Adrian C. Peña, M.D., 1 Camilo C. Roa, M.D, 2 Nazario A. Macalintal, M.D. 3 Vincent M. Balanag, Jr. M.D., 4 and Myrna T. Mendoza, M.D.

Transcription

1 Safety and Efficacy of Intravenous and Oral Azithromycin in Community Acquired Pneumonia: Results of an Open, Multicenter Study Among Filipino Patients Adrian C. Peña, M.D., 1 Camilo C. Roa, M.D, 2 Nazario A. Macalintal, M.D. 3 Vincent M. Balanag, Jr. M.D., 4 and Myrna T. Mendoza, M.D. 5 ( 1 East Avenue Medical Center, 2 Philippine General Hospital, 3 Mandaluyong City Medical Center, 4 Lung Center of the Philippines, 5 National Kidney and Transplant Institute; Correspondence: Dr. Adrian C. Peña, Room 223 University of the East Ramon Magsaysay Memorial Medical Center, Aurora Blvd., Quezon City. First published in the Phil J Internal Medicine 2003; 41: Reprinted with permission with modifications to conform to this journal s format.) ABSTRACT The mortality and morbidity associated with community-acquired pneumonia (CAP) remain significant. Recommendations emphasize the prompt initiation of proper antibiotic treatment, which should include coverage for atypical organisms in hospitalized CAP patients. Newer macrolides, like azithromycin, offer an advantage because of the potential for monotherapy, ease of once-a-day dosing, and convenience for switch therapy. This multicenter, open, non-comparative investigation among adult patients with clinical and radiographic/microbiologic evidence of CAP needing hospitalization was conducted in order to evaluate the efficacy and safety of azithromycin in the treatment of CAP requiring hospitalization. Intravenous azithromycin 500 mg once daily (OD) for at least two days followed by oral azithromycin 500 mg to complete a total of 7-10 days treatment were given to study subjects. Subjects were observed for a total of 35 days. Clinical response, radiographic and microbiological outcome, and adverse events were monitored at regular intervals. A total of fifty patients were enrolled and forty-one completed the study. These were mainly females who were tachypneic and slightly febrile on admission with leukocytosis and neutrophilic predominance. The most frequent microorganism isolated by culture was Streptococcus pneumoniae. Significant improvement in clinical parameters and physical findings were observed from initial to succeeding visits even after intention-to-treat analysis. Clinical improvement was documented in 98% (42/43) after at least 10 days with at least a presumed bacteriological eradication in 74% (32/43). The mean duration of IV therapy was three days with a mean total duration of eight days. Majority was switched to oral formulation by the fourth day. The most common adverse event reported was gastrointestinal disturbance, which occurred in eight subjects. Azithromycin, given as a single agent, is effective in adult CAP patients with no co-morbidities requiring hospitalization. Clinical response was very favorable with no documented relapse. It is generally safe and well tolerated. [Phil J Microbiol Infect Dis 2003; 32(4): ] Key Words: Community acquired pneumonia, CAP, azithromycin, azalide INTRODUCTION Community acquired pneumonia (CAP) is a surging health problem and continues to be a significant cause of mortality and morbidity even in developed countries. In the United States, approximately 1.7 million hospitalizations for CAP are reported each year at an annual cost of about US$ 23 billion. 1 In the Philippines, CAP remains to be among the top five causes of death and the figures have not changed significantly in the past few years. 2 These numbers might be more significant especially among the geriatric age group where death rates approach 40%. 3

