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39:979-985, 1991
A Randomized Study of Cimofloxacin versus Ceftriaxone in the Treatmeht of Nu.rsi Home-Acquired Lower Respirat:ory Tract Infections Cheryl A. 1. Hirata-Dulas, PharmD, Daniel 1. Stein, MD, David R. P. Guay, PharmD, Robert P. Gruninger, MD, and Phillip K. Peterson, M D
Objective: To compare the efficacy and safety of ciprofloxacin and ceftriaxone in patients with nursing homeacquired lower respiratoy tract infections requiring initial hospitalization. Design: Prospective, randomized trial. Setting: Extended care nursing homes affiliated with a teaching hospital. Patients: Fifty patients aged 60 years or older with normal or mildly impaired renal function admitted to the hospital for treatment of lower respiratory tract infections. Interventions: Twenty-four patients received initial therapy with intravenous ciprofloxacin, 200 mg eve ry 12 hours (19 patients) or 400 mg every 12 hours (5 patients) during the acute phase followed by 750 mg orally every 12 hours during the convalescence phase. Twenty-six patients received initial therapy with intravenous ceftriaxone, 2 g every 24 hours during the acute phase followed by 1 g administered intramuscularly eve y 24 hours during the convalescent phase. The total duration of therapy was 14 days. Main Outcome Measurements: Successful outcome was
defined as resolution or marked improvement in clinical signs and symptoms of lower respirato y tract infection upon completion of the treatment course. Results: Twelve (50%) of the ciprofloxacin-treated and 14 (54%) of ceftriaxone-treated patients had successful outcomes. Recurrent orophayngeal aspiration was the reason for treatment failure in most patients refractory to either antibiotic. Mortality during therapy was 8% in each group. From 21 satisfactoy sputum specimens collected, S. pneumoniae was the most common isolate, followed by H. influenzae and other Gram-negative bacteria. Ciprofloxacin therapy was well tolerated; ceftriaxone therapy was discontinued in two patients (8%) due to adverse reactions (intramuscular pain and drug fever). Conclusions: Sequential intravenousloral ciprofloxacin appears to be as safe and effective as sequential intravenouslintramuscular ceftriaxone. The optimal dosage of intravenous ciprofloxacin in this patient population appears to be 400 mg evey 12 hours; however, additional clinical and pharmacokinetic studies with this regimen are warranted. J Am Geriatr SOC39:979-985, 1991
n the elderly, lower respiratory tract infections acquired in the nursing home are a source of considerable morbidity, mortality, and health care expenditure. Bronchopulmonary infections account for 13%-48% of all institutionally-acquired infections' and in one study were responsible for over
I
10% of all hospital admissions from an extended care nursing home system.* In the elderly nursing home population, the mortality associated with lower respiratory tract infection is reported to be as high as 40%.3-5 Several factors place elderly nursing home patients
From the Nephrology (The Drug Evaluation Unit), Infectious Diseases, and Geriatric Medicine Divisions of the Department of Medicine and the Department of Pathology, Hennepin County Medical Center, Minneapolis, Minnesota; and School of Medicine and College of Pharmacy, University of Minnesota, Minneapolis, Minnesota. Work was performed at Hennepin County Medical Center, Minneapolis, Minnesota and affiliated Extended-Care Program nursing homes.
Supported by a grant-in-aid from Miles, Inc., West Haven, Connecticut. Presented in part at the Third International Symposium on New Quinolones, Vancouver, Canada, July 1990. Address correspondence and reprint requests to Cheryl HirataDulas, PharmD, The Drug Evaluation Unit, Division of Nephrology, Hennepin County Medical Center, 701 Park Avenue South, Minneapolis, MN 55415.
