In Japan, pneumonia is the fourth-leading cause of

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1 Reappraisal of Clindamycin IV Monotherapy for Treatment of Mild-to- Moderate Aspiration Pneumonia in Elderly Patients* Maiko Kadowaki, MD; Yoshiki Demura, MD, PhD; Shiro Mizuno, MD, PhD; Daisuke Uesaka, MD; Shingo Ameshima, MD, PhD; Isamu Miyamori, MD, PhD; and Takeshi Ishizaki, MD, PhD, FCCP Background: As the number of elderly people has increased in Japan, the occurrence of aspiration pneumonia has also increased. Guidelines for the treatment of pneumonia have been proposed, in which the use of antibiotics, such as -lactam plus -lactamase inhibitor, clindamycin, and carbapenem, has been recommended as effective against anaerobic bacteria in the treatment of aspiration pneumonia. However, to our knowledge, a prospective comparison of these antibiotics regarding their clinical efficacy in aspiration pneumonia has not been performed. Study objectives: We compared the effects of IV administration of a half dose of ampicillin/ sulbactam (), normal dose of, IV clindamycin, and IV panipenem/betamiprom (PAPM/BP) for treatment of mild-to-moderate aspiration pneumonia in elderly patients. Design: Randomized prospective study. Patients: One hundred adult patients with compatible signs and symptoms of aspiration pneumonia. Assessments: Patients were assessed before, during, and after treatment regarding symptoms, as well as results of laboratory values, chest radiograph examinations, and sputum bacterial cultures. Results: We found few differences between the groups regarding cure rate, duration of IV medication, and occurrence of adverse effects with the tested therapies. However, clindamycin therapy was less expensive and was associated with a lower rate of posttreatment occurrence of methicillin-resistant Staphylococcus aureus. Conclusions: Clindamycin therapy for mild-to-moderate aspiration pneumonia is clinically effective, and provides economic advantages as compared to or PAPM/BP therapy. (CHEST 2005; 127: ) Key words: ampicillin/sulbactam; aspiration pneumonia; clindamycin; medical cost; methicillin-resistant Staphylococcus aureus; panipenem/betamiprom; prospective clinical study Abbreviations: CRP C-reactive protein; IDSA Infectious Diseases Society of America; MRSA methicillinresistant Staphylococcus aureus; PAPM/BP panipenem/betamiprom; PBP penicillin-binding protein; PORT Patient Outcome Research Team; ampicillin/sulbactam In Japan, pneumonia is the fourth-leading cause of death in elderly people. As the number of elderly people has increased, the occurrence of aspiration pneumonia has also been increasing. Kikuchi et al 1 *From the Third Department of Internal Medicine (Drs. Kadowaki, Demura, Mizuno, Uesaka, Ameshima, and Miyamori) and Nursing Science (Dr. Ishizaki), Medical Faculty, University of Fukui, Fukui Prefecture, Japan. Manuscript received April 13, 2004; revision accepted November 16, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( permissions@chestnet.org). Correspondence to: Maiko Kadowaki, MD, Third Department of Internal Medicine, Medical Faculty, University of Fukui, 23 Shimoaiduki Matsuoka-cho, Fukui Prefecture, , Japan; address: maik@fmsrsa.fukui-med.ac.jp reported that silent aspiration in the elderly with an acute episode of pneumonia occurred more frequently (70%) than in control subjects (10%). Bartlett et al 2 prospectively studied 54 cases of pulmonary infection following aspiration and concluded that anaerobes that normally colonize the oral cavity play a key role in most cases of aspiration pneumonia. Furthermore, it is not uncommon for anaerobic bacteria to be resistant to a number of -lactam antibiotics because of the production of -lactamase. 3 Therefore, it has been recommended that antibiotics such as a -lactam plus -lactamase inhibitor, clindamycin, and carbapenem should be used, each of which are effective against anaerobic bacteria. 4 6 However, to our knowledge, the effi Clinical Investigations