2 Various consensus guidelines have been presented with emphasis on the proper diagnostic and therapeutic approach to pneumonia. 1,2,4,5 They consistently stress the critical aspect of initiating the proper antibiotic agents promptly, which is associated with more favorable outcome. 5 The role of empiric therapy is likewise stressed since causative pathogens are identified in fewer than 50% of patients despite exhaustive investigations. The chosen antimicrobial regimen should cover for core organisms such as Streptococcus pneumoniae, Hemophilus influenzae, and Moraxella catarrhalis, as well as atypical organisms. 1,2,4 The role of macrolides as a single agent or in combination with other antimicrobials has been recognized by panel recommendations principally because of its excellent activity against commonly encountered organisms in CAP patients requiring hospitalization. 5 Newer agents of this class, like azithromycin, offer excellent activity against H. influenzae, fewer adverse events compared to erythromycin, convenience of once daily dosing, and high tissue concentrations. The American Thoracic Society (ATS) has recommended monotherapy with intravenous azithromycin for hospitalized CAP patients who do not require ICU admission, without cardiopulmonary disease and modifying factors (group IIIb). 1 The importance of switching therapy from intravenous to oral formulation is likewise an issue because this will potentially increase compliance and was proven to shorten hospital stay and reduce overall cost of care. 6 Antimicrobial preparations with superior bioavailability and tissue concentration after ingestion will definitely offer an advantage in terms of management. This study was primarily undertaken to evaluate the safety of azithromycin and clinical response of patients to azithromycin in the management of CAP requiring hospitalization. This is the first local study to investigate the efficacy of intravenous followed by oral azithromycin as monotherapy among this group of CAP patients. MATERIALS AND METHODS Study Design. This was an open, non-comparative multicenter investigation conducted in in-patient setting of the following centers: East Avenue Medical Center, Philippine General Hospital, National Kidney and Transplant Institute, Lung Center of the Philippines, and Mandaluyong City Medical Center. The study was conducted in accordance with the ethical principles contained in the Declaration of Helsinki and International Conference on Harmonization (ICH) - Good Clinical Practice Guidelines. All patients gave their written informed consent prior to participating in the study. Patient Selection. Patients with clinical and radiological evidence of CAP were included in this study with the following inclusion criteria: A. Men and women who were at least 18 years of age. Women of childbearing potential, including women who are postmenopausal for less than two years, must have a negative urine gonadotropin pregnancy test prior to entry into the study, confirmed by a negative serum gonadotropin pregnancy test. All women with childbearing potential, including women who are postmenopausal for less than 2 years, must use adequate contraception both during and for 3 months after the last dose of study drug has been taken.

3 B. Clinical and radiographic findings consistent with CAP: 1. New pulmonary infiltrate on chest x-ray that cannot be attributed to some other etiology 2. Any one of the following: a. cough b. tachypnea (RR> 20/min) c. tachycardia (HR>100/min) d. fever (T>37.8 C) AND 3 at least one abnormal physical chest finding of rhonchi, crackles or wheezes. Pneumonia is of a severity that warrants hospitalization and initial IV therapy. Criteria for exclusion 1. Pregnant or lactating women or women of childbearing potential not practicing adequate methods of contraception 2. Treatment with any other potentially effective antibiotic within 24 hours prior to enrollment or concomitantly with the study drug 3. Known sensitivity or intolerance to macrolide antibiotics 4. Presence of infection at enrollment that may require treatment with an antibiotic other than the study drug 5. Severe pneumonia requiring critical care interventions or additional antimicrobials 6. Patients with underlying lung disease, significant hematological, renal, cardiovascular, or hepatic disease, AIDS, HIV infection, or metastatic tumor 7. Donation of blood or blood products for transfusion during and for 6 weeks after the study Medication. Following a full assessment at the initial screening visit, eligible patients were given azithromycin administered at a dose of 500 mg OD in 250 ml or 500 ml compatible diluent. The infusate concentration and rate of infusion for azithromycin was either 1 mg/ml over 3 hours or 2 mg/ml over 1 hour for 2-5 days, depending upon the clinician s judgment. Azithromycin intravenous administration was followed by the oral capsule preparation at a dose of 500 mg OD to complete a total of 7-10 days of therapy, depending on clinical scenario. Oral azithromycin was given at least one hour before or 2 hours after meals. Monitoring. Each patient was evaluated by the investigator on four subsequent visits: Day 1 or before starting treatment (Visit 1 or baseline visit), after 3 days (Visit 2), after 10 to 14 days (Visit 3), and thereafter on Days 28 to 35 (Visit 4). During the baseline visit, the following were obtained: 1. Baseline physical examination and clinical assessment of signs and symptoms 2. Chest x-ray, postero-anterior view (CXR-PA) 3. CBC with differential count 4. Liver function test, BUN, creatinine, glucose, sodium, potassium

