitalizations in the US annually 1 and results in an enormous burden to hospitals at a time of intense economic pressure. CAP is the leading cause of mortality due to infectious disease, and one estimate calculated the total annual inpatient costs in the US of $4.4 billion (in 1995 dollars) due to this disease. 2 To reduce the number of unnecessary admissions, treatment guidelines have provided recommendations for appropriately screening patients for hospitalization. 1,3 Additionally, some hospitals have implemented critical pathways to limit hospital admissions and length of stay to minimize overall healthcare costs. 4 The Pneumonia Severity Index (PSI) score developed by Fine et al. is commonly used to identify patients at risk for death, thereby making hospital admission decisions more evidence-based. 3,5,6 Short-course antibiotic therapy may provide new means to reduce healthcare costs. Numerous studies have investigated the practical aspects of short-course therapy for CAP, though few have focused on the more severely ill population. 7 9 In general, these patients are older, present with comorbidities, may be at a greater risk of treatment failure, and tend to have longer length of stay at hospitals. 10 For these reasons, hospitalization and more aggressive antimicrobial therapy may be necessary to achieve optimal clinical outcomes. 1,11 Higher doses of antimicrobials, such as a 750-mg dose of levofloxacin, may allow the use of shortcourse regimens without compromising clinical outcomes. The 750-mg levofloxacin dose provides a number of theoretical advantages for treating these patients. As with all fluoroquinolones, levofloxacin exhibits concentration-dependent bactericidal activity, and microbiologic eradication is dependent on the ratio of the area under the concentration time curve to minimal inhibitory concentration (AUC/MIC), or the peak concentration to MIC (C max /MIC). 12 Compared to the 500-mg dose, the 750-mg dose provides approximately double the serum AUC and C max values, 13,14 and in vitro pharmacodynamic studies suggest more rapid bacterial killing with the higher dose, including effective eradication of tested strains of ciprofloxacin-resistant Streptococcus pneumoniae. 15 The more rapid eradication may lead to earlier symptom resolution as well as a decreased risk for resistance emergence. Recently, the 750-mg, 5-day levofloxacin regimen was shown to achieve comparable clinical and microbiological outcomes to those of a 500-mg levofloxacin regimen for 10 days. 16,17 Evidence also suggested that the 750-mg dose results in more rapid symptom resolution, particularly resolution of fever. 18 Not presented in the original study report was an analysis of levofloxacin efficacy in the more severely ill or bacteremic CAP patients. 19 Our current report provides a subgroup analysis of patients in the trial who belonged to PSI Class III/IV and required hospitalization, as well as all patients diagnosed with bacteremia. These patients may also be more prone to tolerability issues because of the presence of comorbidities and reduced renal elimination. This analysis attempts to determine if a high-dose levofloxacin regimen can safely and effectively treat PSI III/IV CAP patients with a short course and whether the 750-mg dose affects the time for symptom resolution compared to the 500-mg levofloxacin dose. Patients and methods Study design This was a retrospective subgroup analysis of a randomized, double-blind, active-treatment-controlled, noninferiority study. The study design has been previously described. 17 Briefly, adult (X18 years old) men and women with a diagnosis of mildto-severe CAP were eligible for enrolment. For this analysis, only those patients that belonged to PSI Class III (Score 470 but p90) or PSI Class IV (490 but p130) were included. 3 Five patients in the intent-to-treat (ITT) population belonged in PSI Class V. However, since all of them were in the

3 Levofloxacin for severe CAP mg treatment group, these patients were not included in this analysis. Clinical signs and symptoms were reassessed for each group during an on-therapy visit (day 3), the posttherapy visits (7 14 days after study entry), and a poststudy visit (31 38 days after study entry). The protocol was approved by the participating institutions institutional review boards; written informed consent was obtained before initiation of study procedures. Statistical analysis A two-sided 95% CI with continuity correction was calculated around the difference of clinical success rates of the two treatment groups (levofloxacin 500-mg, 10-day regimen minus levofloxacin 750- mg, 5-day regimen). The change in the percentage of patients reporting the symptom between admission and day 3 for the 750- and 500-mg treated patients was compared using a two-sample McNemar s test, as previously reported. 