2 cacy, bacteriologic effects, and adverse effects of these antibiotics have not been compared prospectively. We studied patients who received an administration of a -lactam plus -lactamase inhibitor (ampicillin/sulbactam []), clindamycin, or carbapenem (panipenem/betamiprom [PAPM/BP]) who had mild-to-moderate aspiration pneumonia. Materials and Methods Patients One hundred patients aged 71 to 94 years were studied between July 2000 and October These patients were hospitalized in Fukui or Ishikawa Prefecture in Japan and had mild or moderate aspiration pneumonia. The majority of the enrolled patients were nursing home residents. The diagnosis of aspiration pneumonia was made based on symptoms of fever, cough, and purulent sputum, as well as observed aspiration and a predisposition to aspirate due to dysphagia, and the results of blood analyses and radiographic examinations, such as chest radiograph and CT imaging, which revealed characteristic images compatible with aspiration pneumonia in the posterior segments of the lower lobes. 6 7 Clinical signs suggesting the presence of dysphagia were delayed swallowing, coughing or choking before, during, and after swallowing, and decreased oral/pharyngeal sensation. 8 Chemical aspiration pneumonitis that occurred after apparent vomiting was excluded. 7 The severity was graded by criteria for pneumonia established by the Japan Society of Chemotherapy, 9 which included body temperature, chest radiograph score (Table 1, Fig 1), WBC count, and C-reactive protein (CRP) [Table 2]. 9 Applying to the classification of communityacquired pneumonia by the American Thoracic Society 10 or that by the Infectious Disease Society of America (IDSA), 6 our patients were designated to group 3 and class IV, respectively. Exclusion Criteria Patients with severe pneumonia, severe complications, and known allergies to the tested antibiotics, as well as those who had received other antibiotic therapy within 1 month prior to enrollment, were excluded. Informed consent was obtained from all patients prior to their participation. Table 1 Scoring Criteria for Pneumonia Based on Chest Radiograph Findings of Area of Involvement* Pneumonia score Area of Involvement 0 No abnormal infiltrates 1 Very small infiltrates limited to one intercostal site 2 Between one and three intercostal sites 3 Infiltrate involving one tenth of one lung 4 Between three and five intercostal sites 5 Infiltrate involving one third of one lung 6 Between five and seven intercostal sites 7 Infiltrate involving two thirds of one lung 8 Infiltrate involving nearly one entire lung 9 Between eight and ten intercostal sites 10 Infiltrates involving nearly completely both lungs *From Saito et al. 9 Figure 1. Scoring criteria for pneumonia based on chest radiograph findings of area of involvement. 9 Study Design Following enrollment, the patients were randomly assigned to one of four IV treatment regimens. After beginning the study, two younger and three older patients were excluded because of age limitation, while one patient was admitted for a different disease (colon cancer). Patients in group 1 received a half dose of (1.5 g bid), those in group 2 received a normal dose of (3 g bid), those in group 3 received clindamycin (600 mg bid), and those in group 4 received PAPM/BP (0.5 g bid). Randomization was achieved by sealed envelopes, and the balance among groups was achieved by block randomization. When the number of patients reached 25 in each treated group, we preliminarily analyzed the results. Since we found methicillinresistant Staphylococcus aureus (MRSA) in three of the treatment groups but not in the clindamycin group, we decided to discontinue the study early. Assessments We assessed the results by focusing on five parameters: healing effect, occurrence of adverse effects, duration of IV medication, new appearance of antibiotic-resistant bacteria, and antibiotic cost. The healing effect was determined by assessing body temperature, chest radiograph score, WBC count, and CRP (Table 3). 9 Those examinations were performed on day 1 (just prior to beginning therapy), day 3, day 7, and in some cases day Table 2 Evaluation of Severity of Infection in Pneumonia* Parameters Severity of Disease Mild Moderate Severe Body temperature, C Number of infiltrates on chest 4 6 radiograph Peripheral WBC count, L 1,000 15,000 CRP, mg/dl *From Saito et al. 9 Satisfies one or more of the defined criteria. Cases that are neither mild nor severe. Satisfies three or more of the defined criteria. CHEST / 127 / 4/ APRIL,