4 5. Prothrombin time, partial thromboplastin time 6. Two sets of blood culture obtained from two different sites. If blood culture turns out to be positive for a pathogen, follow-up blood cultures were obtained during subsequent evaluations until they were negative 7. Urine for pregnancy test on women of childbearing potential and urinalysis 8. Arterial blood gases, if clinically indicated 9. Expectorated sputum or endotracheal aspirate for Gram stain and routine aerobic bacterial culture 10. Any material from the respiratory system like pleural fluid or tissue was sent for culture upon the clinicians discretion Patients with no isolated pathogen from adequate samples were considered bacteriologically non-evaluable but were followed up for clinical response and evaluation Throughout their hospital stay, patients were monitored daily for any adverse event, clinical assessments of signs and symptoms were recorded, changes in concomitant medication were noted, and arterial blood gases were obtained if indicated. On the third day of hospitalization and at the end of treatment, CXR films, urinalysis, baseline blood tests, Gram stain of any respiratory specimen, and two sets of blood culture (if baseline culture was positive) were repeated. Vital signs (temperature, RR, PR, and blood pressure) were monitored and recorded at every visit. The severity of fever, cough, purulent sputum, dyspnea, cyanosis, rales, rhonchi and wheeze were graded from 0 to 3, corresponding to none, mild, moderate, and severe, respectively. After at least one month from entry into the study, individuals were followed up and physical examinations and clinical assessments for signs and symptoms were performed. CXR films were repeated if radiographs taken at initial visits did not show improvement or if the subjects clinical condition deteriorated. Bacteriologic examination of respiratory specimen and a repeat laboratory evaluation was performed if these were indicated or if the subject experienced a clinically significant adverse event. At any point during the study, the investigator could discontinue treatment or withdraw the patient upon his discretion with the surrounding circumstances clearly documented. Assessment of clinical response. The clinical, bacteriological, and radiological responses of the patients were recorded based on a preset criteria (see Appendix I). All adverse events were also recorded. Assessment of safety. This was assessed via: 1) adverse events observed by the investigators or volunteered by patients at each study visit, regardless of suspected causal relationship to the study medication; 2) clinically significant changes in physical examination findings; and 3) changes in standard laboratory test values requiring a change in drug dosage, discontinuation, or other interventions. A serious adverse event is defined as any drug experience occurring at any dose that: 1) results in death; 2) is life-threatening; 3) results in in-patient hospitalization or prolongation of existing hospitalization; 4) results in a persistent or significant disability/incapacity; or 5) results in congenital anomaly/birth defect.

5 Statistical Analysis. Means (for quantitative variables) and percent-ages (for categorical variables) were calculated to describe the characteristics of patients. Temperature, RR, PR and blood pressure were analyzed by repeated measures ANOVA to determine improvement of vital signs over time. The Friedman test was employed to compare each respiratory symptom of fever, cough, purulent sputum, dyspnea, cyanosis, rales, rhonchi and wheeze from baseline up to the last visit. Two sided tests were used and p values of.05 or less were taken to be statistically significant. Intention to treat analysis was carried out for patients who had at least one dose of the test drug. For patients withdrawn before the conclusion of the study, the last available examination was carried forward in the calculations. RESULTS Baseline Characteristics A total of 63 patients were screened of which 50 were subsequently included in the study. The demographics of the 50 subjects are shown in Table 1. Table 1. Demographic and clinical data characteristics of the patients studied (ITT population; n=50) Sex: Male (n, %) 21 (40%) Female (n, %) 29 (60%) Age: mean (range) in years 47.8 (18 89) Temperature at baseline: mean and SD in centigrade / Respiratory rate (bpm): mean and SD 25 +/ White Blood Cell (WBC) count (x 10 9/ L): mean and SD / Organisms isolated (n= 34 culture isolates) Streptococcus pneumoniae 9 Staphylococcus epidermidis 5 Alpha-hemolytic Streptococcus 4 Hemophilus influenzae 4 Klebsiella pneumoniae 2 Hemophilus parainfluenzae 2 Enterobacter aerogenes 2 Others 6 Forty-one subjects completed the study and were available for evaluation. Nine were withdrawn for the following reasons: lost to follow-up, patient went home against medical advice, high suspicion of underlying pulmonary tuberculosis, significant protocol violations in three cases and occurrence of serious adverse events in three cases. The study population was predominantly female with a wide range of ages, the oldest being 89 years old. Majority of the patients were slightly febrile and were tachypneic. All of them demonstrated an abnormal lung finding on physical exam with unilateral crackles being present in 90% of cases. An elevated WBC count was documented, the highest being x 10 9 /L with all cases showing a neutrophilic predominance in the differential count. Clinical Response Evaluation There was a significant (p value <0.001) normalization of temperature, RR and PR from initial visit to succeeding visits (Figure 1). These findings were similar after an