16 For adverse events, a P-value was computed with a w 2 test to determine the significance of the difference in the number of patients with treatment-emergent adverse events between the treatment groups. Results Patient demographics and baseline characteristics The distribution of patient populations is illustrated in Fig. 1. Of the 528 patients in the intent-to-treat (ITT) population for the study, 219 (41.5%) patients belonged to PSI Class III or IV, with 101 patients treated with 750-mg levofloxacin and 118 patients treated with 500-mg levofloxacin. Baseline demographics of the ITT and clinically evaluable (CE) populations were comparable between treatment groups, including the presence of comorbidities. The mean age was in the 750-mg group, compared to in the 500-mg group. (This compares to a mean age in the overall study of 53.1 and 55.3 for the 750- and 500-mg groups, respectively.) The mean overall PSI scores for the CE population were 87.6 for the 750-mg group and 88.6 for the 500-mg group. For patients belonging to PSI Class III, the mean scores were 78.7 and 79.1 for the 750- and 500-mg groups, respectively. Among patients in PSI Class IV, the mean scores were and for those treated with 750- and 500-mg levofloxacin, respectively. 256 Patients Received Levofloxacin 750 mg, 5 days (ITT) ITT Patients in PSI Class III/IV 61 Patients in PSI III 40 Patients in PSI IV Clinically-evaluable Patients in PSI Class III/IV 49 Patients in PSI III 27 Patients in PSI IV Microbiologicallyevaluable Patients in PSI Class III/IV 27 Patients in PSI III 9 Patients in PSI IV 528 Patients Treated Intent-to-Treat Population (ITT) Figure 1 Patient populations. Clinical success and microbiologic eradication rates The clinical success rates for patients belonging to PSI Class III/IV are shown in Table 1. As reported earlier, the overall cure rates were lower in these patients than in the less severely ill CAP patients (PSI Class I/II) (88.1% for PSI Class III/IV vs 94.7% for PSI Class I/II, both treatment groups combined). 17 Overall, both treatment regimens achieved comparable clinical success rates, though the 750-mg regimen resulted in slightly higher rates overall (90.8% vs 85.5%; 95% CI, 15.9 to 5.4), and for both PSI Class III and IV patients assessed individually. Both treatment regimens also resulted in comparable microbiologic eradication rates in the overall ME population (88.9% for the 750-mg group, and 87.5% for the 500-mg group; 95% CI, 18.3 to 15.6). When patients were analyzed according to the primary pathogen of interest, both levofloxacin regimens showed comparable effectiveness against each of the most common pathogens identified (Table 2). Patients with bacteremia 272 Patients Received Levofloxacin 500 mg, 10 days (ITT) ITT Patients in PSI Class III/IV 68 Patients in PSI III 50 Patients in PSI IV Clinically-evaluable Patients in PSI Class III/IV 51 Patients in PSI III 32 Patients in PSI IV Microbiologicallyevaluable Patients in PSI Class III/IV 17 Patients in PSI III 15 Patients in PSI IV Positive blood cultures were obtained from 9 microbiologically evaluable patients in this study,

4 2132 A.F. Shorr et al. Table 1 Clinical success rates for the clinically evaluable population at posttherapy, based on PSI score. n/n (%) of Patients 95% CI y 750 mg 500 mg PSI classes III and IV 69/76 (90.8) 71/83 (85.5) 15.9 to 5.4 PSI classes III only 44/49 (89.8) 44/51 (86.3) 17.2 to 10.2 PSI classes IV only 25/27 (92.6) 27/32 (84.4) 26.1 to 9.6 Clinical success includes cured and improved. y Two-sided 95% CI with continuity correction were calculated around the difference (levofloxacin 500-mg/10-day regimen minus levofloxacin 750-mg/5-day regimen). Table 2 Microbiologic eradication rates at posttherapy by pathogen of primary interest identified in PSI Class III/IV microbiologically evaluable patients. n/n (%) of Patients 95% CI y 750 mg (N ¼ 36) 500 mg (N ¼ 32) Total patients 32/36 (88.9) 28/32 (87.5) 18.3 to 15.6 Respiratory cultures (typical pathogens) H. influenzae 6/7 (85.7) 4/5 (80.0) H. parainfluenzae 3/3 (100) 4/5 (80.0) S. pneumoniae 6/7 (85.7) 6/8 (75.0) Serologies (atypical pathogens) C. pneumoniae 5/6 (83.3) 4/4 (100) L. pneumophila 4/4 (100) 2/2 (100) M. pneumoniae 9/10 (90.0) 10/11 (90.9) Eradication rates include eradicated and presumed eradicated. y Two-sided 95% CI with continuity correction was calculated around the difference (levofloxacin 500-mg/10-day regimen minus levofloxacin 750-mg/5-day regimen). regardless of PSI class (5 patients treated with 750- mg levofloxacin and 4 patients treated with the 500-mg dose). In the 750-mg treatment group, 3 were identified with Escherichia coli (all of which were eradicated with treatment) and 2 were infected with S. pneumoniae (both of whom were presumed persisted after treatment although no