Q 1991 by the American Geriatrics Societv
0002-8614/91/$3.50
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the study drugs; (3) serum creatinine greater than 3.0 mg/dL; (4) contraindication to intramuscular therapy; (5) designation as supportive care only status; or (6) previous study enrollment. The study was approved by the Human Subjects Research Committee at Hennepin County Medical Center, and written, informed consent was obtained from the patient or from his/her surrogate before entry into the study. Patients were randomized to receive a 14-day total course of either ciprofloxacin (200 mg administered intravenously every 12 hours, followed by 750 mg administered orally every 12 hours) or ceftriaxone (2 g administered intravenously every 24 hours, followed by 1 g administered intramuscularly every 24 hours). Intravenous therapy was administered for a minimum of 2 days. In April 1989, the dose of intravenous ciprofloxacin was increased from 200 mg to 400 mg every 12 hours. Pharmacokinetic assessments revealed that at steady state, serum concentrations achieved after multiple intravenous doses of 200 mg were approximately 50% of those achieved after multiple oral doses of 750 mg." Consequently, 19 patients received initial therapy with intravenous ciprofloxacin at a dose of 200 mg every 12 hours, and five patients received 400 mg every 12 hours. Twenty-six patients received ceftriaxone. Ceftriaxone for intramuscular injection was reconstituted in 1%lidocaine to reduce injection pain. During ciprofloxacin therapy, antacids and sucralfate were avoided, and theophylline serum concentrations were monitored. On admission to the hospital, all patients underwent a thorough history and physical examination. Baseline laboratory studies included hematology, serum chemistries, urinalysis, chest roentgenography, and sputum and blood cultures. Hematology, serum chemistries, and urinalysis were performed weekly during drug administration and at the end of therapy. Abnormal laboratory values were repeated at appropriate intervals until resolution. METHODS Sputum samples for microscopic analysis and culture From January 1988 to March 1990, 50 elderly (de- were obtained by expectoration. Sputum was collected fined as age 60 years or older) nursing home residents by a respiratory therapist, and, if necessary, was inin the Extended Care P r ~ g r a m ' ~at, ' Hennepin ~ County duced by saline nebulization or recovered by nasotraMedical Center, who were admitted to the hospital for cheal suction. Sputum specimens were Gram-stained, treatment of lower respiratory tract infections, were and specimens were considered satisfactory if there enrolled in the study. The criteria for the diagnosis of were greater than 25 white blood cells and less than pneumonia were (1) at least one of the following: 10 squamous epithelial cells per low power field. Spucough, oral temperature greater than 37.2OC, dyspnea, tum and blood cultures were processed in a routine peripheral white blood cell count greater than lO,OOO/ manner, and initial susceptibility studies were permm,3 and (2) the presence of new infiltrates on chest formed on all bacterial isolates based on the standard roentgenogram interpreted as compatible with the di- disk testing method using 5-pg disks of ciprofloxac~ agnosis. Acute bronchitis was defined as previously and 30-pg disks of ceftriaxone." Subsequently, the minimum inhibitory concentrations(MICs)of the study de~cribed.'~ Patients were excluded for the following reasons: (1) drugs were determined at concentration ranges of documented allergy to ciprofloxacin, ceftriaxone or re- 0.125 to 128 pg/mL using a microdilution technique in lated compounds; (2) concomitant antimicrobial ther- Mueller-Hinton agar. The following breakpoints were apy with an agent similar in antibacterial spectrum to used to define susceptibility to ciprofloxacin: 1.0 pg/
at risk for lower respiratory tract infection including compromised immune defense^.^,' associated medical conditions,' and oropharyngeal colonization with Gram-negative bacilli.' The absence of classical clinical signs and symptoms of lower respiratory tract infection often results in delayed diagnosis and treatment,' and this factor may also play a role in the increased morbidity and mortality reported in elderly patient^.^ The bacteria that cause lower respiratory tract infections in nursing home patients are often difficult to identify. The replacement of normal oropharyngeal bacterial flora by Gram-negative bacteria in the respiratory tract' supports the need for empiric treatment with broad spectrum antibiotics. Ciprofloxacin, a fluoroquinolone antibiotic, has been proposed as a treatment for lower respiratory tract infections because of its activity against a wide variety of Gram-negative and Gram-positive aerobic bacteria," high degree of penetration into lung tissue and sputum,",'* and low incidence of adverse effect^.'^ Lower respiratory tract infections in elderly nursing home patients have been examined in only a few clinical studies. We recently demonstrated that oral ciprofloxacin therapy was as safe and effective as intramuscular cefamandole in treating patients with relatively mild lower respiratory tract infections acquired in the nursing home.14 The present study was conducted in elderly nursing home patients with moderate to severe lower respiratory tract infections requiring hospitalization for initial intravenous antimicrobial therapy. The purpose of this clinical trial was to evaluate the safety and efficacy of ciprofloxacin administered in an intravenous followed by an oral dosage regimen sequence. Ceftriaxone, administered in an intravenous followed by an intramuscular dosage regimen sequence, was selected as a comparative agent because of its similar spectrum of activity and convenient once a day dosage.