6 intention-to-treat analysis was done (Figure 2). Likewise, there was a significant improvement over succeeding visits for fever, cough, purulent sputum, dyspnea and rales considering the fifty individuals enrolled in the study (p value <0.001) (Figure 3). The finding of crackles was likewise reduced by the third day of therapy. There was no reported relapse in these parameters and improvement was well documented until the end of the study. Decreased breath sounds, chest pain/tightness, back pain, weakness and anorexia were other reported symptoms, which eventually disappeared on succeeding visits. (p value for PR, RR and temperature = <0.001) Figure 1. Mean values of clinical parameters for patients who completed all visits (n= 41) Figure 2. Mean values of clinical parameters after intention-to-treat analysis (n=50)

7 Figure 3. Mean scores of symptoms during visits (n=50) The overall clinical response at visit 3 (day 10-14) can be assessed in 43 patients and 98% (42 out of 43) showed at least an improvement of their clinical condition. At visit 4, overall clinical response of cure is 90% (Table 2). Table 2. Distribution of Patients According to Clinical Response Visit 3 Visit 4 Cure Improvement 21 Failure 1 3 Lost to follow-up 1 (improvement on Visit 3) Withdrawn due to AE 1 (failure on Visit 3) Bacteriological Evaluation In 34 subjects, Streptococcus pneumoniae was the most common causative agent of the CAP based on sputum culture. The other etiologic organisms are shown in Table 1. The remaining organisms included other Staphylococcus species and Enterococcus. Sixteen patients yielded no organism on culture and therefore, their bacteriological response could not be evaluated. In 91% (31 out of 34) of cases, at least a presumed eradication was concluded by the end of a 7-10 day treatment period. All organisms were sensitive to azithromycin except for two cases of Enterobacter aerogenes and one isolate of Pseudomonas aeruginosa. The overall bacteriological response of the 43 patients who had completed visit 3 is shown in table 3. Radiological Evaluation The chest x-rays of the 41 patients who completed the study revealed that only 15 normalized while the rest remained abnormal. Considering those who reached Visit 3 and Visit 4, the radiological response of these 43 patients are summarized in table 4.