3 Table 3 Evaluation Standards for Efficacy of Antimicrobial Agents for Pneumonia* Evaluation Parameters Effective Ineffective Evaluation not Possible Body temperature Lowered to 37 C Does not satisfy the efficacy standards Chest radiograph Lowered to 70% of the previous score value WBC count Reduced to 9,000/ L CRP Lowered to 30% of the previous value *From Saito et al. 9 Satisfies three or more of the defined criteria. Not possible to evaluate the efficacy for any reason 14 of the hospitalization. As soon as the therapy was considered to be ineffective, the physician in charge of the patient changed the antibiotic to one believed more effective. To investigate the biological effects, sputum cultures for bacteria were also examined on days 1, 3, 7, and 14 of hospitalization. Statistical Analysis Statistical analysis was performed using software (StatView 5.0; SAS Institute; Cary, NC) on a personal computer. Categorical data were evaluated using 2 or Fisher Exact Test. To adjust for multiple comparisons, p values were adjusted using the method of Holm. Variable data were evaluated with one-way analysis of variance using the Fisher protected last-significant difference test. The probability of a type-1 error of 0.05 was used to determine statistical significance. When the p value was 0.05 and the power analyses data (1- ) were 0.8, we described the differences in terms of few differences instead of no significant difference. Results Patient Characteristics Table 4 lists the baseline clinical characteristics of the two groups. The details of underlying respiratory diseases were as follows: there were five patients with COPD and one patient with sequelae of pulmonary tuberculosis in the group receiving a half dose of, six COPD patients in the group receiving a normal dose of, nine COPD patients and one patient with sequelae of pulmonary tuberculosis in the group receiving a half dose of, six COPD patients in the clindamycin group, and eight COPD patients in the PAPM/BP group. All of those patients showed compatible images of COPD or changes consistent with previous pulmonary tuberculosis on chest CT images. In these patients, the underlying respiratory diseases were mild. Clinical Efficacy There were few differences regarding the clinical efficacy (p , ), serial changes of CRP (data not shown), and duration of antibiotic therapy among the four groups (Table 5). The three different antibiotic regimens tested showed rather comparable results, with an efficacy of PAPM/BP of 88%, that of a normal dose of of 84%, that of a half dose of of 76%, and that of clindamycin of 76% (Table 5). These results were obtained following 8 to 10 days of treatment in each group (p , ). Table 4 Patient Characteristics* Characteristics Clindamycin PAPM/BP p Value Gender Male 15 (60) 17 (68) 16 (64) 18 (82) Female 10 (40) 8 (32) 9 (36) 7 (28) Median age, yr Severity of pneumonia Mild 10 (40) 10 (40) 7 (28) 9 (36) Moderate 15 (60) 15 (60) 18 (72) 16 (64) Underlying respiratory diseases Yes 6 (24) 6 (24) 10 (40) 8 (32) No 19 (76) 19 (76) 15 (60) 17 (68) *Values are given as No. (%). All patients were in PORT risk class IV Clinical Investigations

4 Variables Table 5 Treatment Effects* Clindamycin PAPM/BP p Value Efficacy 19 (76) 21 (84) 19 (76) 22 (88) Adverse effect Duration of IV treatment, d New appearance of MRSA 5 (22.7) 5 (22.7) 0 (0) 8 (36.4) *Data are presented as No. (%) or mean SD. p vs clindamycin. p vs clindamycin. p vs PAPM/BP. Among the cases considered to be effective. Adverse Events There were few differences in adverse events between the four groups (p , ) [Table 6]. The main side effects noted were digestive problems in group 2, and mild liver dysfunction in groups 1, 3, and 4. None of the patients experienced severe side effects that required any other additional supportive treatment, and each adverse event disappeared as soon as the antibiotic therapy was discontinued. Economic Analysis The cost for a single vial or ampule was calculated as follows, with US dollar amounts based on a current exchange rate of yen to the dollar: PAPM/BP, 2,021 yen ($18.40) for 0.5 g;, 1,385 yen ($12.60) for 1.5 g; and clindamycin, 759 yen ($6.90) for 600 mg (Table 7). Considering the duration of IV medication, the cost was significantly lower in the clindamycin group (13,982 yen, $12.70) as compared to the 3 g/d group (22,889 yen, $208.10), 6 g/d group (48,805 yen, $443.70), and PAPM/BP group (40,420 yen, $367.50) [p , ]. Furthermore, the cost for the 3 g/d group was significantly lower than that for the 6 g/d and PAPM/BP groups. Bacteriologic Response Sputum samples for culture