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TABLE 1. CHARACTERISTICS OF PATIENTS AT STUDY ENTRY*
Number of Cases (Percent) Characteristic Number in study Mean age, years (range)
Sex Mean number of medications (range)** Type of Infection:
Pneumonia Bronchitis Underlying diseases Chronic obstructive pulmonary disease Chronic heart disease Dementia 21 Cerebral vascular accident
Ciprofloxacin
Ceftriaxone
24 79.3 (65-101) 13M, 11F 3.9 (0-11)
26 79.4 (64-97) 18M, 8F 3.1 (0-13)
20 (83) 4 (17)
24 (92) 2 (8)
11 (46) 12 (50) 8 (33) 12 (50)
10 (38) 14 (59) 15 (58) 6 (23)
* N o significant differences were observed between the treatment groups. ** Medications prescribed in the nursing home exclusive of pro re nata, vitamins, bowel medications, and topical, otic, and ophthalmic preparations.
TABLE 2. INITIAL CULTURE ISOLATES mL or less, susceptible; 2 pg/mL, intermediately susAND OUTCOME* ceptible; and 4 pg/mL or more, resistant. Breakpoints Number of Cases. for defining susceptibility to ceftriaxone were the fol(% Successful Outcome**) lowing: 8 pg/mL or less, susceptible; 64 pg/mL or more, Specimen Type and resistant. Strains were considered intermediate in susOrganism Ciprofloxacin Ceftriaxone ceptibility when the MICs of ceftriaxone were greater Sputum*** than 8 pg/mL but less than 64 pg/mL. S. pneumoniae 3 (67) 3 (33) S. aureus In selected patients randomized to receive ciproflox1(0) 1 (0) H. influenzae 4 (50)# 1 (0) acin, pharmacokinetic studies at steady-state after inl(lO0) 0 K. pneumoniae travenous and oral dosing were performed; the results l(lO0) 0 E. cloacae have been reported.I6 P. aeruginosa 1 (0) 0 Three categories were established for clinical out9 (44)# 8 (38) Normal oral flora come: success, failure, and indeterminate outcome. Blood S. pneumoniae 0 2 (O)## Success was defined as marked improvement or resolution of the clinical signs and symptoms of lower * N o significant differences were observed between the treatment groups. respiratory tract infection upon completion of the 14- **Marked improvement or resolution of symptoms and clinical signs of day treatment course. Failure was defined as death lower respiratory tract infection on completion of a 14-day course of ciprofloxacin or ceftriaxone therapy. during the study regardless of whether or not it was *** Only sputum specimens with >25 white blood cells and 25 white blood cells and ( 1 0 epithelial cells per low power field (n = 11) were evaluated. More than one organism was isolated in seven sputum specimens. *'* Includes S. pneurnoniae isolates in sputum and blood from one patient during ciprofloxacin therapy. # Unable to obtain minimum inhibitory concentration data for some isolates due to technical problems.
TABLE 4. TREATMENT OUTCOMES* Number of Cases (Percent) -~
Outcome
Death during therapy Therapy outcome Success** Failure*** Indeterminate# Mean number of days hospitalized (range) Mean number of days of intravenous therapy (range)
Ciprofloxacin 2 (8) 12 (50) 10 (42) 2 (8) 5.8 (2-13) 3.4 ( 2 - 6 )
Ceftriaxone 2 (8) 14 (54) 10 (38) 2 (8) 4.5 (2-11) 3.9 (2-10)
* No significant differences were observed between the treatment groups. **Marked improvement or resolution of symptoms and clinical signs of lower respiratory tract infection on completion of a 14-day course of ciprofloxacin or ceftriaxone therapy. *** Early termination due to death, lack of improvement, adverse event, or superinfection. # Early termination due to protocol specification or to factors unrelated to study drug administration.