8 Table 3. Distribution of Patients According to Bacteriological Evaluation Visit 3 Visit 4 Eradication 4 4 Presumed eradication Persistence 3 1 Eradication with reinfection 1 Superinfection Bacteriologically non-evaluable 9 7 Withdrawn 2 Lost to follow-up (1= presumed eradication on Visit 3) Adverse event (1= bacteriologically non-evaluable on Visit 3) Table 4. Distribution of Patients According to Radiologic Evaluation Visit 3 Visit 4 Resolution 6 15 Marked improvement Radiological failure 8 5 Non-evaluable 3 5 No x-ray 2 Withdrawn 2 Lost to follow-up (1= marked improvement on Visit 3) Averse event (1 = radiological failure on Visit 3) Duration of Therapy The mean duration of intravenous treatment was three days with a mean total duration of eight days of therapy. No patient received intravenous azithromycin beyond five days. Oral azithromycin was started by the third day in 6 patients and majority (25 patients) was shifted to oral therapy by the fourth day. Safety Outcome Safety data were available for all 50 patients who took at least one dose of study drug. Table 5 shows a summary of the adverse events. A total of 32 events were reported in 18 patients. Out of these events, seven were considered causally related to the study medication: 2 cases of diarrhea and 5 cases of local pain on intravenous site. All were mild in severity and no serious or severe events classified as treatment-related occurred. The three cases of serious events were withdrawn from the study. One patient had pleural effusion and another had acute respiratory distress syndrome. These medical conditions led to hospitalization and prolongation of existing hospitalization. The patient who had acute myocardial infarction expired on the first day of treatment with azithromycin. According to the investigator s judgment, these serious adverse events were not causally related to the study drug. DISCUSSION The unique structure of azithromycin, being an azalide, makes it ideal for once daily administration. 7 Following an oral dose, azithromycin is rapidly absorbed and distributes rapidly throughout the body. Rapid movement from blood into tissue results in

9 significantly higher drug concentrations in tissue than in plasma. This pharmacokinetic profile and high values for steady-state volumes of distribution suggest that the prolonged half-life is due to extensive uptake and subsequent release of the drug from tissues. Table 5. Adverse Events and Frequency (All Causality) Event Frequency Gastrointestinal disturbance 8 Phlebitis 6 Muscular pain 3 Fever 1 Pruritus 1 Hypertension 3 Cough 1 Asthma exacerbation 1 Chest heaviness 1 Headache 1 Fungal infection 1 Arthritis 1 Angioedema 1 Serious 3 (Myocardial infarction, Pleural effusion Acute Respiratory Distress Syndrome) The causative pathogens identified in this study were similar to other local investigations with S. pneumoniae and H. influenzae accounting for most cases. 8 Although no examination was done to document the possible existence of atypical organisms, the gram stains performed on all sputum samples, which assured a good quality of the respiratory specimen, yielded a variety of organisms. Guidelines on CAP have emphasized adequate antibiotic coverage for patients requiring hospitalization in the treatment of their infection (including atypical organism) who do not have other uncontrolled co-morbidities, a population that was included in this study. 1,4,5 The overall good clinical response to treatment with azithromycin emphasized the excellent activity of this drug in this patient group. The outcomes observed in this study support the in vitro findings demonstrating superior activity against S. pneumoniae, H. influenzae, S. aureus, and atypical organisms such as Mycoplasma pneumoniae and Legionella pneumophila. 7 A number of studies have highlighted the role of atypical organisms as causative agents in hospitalized CAP, 8-12 and antibiotic regimens should have adequate coverage against these pathogens. It is likewise a concern that these groups of bacteria are increasing among the geriatric age group. In our study, the oldest admitted patient was 89 years old. The pharmacokinetics of azithromycin in elderly subjects was shown to be similar to younger patients and no dosage adjustment is necessary. 7 Current investigations have stressed the benefits of adding macrolides into an empiric antibiotic regimen. 13,14 Such practices have led to shorter lengths of hospital stay and lower mortality rates compared to regimens without macrolides. Atypical organisms should always be considered when dealing with hospitalized cases of pneumonia. Majority of the patients (98%) were considered cured or improved at the end of 10 days of treatment. Improvement in clinical parameters from baseline to succeeding visits was significant even after an intention-to-treat analysis was performed.