were obtained in 99 of the 100 cases, of which 42 results (42.4%) were negative (Table 8), The detected organisms were Gram-negative bacilli (48.1%), including Klebsiella pneumoniae (24%), Escherichia coli (4.9%), Enterobacter cloacae (4.9%), Pseudomonas aeruginosa (4.9%), and Haemophilus influenzae (3.7%), and Gram-positive cocci (40.7%), including MRSA (12.3%), methicillin-sensitive S aureus (9.8%), and Streptococcus pneumoniae (4.9%). A number of the improved patients showed no disappearance of the detected pathogens following treatment, namely 5 of 18 cases in the half-dose group, 5 of 16 cases in the normal-dose group, 4 of 17 cases in the clindamycin group, and 4 of 21 cases in the PAPM/BP group. New Appearance of MRSA The rate of postantibiotic treatment appearance of MRSA was significantly lower in the clindamycin group (no cases, 0%) as compared with the SBT/ ABPC 3 g/d group (five cases, 22.7%), 6 g/d group (five cases, 25%), and PAPM/BP group (eight cases, 34.8%) [p , ]. Discussion In the present study, we obtained three new findings that suggest that clindamycin is advantageous for treating mild-to-moderate aspiration pneumonia in elderly patients. First, clindamycin therapy did not induce the new appearance of MRSA, whereas and PAPM/BP therapy induced Table 6 Drug-Related Adverse Effects* Adverse Effects Clindamycin PAPM/BP Liver disorder Diarrhea 1 Bloody bowel discharge 1 Eosinophilia 1 Total *Values are given as No. CHEST / 127 / 4/ APRIL,

5 Antibiotic Cost * Table 7 Antibiotic Cost Clindamycin PAPM/BP p Value Cost Yen 22,889 48,804 13,982 40, US dollars *p vs PAPM/BP. p vs clindamycin. p vs normal dose of. p vs clindamycin. p vs PAPM/BP. MRSA at a high rate. Second, the cost of clindamycin therapy was significantly lower than that of the other antibiotic therapies. Finally, clindamycin therapy showed satisfactory clinical efficacy as compared with the other tested -lactams, and the occurrence of adverse side effects was not as high as that with the other therapies. Our bacterial examination showed that 57.6% of the detected pathogens were the same kind of bacteria as listed in the report of patients with pneumonia acquired in nursing homes. 11 But, interestingly, 19.0 to 31.3% of the successfully treated patients still had the same pathogen regardless of the treatment. In some reports of nonsevere pneumonia, the microbiological studies were noncontributory. Theerthakarai et al 12 reported that sputum cultures in nonsevere community-acquired pneumonia patients identified pathogens in only 5%. However, as the IDSA guidelines have noted for elderly patients, microbiological studies are valuable for preventing nosocomial infection such as MRSA, or when considering changing antibiotics. 6 MRSA is an increasingly common cause of nosocomial infections, and its prevalence has become a serious problem in clinical medicine. Once MRSA appears, even if it does not affect the patient, greater medical costs are generated, as clinicians are required to observe special precautions to prevent the spread of MRSA. 13 It has been reported that the use of broad-spectrum antibiotics is a critical risk factor for colonization or infection with antibiotic-resistant bacteria. 14 Malin et al 15 recommended the use of drugs with a narrow antimicrobial spectrum or older antibiotics to curtail the development of antimicrobial resistance. In our study, the rate of postantibiotic appearance of MRSA was significantly higher in the groups that received or PAPM/BP therapy, as compared with those who received clindamycin. As for why clindamycin therapy did not induce a comparable appearance of MRSA, we considered the fact that -lactams (such as, PAPM/ BP) combine with penicillin-binding proteins (PBPs), and then inactivate their transpeptidase and carboxypeptidase activities, which are responsible for catalyzing the final transpeptidation step of bacterial cell wall biosynthesis Although all strains of S aureus have four PBPs (PBP-1 to PBP-4), only Table 8 Bacterial Findings Before Treatment* Variables Clindamycin PAPM/BP Total Methicillin-sensitive S aureus Methicillin-sensitive Staphylococcus epidermidis 1 1 MRSA S pneumoniae Corinebacterium 1 1 H influenzae E coli Citrobacter 2 2 K pneumoniae Enterobacter Serratia P aeruginosa Others Negative *Data are presented as No Clinical Investigations