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S. pneumoniae pneumonia with bacteremia (superinfection) that occurred during ciprofloxacin therapy was the cause of treatment failure in one patient. The patient, a 74-year-old Caucasian male with chronic obstructive pulmonary disease, presented with increasing dyspnea, fever, lethargy, and hypertension. He was intubated and later required a dopamine infusion for blood pressure support. Left lower lobe and lingular infiltrates were observed on initial chest roentgenogram. The patient was randomized to receive intravenous ciprofloxacin 200 mg every 1 2 hours, and he defervesced and remained afebrile during the first 3 days of admission. Initial blood and urine cultures were negative, and normal oral flora was isolated in sputum culture. The patient was extubated on day three, and he was switched to oral ciprofloxacin. After four doses of oral therapy, reinstitution of intravenous ciprofloxacin was required due to increasing dyspnea, persistently elevated white blood cell count, and spiking temperatures. A chest roentgenogram on day six showed worsening of the left lung infiltrates and new right basilar infiltrates. S. pneurnoniae was isolated from sputum and blood cultures on day eight. The MICs of ciprofloxacin to these isolates were 4 pg/mL and 2 wg/ mL, respectively. A pharmacokinetic assessment, performed after the fifth intravenous dose of ciprofloxacin 200 mg, revealed that the serum ciprofloxacin concentrations at the end of a 1-hour infusion and at the end of the dosing interval were 3.54 &mL and 0.27 pg/ mL, respectively. On day eight, the patient was switched to intravenous penicillin G with eventual resolution of the pneumonia. Of the seven patients from whom S. pneumoniae was isolated on hospital admission in sputum and/or blood, outcomes were successful in two of the three patients who received ciprofloxacin (all three patients received initial therapy with intravenous ciprofloxacin 200 mg every 12 hours) and in one of four patients who received ceftriaxone. Although one failure to ceftriaxone was attributed to an adverse event (intramuscular pain), two were attributed to primary antibiotic failure. Reasons for early withdrawal from the study for the four patients categorized as indeterminate in outcome were: H. influenzae resistant to study drugs on initial disk susceptibility testing, enterococcus isolated in urine resistant to ceftriaxone, inadvertent withdrawal from study due to pharmacy error, and physician request despite patient improvement. Adverse drug reactions regarded as possibly or probably due to the study drugs were infrequent in both groups. In patients receiving ciprofloxacin, laboratory abnormalities included transient elevations in serum aspartate aminotransferase (n = 2), serum alanine aminotransferase (n = 2), alkaline phosphatase (n = l), lactate dehydrogenase ( n = l), and eosinophil count ( n = 1). Six ciprofloxacin-treated patients received con-
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comitant theophylline therapy; no signs or symptoms of theophylline toxicity were observed. Laboratory abnormalities observed during ceftriaxone therapy included transient elevations in serum aspartate aminotransferase (n = l), alkaline phosphatase (n = l), and eosinophil count ( n = 1). Diarrhea was reported in four patients during ceftriaxone therapy. Pseudomembranous colitis was diagnosed in one patient after completion of ceftriaxone therapy. One patient was discontinued from ceftriaxone therapy due to presumed drug fever, and one patient withdrew secondary to intolerable intramuscular injection pain. Three patients in each group developed candiduria during antimicrobiaI therapy.