blood cultures were done to confirm this). All 4 bacteremic patients in the 500-mg group were identified with S. pneumoniae infections. Three patients had the infection eradicated after treatment while one patient s infection (S. pneumoniae) persisted at the posttherapy evaluation. The patient withdrew from study medication after taking 3 doses of 500 mg levofloxacin and was hospitalized for 11 days and received piperacillin/ tazobactam (4.5 g IV) and levofloxacin (500 mg IV). The levofloxacin MIC of this isolate remained unchanged at 1 mg/ml. Isolates were unavailable from the two patients in the 750-mg group that failed therapy. Safety The overall safety profiles of the 750- and 500-mg levofloxacin regimens are shown in Table 3 for the ITT population. Overall, 62.4% of patients receiving the 750-mg regimen experienced at least 1 treatmentemergent adverse event, compared with 69.0% of patients receiving the 500-mg dose (P ¼.307). The percentages of patients experiencing adverse events considered to be drug-related were also similar (19.8% for the 750-mg group compared to 19.8% for the 500-mg group; P ¼.996), suggesting the higher dose of levofloxacin was as well tolerated as the 500- mg dose in these patients. The most common treatment-emergent adverse events for the 750- and 500-mg treatment groups, respectively, were insomnia (3.0% and 8.6%), peripheral edema (3.0% and 4.3%), nausea (4.0% and 2.6%), constipation (4.0% and 1.7%) and pain (1.0% and 4.3%) (Table 4). The overall rates of adverse events were not significantly different between the treatment groups.

5 Levofloxacin for severe CAP 2133 Table 3 Overall safety results (PSI classes III and IV intent-to-treat patients). n/n (%) of Patients 750-mg (N ¼ 101) 500-mg (N ¼ 116) P-value y Patients with X1 treatment-emergent AE 63 (62.4) 80 (69.0).307 Patients with X1 treatment-related AE 20 (19.8) 23 (19.8).996 Patients with X1 serious AE 13 (12.9) 22 (19.0).223 Discontinuation due to AEs 7 (6.9) 12 (10.3).375 Deaths z 3 (3.0) 6 (5.2).508 y Two patients were excluded from the safety analysis due to lack of postadmission safety data. y P-values determined by w 2 test unless otherwise noted. z None of the deaths in either treatment group were assessed as related to study drug. y P-value determined by Fischer s exact test. Table 4 Incidence of treatment-emergent AEs (X2% of either treatment group). Adverse event by body system 750-mg (N ¼ 101) n (%) 500-mg (N ¼ 116) n (%) Any adverse event 63 (62.4) 80 (69.0) Body as a whole Edema, peripheral 3 (3.0) 5 (4.3) Condition aggravated 2 (2.0) 3 (2.6) Pain 1 (1.0) 5 (4.3) Cardiovascular Hypotension 3 (3.0) 2 (1.7) CNS Headache 3 (3.0) 2 (1.7) Dizziness 2 (2.0) 0 (.0) Gastrointestinal Constipation 4 (4.0) 2 (1.7) Nausea 4 (4.0) 3 (2.6) Vomiting 3 (3.0) 0 (.0) Diarrhea 1 (1.0) 4 (3.4) Metabolic and nutritional Hypokalemia 3 (3.0) 2 (1.7) Myocardial disorder Myocardial infarction 2 (2.0) 0 (.0) Platelet, bleeding and clotting Epistaxis 2 (2.0) 0 (.0) Psychiatric Insomnia 3 (3.0) 10 (8.6) Respiratory system Chronic obstructive airways disease 4 (4.0) 0 (.0) Skin Rash 1 (1.0) 3 (2.6) Rash erythematous 0 (.0) 4 (3.4) Resolution of CAP symptoms Previous analyses have indicated that, though clinical and microbiologic results were comparable between the 750- and 500-mg levofloxacin regimens, there were differences in the proportion of patients experiencing symptom resolution between admission and day 3 of treatment. Symptom resolution results for patients in PSI Class III and IV (ITT population) are shown in Table 5. A

6 2134 Table 5 A.F. Shorr et al. Resolution of CAP symptoms by day 3 of therapy (PSI classes III and IV intent-to-treat patients). n/n (%) of Patients P-value y 750-mg 500-mg Purulent sputum 46/95 (48.4) 30/109 (27.5).007 Fever (patient reported) 63/95 (66.3) 52/109 (47.7).008 Fever (measured) 44/91 (48.4) 36/106 (34.0).046 Pleuritic chest pain 34/95 (35.8) 28/109 (25.7).135 Shortness of breath 31/95 (32.6) 29/109 (26.6).419 Chills 51/95 (53.7) 54/109 (49.5).571 Cough 15/95 (15.8) 15/109 (13.8).736 Total number of patients assessed who had a response documented at both baseline and Day 3. For each symptom analysed, n ¼ (# patients reporting yes at baseline and no at Day 3) (# patients reporting no at baseline and yes at Day 3). y P-value was computed from a two-sample McNemar s test. significantly greater proportion of patients receiving the 750-mg regimen experienced resolution of fever (patient-reported fever, 66.3% vs 47.7%, P ¼.008; measured fever, 48.4% vs 34.0%, P ¼.046) and purulent sputum (48.4% vs 27.5%; P ¼.007) by day 3 of therapy compared to the 500- mg treatment group. No significant differences were observed between the two groups for other symptoms assessed at day 3 (shortness of breath, chills, cough, and pleuritic chest pain). Discussion This