6 MRSA expresses a specific PBP (PBP0 2 or PBP- 2a) from the meca gene. PBP-2 takes over the biosynthetic functions of normal PBPs in the presence of inhibitory concentrations of -lactams because it has a decreased binding affinity for them. Clindamycin inhibits the formation of 50S subunits in bacterial cells as well as protein synthesis; thus, clindamycin therapy may not induce MRSA. In support of this hypothesis, it has been reported that 39% of cases of community-acquired MRSA were susceptible to clindamycin, 18 as compared to the lack of bactericidal effects shown by the two other tested antibiotics. The guidelines of the Society for Healthcare Epidemiology of America and IDSA for prevention of the spread of antimicrobial resistance in hospitals recommend appropriate use of antimicrobials, including not only limited use of inappropriate agents, but also appropriate selection, dosing, and duration of antimicrobial therapy to achieve optimal efficacy in managing infections. 19 Based on the present results, we recommend clindamycin as an appropriate selection to treat mild-to-moderate aspiration pneumonia in elderly patients. The cost of clindamycin therapy was found to be very low, which may become more important in the future. Currently, the Japanese society is faced with a serious economic problem of rapidly increasing health-care costs. It is estimated that in 2001, the total medical cost was yen, or approximately $ , and that 38.5% of the total medical cost, yen or approximately $ , was spent for patients who were 70 years old. The drug cost of clindamycin was the lowest, while the duration of treatment was the same as with the other -lactams tested. In addition, clindamycin therapy did not induce new appearance of MRSA; therefore, the medical cost related to standard precaution for MRSA would also be reduced. Panipenem is a carbapenem antibiotic that is used extensively in Japan, Korea, and China. Its range of antibacterial activities is broad, including most Gram-negative and Gram-positive aerobic and anaerobic organisms. 20 The antibiotic is administered with an organic anion transport inhibitor, betamiprom, to reduce its renal toxicity, which prevents the uptake of panipenem by the renal cortex. 21 Shibuya et al 22 evaluated the use of PAPM/BP for pneumonia in elderly patients and reported that it was safe and effective. We also directly compared two different doses of. Since the patients were at an advanced age and considered to have lower levels of pharmacometabolism, we anticipated that the half-dose therapy might induce fewer adverse effects than the normal dose. Although the incidence of adverse effects in these two groups was equal, diarrhea or bloody bowel discharge preferably occurred in those who received the normal dose. We know that several guidelines for treating patients with mild-to-moderate pneumonia often recommend macrolide oral therapy rather than IV therapy. 23 However, because our medical insurance system could cover the hospital fee, we pursued follow-up care in these patients, attempting to prevent the repeated aspiration pneumonia. Patients were rehabilitated and taught how to swallow food or drink with dietary modification and received aggressive oral care. 8 Thereafter, patients were permitted to have oral intake. Such care in postaspiration pneumonia is usually provided in Japan. In this study, all the patients improved. According to the Patient Outcome Research Team (PORT) validation cohort, 24 the mortality of patients of class IV who corresponded to our patients severity was 8.2%. In Japan, Nishimura et al 25 examined the utility of the pneumonia PORT prediction rule for evaluating the severity of community-acquired pneumonia. According to this report, the risk-class-specific mortality rate was 3.2% in class IV. Conclusion We conclude that for the treatment of mild-tomoderate aspiration pneumonia in elderly patients, clindamycin is preferable as an initial therapy, as we have shown it to be cost-effective and to prevent the emergence of antibiotic-resistant bacteria. ACKNOWLEDGMENT: The authors thank Professor N. F. Volkel (University of Colorado Health Sciences Center) for his advice and assistance with the preparation of this article. References 1 Kikuchi R, Watanabe N, Konno T, et al. High incidence of silent aspiration in elderly patients with community-acquired pneumonia. 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