DISCUSSION Our understanding of the pathophysiology, bacteriology, and clinical features of lower respiratory tract infection acquired in the nursing home has improved significantly over the past d e ~ a d e . ' ~ ~However, ~ ' * ~ ' ~ the treatment of this infectious disease entity has been examined in only a few prospective, randomized clinical trials. Two recent comparative studies combined nursing home-acquired lower respiratory tract infections with community-acquired and/or hospital-acquired pneumonia,z0*21and, thus, potentially overlooked important characteristics of elderly nursing home patients such as differences in etiology and preexisting medical conditions. In the present study, the microbiologic findings in expectorated sputum were consistent with previous ~ t u d i e s ~supporting ,'~ the importance of S. pneumoniae and Gram-negative organisms as etiologic agents of lower respiratory tract infection acquired in the nursing home. Unfortunately, satisfactory sputum specimens for diagnosis were not obtainable in all patients. Invasive procedures for procuring more reliable specimens for culture were not practical in this acutely ill, medically fragile nursing home population. The bacteriologic etiology of pneumonia was established by positive blood cultures in only two patients. Other investigators have also noted a low frequency of bacteremia in elderly patients with p n e ~ m o n i a . ' ~ ~ ~ ~ ~ ~ ~ Most isolated pathogens were susceptible to both study drugs. Discrepancies between the disk sensitivity and microdilution tests were few. The occurrence of in vifro test differences has been noted previouslyz4and may be caused by subtle technical variables in testing such as inoculum size and end-point determinations. The implications of these differences as they influence the selection of antimicrobial agents is unknown. The clinical success rate in the present study of approximately 50% in both groups is lower than that reported in our previous study (76%).14 In addition, patients required hospitalization for a slightly longer duration than in our previous study (mean of 4 days).I4
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These differences possibly reflect the greater severity of illness among patients enrolled in the present study. The lower mortality rates observed in the present study (8%) and our previous study (6.5%),14compared to other may be attributed to early recognition of the frequently atypical presentation of bronchopulmonary infection in the elderly nursing home patient. Identifyinginfection early in its course was made possible by the structure of our Extended Care Program.'4*'5 Aspiration of oropharyngeail contents is the predominant pathophysiological mechanism of lower respiratory tract infection in nursing home patient^.'^ Over 50% of the treatment failures were patients who experienced recurrent episodes of clinically evident oropharyngeal aspiration. In some of these patients, normal oral flora was isolated in sputum culture. Normal oral flora isolated in sputum has unknown significance but may be pathogenic in the context of aspiration pneumonia.26Evidence exists that ciprofloxacin may be active against oropharyngeal flora,27but it is possible that treatment failures were (duein part to its relative lack of antianaerobic activity." Another major reservation regarding the use of ciprofloxacin in patients such as those reported here is its modest in vitro activity against S. pneumoniae. The case of S. pneumoniae pneumonia (including bacteremia) during therapy with ciprofloxacin was instructive. Although this infection was considered a superinfection, it is possible that the organism was present initially but not isolated in either blood or sputum. Alternatively, administration of ciprofloxacin could have allowed colonization and subsequent infection of the respiratory tract to occur with S. pneumoniae as suspected in a recent case report.28 Some investigators believe that a useful predictor of bacterial eradication in patients with nosocomial lower respiratory tract infections is the length of time that the serum concentration of the antimicrobial agent remains above the MIC.29*30 Our patient received intravenous ciprofloxacin 200 mg every 12 hours during the acute phase of infection., which achieved a peak serum concentration of ciprofloxacin that was below the MIC for the strain of S. pneumoniae isolated in the sputum. Although data from other clinical studies indicate that the high MICs of ciprofloxacin to s. pneumoniae do not impair its effectiveness, probably because concentrations in sputum and lung tissue are several times greater than those achieved in initial therapy with a higher dose of ciprofloxacin may have circumvented this complication. In the small number of ]patients with probable S. pneumoniae infection in the present series, no significant difference in outcome between the ciprofloxacinand ceftriaxone-treated patients was observed. Other studies in which ciprofloxacin was used to treat S.