subgroup analysis of a prospective, randomized, double-blind, active treatment-controlled, noninferiority study showed that a 750-mg, 5-day levofloxacin regimen achieved comparable clinical and microbiological results to the 500-mg, 10-day course for hospitalized PSI III/IV CAP patients. In the overall clinically evaluable population, the 750- mg course achieved over 90% success rate, while both regimens were effective against a variety of pathogens identified in the microbiologically evaluable population. Importantly, the higher dose of levofloxacin was as well tolerated as the 500-mg dose. The safety of fluoroquinolones has garnered much attention recently, in particular with regards to cardiovascular effects and glucose homeostasis This can be of particular importance with the more severely ill population as these patients may present with comorbidities and have hepatic or renal dysfunction, thereby affecting normal elimination of the agent. In particular, one study has indicated a dose-dependent effect of fluoroquinolones on QTc interval prolongation in healthy adults. 25 The higher dose of levofloxacin in the present clinical study did not reveal a higher incidence of treatment-emergent or serious adverse events compared to the 500-mg dose. A greater proportion of patients receiving 750- mg levofloxacin experienced resolution of fever and purulent sputum by day 3 of therapy. This can be particularly important in the hospital setting, as clinical stability is commonly used as one of the criteria to determine switch from IV to oral therapy. 4,26 28 An earlier switch to oral medication can provide numerous clinical and economic benefits, including improved patient comfort, reduced nosocomial acquisition rates, and a reduced risk for adverse events associated with IV medications (such as injection site reactions and line sepsis). In a time of increasing pressure for cost efficiency at hospitals, a more rapid switch to oral medication will lower overall drug costs and reduce the time and resources required for drug preparation and administration by healthcare personnel. Reducing the time to switch may also lead to an earlier hospital discharge as illustrated in several studies from hospitals that have utilized automatic IV-tooral switch programs. 4,26,29,30 In the overall patient population of this study, the general trend revealed more rapid IV-to-oral switch for the 750-mg group compared to the 500-mg group, though the difference was not significant. 18 Approximately 70% of PSI III/IV patients in this study were initially treated with IV dosing. Unfortunately, specific protocols for determining the time to switch were not instituted. Therefore, interpreting any results in switch time would be difficult given the heterogeneity in prescribing across the multiple centres included in the trial. The main limitations of this analysis relate to its being a post hoc subgroup analysis of a prospective study. Some data that may have been pertinent to

7 Levofloxacin for severe CAP 2135 include in this report were not collected, such as length of hospital stay, which may have provided some insight on the pharmacoeconomic implications of the 750-mg, short-course regimen. A specific protocol was not provided to investigators for determining the time of IV-to-oral switch. The number of bacteremia patients was low, as were the number of PSI Class V patients, so definitive conclusions regarding the 750-mg, 5-day levofloxacin regimen cannot be appropriately transferred to these patient populations. However, one report documented the efficacy of 500- or 750-mg levofloxacin in 108 cases of pneumococcal bacteremia, with a clinical success rate over 90%, suggesting this agent is highly effective against these types of infections. 31 Finally, this study did not investigate the emergence of resistance following antibacterial treatment. It is important to note that this study introduces two variables in the study design, dosing and duration, so that it is difficult to directly compare the efficacy of 750- and 500-mg levofloxacin dosing. Therefore, hypothetically, a 500-mg, 5-day levofloxacin regimen may be comparable to the 750-mg regimen. The 750-mg dose, however, does suggest more rapid resolution of CAP symptoms, as these were measured by day 3 of therapy. The higher dose may also reduce the risk of resistance development and be effective against less susceptible pathogens, though further studies are needed to assess this. Acknowledgements This subgroup analysis was previously presented at the 100th International Conference of the American Thoracic Society, The clinical trial was supported by Ortho-McNeil Pharmaceutical, Inc. (Raritan, NJ). References 1. Mandell LA, Bartlett JG, Dowell SF, File Jr. TM, Musher DM, Whitney C. 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