10 Furthermore, even symptoms were significantly fewer by the third day of treatment in all cases. More than half of these patients were safely switched to oral therapy by the third or fourth day. The favorable clinical response of patients by the second to third day of intravenous treatment made it possible to shift to oral azithromycin rapidly. This implies that the causative organism(s) in these hospitalized pneumonia cases were appropriately covered with azithromycin given as monotherapy. These findings are consistent with a landmark study by Ramirez and colleagues on switch therapy among hospitalized CAP patients. 6 In that study, majority of patients can be safely switched to oral antibiotics by the third day of treatment. In addition, his study demonstrated that such practice leads to a shorter hospital stay and a reduction in the overall cost of care. Overall, this translated to improved patient outcome and satisfaction. A once-a-day drug, which can be given as a single agent, might probably improve patient compliance with treatment. The clinical responses in this study were maintained up to three to four weeks after treatment. There were no reported cases of relapse. Most of the adverse events reported in this study were related to gastrointestinal symptoms, consisting mainly of diarrhea and nausea, and local irritation at the intravenous site. This was similar to a larger study, which showed diarrhea in 5.4% of cases followed by irritation at the insertion site in 3.5%. 15 However these rates are significantly lower compared to a regimen with cefuroxime and erythromycin. 16 Overall, in a larger study among 8,000 subjects, oral azithromycin was well tolerated by the vast majority who received short-duration therapy, regardless of their underlying disease severity and their age. (7) Treatment related side effects occurred in 13.8% and discontinuation due to these reactions occurred in only 0.7% of patients. In our study, the three serious events were attributed mainly to the patients underlying concomitant illness. CONCLUSION Azithromycin is safe, well tolerated and effective among hospitalized CAP patients without co-morbidities. The once daily regimen can be administered as a single agent in this group of patients with the majority exhibiting favorable clinical response by the third day of treatment. Most patients can be switched to oral azithromycin by the 3 rd or 4 th day. Optimal clinical and bacteriological responses were documented and no relapse was evident after approximately a month of follow up. Acknowledgement This study was supported by Pfizer, Inc. REFERENCES 1. American Thoracic Society. Guidelines for the management of adults with community-acquired pneumonia: diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 2001; 163: Task Force on CAP, Philippine Clinical Practice Guidelines Group in Infectious Diseases. Community-Acquired Pneumonia: Clinical Practice Guideline. PPG-ID Philippine Society for Microbiology and Infectious Diseases. Volume 1 Nuo.2, Quezon City, Philippines: NCP Publishing Corp., Ruiz M, Ewig S, Marcos MA. Etiology of community-acquired pneumonia: impact of age, co-morbidity, and severity. Am J Respir Crit Care Med 1999; 160:

11 4. Bartlett JG, Donnell SF, Mandell LA, et al. Practice guidelines for the management of community-acquired pneumonia in adults. Clin Infect Dis 2000; 31: ASCAP Panel: Community-Acquired Pneumonia (CAP) Year 2002 Antibiotic Selection and Management Update: evaluation, risk stratification, and current antimicrobial treatment guidelines for hospital-based treatment of CAP. Hospital Medicine Consensus Reports 2002: Ramirez JA, Srinath L, Ahkee S, et al. Early switch from intravenous to oral antibiotics in the treatment of hospitalized patients with community-acquired pneumonia. Arch Intern Med 1995; 155: Pfizer data on file: 19 February Bernas G, Galvez B. Community-acquired pneumonia: etiology, clinical profile, and outcome. Phil J Chest Diseases 1997; 5(1): Bates JH, Campbell GD, Baron AL, et al. Microbial etiology of acute pneumonia in hospitalized patients. Chest 1992; 101: Woodhead MA, MacFarlane JT, McCracken JS, et al. Prospective study of the etiology and outcome of pneumonia in the community. Lancet 1987; 1: Marrie TJ, Durant H, Yates L. Community-acquired pneumonia requiring hospitalization: a 5-year prospective study. Rev Infect Dis 1989; 11: Marston BJ, Plouffe JF, File TM, et al. Incidence of community-acquired pneumonia requiring hospitalization: results of a population-based active surveillance study in Ohio. The Community-Based Pneumonia Incidence Study Group. Arch Intern Med 1997; 157: Stahl J, Barza M, Dejardin J, et al. Effect of macrolides as part of initial empiric therapy on length of stay in patients hospitalized with community-acquired pneumonia. Arch Intern Med 1999; 159: Gleason P, Mechar T, Fine J, et al. Associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia. Arch Intern Med 1999; 159: Plouffe J, Schwartz D, Kolokathis A, et al. Clinical efficacy of intravenous followed by oral azithromycin monotherapy in hospitalized patients with community-acquired pneumonia. Antimicrob Agents and Chemotherapy 2000; 44(7): Garey KW, Amsden GW. Azithromycin vs. cefuroxime plus erythromycin in CAP. Ann Pharmacother 1999; 33: APPENDIX I CRITERIA FOR EVALUATED RESPONSE Clinical Response The clinical response will be classified by the investigator post-therapy for each patient at the end of treatment visit (10-14 days post therapy) as follows: Cure: Complete resolution of all signs and symptoms of pneumonia, no need to start additional antibiotics for pneumonia after the end of the study treatment. Improvement: Incomplete resolution of all signs and symptoms of pneumonia but no need to start additional antibiotics for pneumonia after the end of study treatment. Failure: Any of the following conditions: persistence or progression of all signs and symptoms after 3 days of therapy; development of new clinical findings consistent with active infection; death from pneumonia; or inability to complete the study because of adverse effects. The clinical response will be evaluated by the investigator post-therapy for ach patient at the 4-6 week posttherapy follow-up visit as follows: Cure: complete resolution of all signs and symptoms of pneumonia. Failure: Any of the following conditions: persistence or progression of all signs and symptoms after 3 days of therapy; development of new clinical findings consistent with active infection; death from pneumonia; or inability to complete the study because of adverse effects. Bacteriological Response The bacteriological response will be classified by the sponsor for each pretreatment causative pathogen for each patient at the end-of-therapy visit(10-14 days post-therapy) and at the 4-6 week post-therapy followup visit as follows:

12 Eradication: Elimination of the original causative organism(s) from the same site during or upon completion of therapy. Presumed eradication: Absence of adequate culture material for evaluation because the patient is clinically improved and there is no more sputum production, or repeat aspiration of pleural fluid is no longer justified. Persistence: Failure to eradicate the original causative organism(s) at all post-baseline time points from site previously listed whether signs of inflammation are present or not. Relapse: Reappearance of original causative organism from the original site of infection within 5 days of discontinuation of treatment or during treatment after a post-baseline culture has been negative. Superinfection: Development of a new lower respiratory tract infection during treatment or within 3 days post-treatment, that is due to a new or resistant pathogen which was not recognized as the original causative organism(s). Colonization: Positive sputum culture yielding a bacterial strain other than the primary causative isolate, appearing greater than 48 hours after starting therapy, persisting in at least two repeated cultures, and not associated with fever, leukocytosis, persistence or progression of pneumonia, or evidence of infection at a distant site. Eradication with reinfection: Elimination of the initial infecting pathogen followed by replacement with a new species, or new serotype or biotype of the same organism, in sputum, pleural fluid or blood, in the presence of signs and symptoms of infection after completion of therapy. Radiological Assessment Consecutive chest x-rays will be evaluated and their evolution graded as: Resolution: Disappearance of all radiological signs of infection. Marked improvement: Significant improvement in the radiological signs of infection compared to the baseline. Radiological failure: No change or worsening in the radiological signs of infection compared to the baseline. APPENDIX II Members of the study group who conducted this trial were: East Avenue Medical Center: Principal Investigator: Adrian C. Peña. Co-investigators: Michelangelo Sabas, Cecil Santos. Study Coordinator: Maria Theresa Gomez. Philippine General Hospital: Principal Investigator: Camilo C. Roa. Co-investigators: Lalaine Mortera, Jennifer Sandoval. Study Coordinator: Rachel Manansala. Mandaluyong City Medical Center: Principal Investigator: Nazario A. Macalintal. Co-investigators: Cesar Matias, Lovey Labayog. Study Coordinator: Czarina Fabiana, Emma Viernes. Lung Center of the Philippines: Principal Investigator: Vincent M. Balanag. Co-investigators: Teresa Barzaga, Romeo Labao Jr. National Kidney and Transplant Institute: Principal Investigator: Myrna T. Mendoza. Co-investigator: Primo Valenzuela