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pneumoniae isolated in the respiratory tract reported favorable overall clinical cure In only one study37was an unfavorable clinical outcome reported (9/26 patients improved, and 17/26 patients failed therapy); the reason for the discrepancy in results between this study and others is not clear. Ciprofloxacin 400 mg administered intravenously every 12 hours would theoretically provide better coverage against S. pneumoniae and appears to be the standard dose for these patients assuming that creatinine clearance exceeds 25 mL/min. However, clinical and pharmacokinetic studies of this regimen have not yet been performed in elderly patients, and it is not known whether significant accumulation occurs with multiple dosing regimens. While ciprofloxacin should not be the sole or preferred therapy when S. pneumoniae infection is documented, empiric therapy with ciprofloxacin is appropriate when infection with any of a variety of bacterial pathogens is likely, such as in nursing homeacquired pneumonia. In cases when sputum Gramstrains are suggestive of s. pneumoniae infection, the addition of penicillin may be appropriate. Intravenous ciprofloxacin has only recently been approved for commercial use, and a cost comparison of the intravenous regimens is not currently available. Upon hospital discharge, switching to an oral agent, such as ciprofloxacin, is more cost effective than changing to intramuscular ceftriaxone. In addition to the lower cost of ciprofloxacin itself ($9/day for two 750 mg ciprofloxacin tablets compared with $37/day for ceftriaxone 1 g at our institution), other expenses associated with parenteral therapy including preparation time, administration, and potential complications must be considered. In the minority of cases in which the pathogen is established by positive blood culture, therapy can be individualized based on sensitivity patterns of the organism isolated, as well as cost considerations. The results of the present study indicate the ciprofloxacin is as safe and effectiveas ceftriaxone in treating elderly patients with nursing home-acquired lower respiratory tract infections requiring initial hospitalization. Both agents can be administered intravenously in the hospital, then changed to the same drug for administation by the oral (ciprofloxacin) or intramuscular (ceftriaxone) route to complete therapy in the nursing home. Oral ciprofloxacin offers significant advantages over intramuscular ceftriaxone, such as convenience and cost savings. However, neither drug may be the antimicrobial agent of choice for treating nursing home patients who have a history of recurrent aspiration. With the development of newer broad spectrum agents, it is likely that in the future other agents will provide similar or superior safety and efficacy profiles compared to those of ciprofloxacin and ceftriaxone. Additional studies are also warranted to evaluate whether clinically stable patients with nursing home-
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TREATMENT OF NURSING HOME-ACQUIRED PNEUMONIA
acquired lower respiratory tract infections can safely and effectively be treated in the nursing home without initial hospitalization.
ACKNOWLEDGMENTS We are deeply grateful to the Extended Care Program nurses and internal medicine residents who assisted with the conduct of this study.
REFERENCES 1 . Crossley KB, Thum JR. Nursing home-acquired pneumonia. Semin Respir Infect 1989;4:64-75 2. lrvine PW, Van Buren N, Crossley K. Causes for hospitalization of nursing home residents: The role of infection. J Am Geriatr SOC1984;32:103-107. 3. Saah AJ, Neufeld R, Rodstein M et al. Influenza vaccine and pneumonia mortality in a nursing home population. Arch Intern Med 1986;146:2353-2357. 4. Berman P, Hogan DB, Fox RA. The atypical presentation of infection in old age. Age Ageing 1987;16:201-207. 5. Marrie TJ, Durant H, Kwan C. Nursing home-acquired pneumonia: A case-control study. J Am Geriatr SOC1986;34:697-702. 6. Saltzman RL, Peterson PK. Immunodeficiency of the elderly. Rev Infect Dis 1987;9:1127-1139. 7. Smith PW. Nosocomial infections in the elderly. Infect Dis Clin North Am 1989;3:763-777. 8. Garibaldi RA, Nurse BA. Infections in the elderly. Am J Med 1986;81 (suppl 1A):53-58. 9. Valenti WM, Trudell RG, Bentley DW. Factors predisposing to oropharyngeal colonization with Gram-negative bacilli in the aged. N Engl J Med 1978;298:1108-1111. 10. Campoli-Richards DM, Monk JP, Price A et al. Ciprofloxacin:A review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 1988;35:373-447. 11. Schlenkhoff D, Dalhoff A, Knopf J et al. Penetration of ciprofloxacin into human lung tissue following intravenous injection. Infection 1986;14:299-300. 12. Thys JP, Klastersky J, Jacobs F et al. Penetration of ciprofloxacin into bronchial secretions and pleural fluid. In: Neu HC, Weuta H, eds. Proceedings of the 1st International Ciprofloxacin Workshop. Amsterdam: Excerpta Medica, 1986, pp 153-156. 13. Arcieri G, August R, Becker N et al. Clinical experience with ciprofloxacin in the USA. Eur J Clin Microbiol 1986;5:220-225. 14. Peterson PK, Stein D, Guay DRP et al. Prospective study of lower respiratory tract infections in an extended-care nursing home program: Potential role of oral ciprofloxacin. Am J Med 1988;85:164-171. 15. Breitenbucher RB, Schultz AL. Extended care in nursing homes: A program for a county teaching medical center. Ann Intern Med 1983;98:96-100. 16. Hirata CAI, Guay DRP, Awni WM et al. Steady-state pharmacokinetics of intravenous and oral ciprofloxacin in elderly patients. Antimicrob Agents Chemother 1989;33:1927-1931. 17. Baron EJ, Finegold SM. Methods for testing antimicrobial effectiveness. In: Bailey and Scott’s Diagnostic Microbiology, 8th ed. St. Louis: CV Mosby Co, 1990, pp 171-194.
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18. Bartlett JG, O’Keefe P, Tally FI‘, et al. Bacteriology of hospitalacquired pneumonia. Arch Intern Med 1986;146:868-871. 19. Marrie TJ, Durant H, Yates L. Community-acquired pneumonia requiring hospitalization: 5-year prospective study. Rev Infect Dis 1989;11:586-599. 20. Khan FA, Basir R. Sequential intravenous-oral administration of ciprofloxacin vs ceftazidime in serious bacterial respiratory tract infections. Chest 1989;96:528-537. 21. Trenholme GM, Schmitt BA, Spear J et al. Randomized study of intravenous/oral ciprofloxacin versus ceftazidime in the treatment of hospital and nursing home patients with lower respiratory tract infections. Am J Med 1989;87 (suppl 5A):116S-l18S. 22. Garb JL, Brown RB, Garb JR et al. Differences in etiology of pneumonias in nursing home and community patients. JAMA 1978;240:2169-2172. 23. Ebright JR, Rytel MW. Bacterial pneumonia in the elderly. J Am Geriatr SOC1980;28:220-223. 24. Kamm W, Wenger A, Bille J. Evaluation of the Cobas-Bact system for direct and rapid identification and antimicrobial susceptibility testing of Gram-negative rods from positive blood culture broths. J Clin Microbiol 1989;27:102-105. 25. Verghese A, Berk SL. Bacterial pneumonia in the elderly. Medicine 1983;62:271-285. 26. Chow JW, Yu VL. Antibiotic studies in pneumonia: Pitfalls in interpretation and suggested solutions. Chest 1989;96:453-456. 27. Appelbaum PC, Spangler SK, Strauss M. Reduction of oral flora with ciprofloxacin in healthy volunteers. J Antimicrob Chemother 1988;21:243-249. 28. Gordon JJ, Kauffman CA. Superinfection with Streptococcus pneumoniae during therapy with ciprofloxacin. Am J Med 1990;89:383-384. 29. Schentag JJ, Swanson DJ, Smith IL. Dual individualization: Antibiotic dosage calculation from the integration of in-vitro pharmacodynamics and in-vivo pharmacokinetics. J Antimicrob Chemother 1985;15 (suppl A):47-57. 30. Nix DE, Sands MF, Peloquin CA et al. Dual individualization of intravenous ciprofloxacin in patients with nosocomial lower respiratory tract infections. Am J Med 1987;82 (suppl 4A):352356. 31. Gleadhill IC, Ferguson WP, Lowry RC. Efficacy and safety of ciprofloxacin in patients with respiratory tract infections in comparison with amoxycillin. J Antimicrob Chemother 1986;18 (SUPPI D): 133-1 3 8. 32. Raoof S, Wollschlager C, Khan F. Treatment of respiratory tract infections with ciprofloxacin. J Antimicrob Chemother 1986;18 (SUPPI D):139-145. 33. Kobayashi H. Clinical efficacy of ciprofloxacin in the treatment of patients with respiratory tract infections in Japan. Am J Med 1987;82 (SUppl4A):169-173. 34. Ernst JA, Sy ER, Colon-Lucca H et al. Ciprofloxacin in the treatment of pneumonia. Antimicrob Agents Chemother 1986;29:1088-1089. 35. Chrysanthopoulos CJ, Skoutelis AT, Starakis JC et al. Use of intravenous ciprofloxacin in respiratory tract infections and biliary sepsis. Am J Med 1987;82 (suppl4A):357-359. 36. Fass RJ. Efficacy and safety of oral ciprofloxacin in the treatment of serious respiratory infections. Am J Med 1987;82 (suppl 4A):202-207. 37. Davies BI, Maesen FPV, Baur C. Ciprofloxacin in the treatment of acute exacerbations of chronic bronchitis. Eur J Clin Microbiol 1986;5:226-231.
39:979-985, 1991
A Randomized Study of Cimofloxacin versus Ceftriaxone in the Treatmeht of Nu.rsi Home-Acquired Lower Respirat:ory Tract Infections Cheryl A. 1. Hirata-Dulas, PharmD, Daniel 1. Stein, MD, David R. P. Guay, PharmD, Robert P. Gruninger, MD, and Phillip K. Peterson, M D
Objective: To compare the efficacy and safety of ciprofloxacin and ceftriaxone in patients with nursing homeacquired lower respiratoy tract infections requiring initial hospitalization. Design: Prospective, randomized trial. Setting: Extended care nursing homes affiliated with a teaching hospital. Patients: Fifty patients aged 60 years or older with normal or mildly impaired renal function admitted to the hospital for treatment of lower respiratory tract infections. Interventions: Twenty-four patients received initial therapy with intravenous ciprofloxacin, 200 mg eve ry 12 hours (19 patients) or 400 mg every 12 hours (5 patients) during the acute phase followed by 750 mg orally every 12 hours during the convalescence phase. Twenty-six patients received initial therapy with intravenous ceftriaxone, 2 g every 24 hours during the acute phase followed by 1 g administered intramuscularly eve y 24 hours during the convalescent phase. The total duration of therapy was 14 days. Main Outcome Measurements: Successful outcome was
defined as resolution or marked improvement in clinical signs and symptoms of lower respirato y tract infection upon completion of the treatment course. Results: Twelve (50%) of the ciprofloxacin-treated and 14 (54%) of ceftriaxone-treated patients had successful outcomes. Recurrent orophayngeal aspiration was the reason for treatment failure in most patients refractory to either antibiotic. Mortality during therapy was 8% in each group. From 21 satisfactoy sputum specimens collected, S. pneumoniae was the most common isolate, followed by H. influenzae and other Gram-negative bacteria. Ciprofloxacin therapy was well tolerated; ceftriaxone therapy was discontinued in two patients (8%) due to adverse reactions (intramuscular pain and drug fever). Conclusions: Sequential intravenousloral ciprofloxacin appears to be as safe and effective as sequential intravenouslintramuscular ceftriaxone. The optimal dosage of intravenous ciprofloxacin in this patient population appears to be 400 mg evey 12 hours; however, additional clinical and pharmacokinetic studies with this regimen are warranted. J Am Geriatr SOC39:979-985, 1991
n the elderly, lower respiratory tract infections acquired in the nursing home are a source of considerable morbidity, mortality, and health care expenditure. Bronchopulmonary infections account for 13%-48% of all institutionally-acquired infections' and in one study were responsible for over
I
10% of all hospital admissions from an extended care nursing home system.* In the elderly nursing home population, the mortality associated with lower respiratory tract infection is reported to be as high as 40%.3-5 Several factors place elderly nursing home patients
From the Nephrology (The Drug Evaluation Unit), Infectious Diseases, and Geriatric Medicine Divisions of the Department of Medicine and the Department of Pathology, Hennepin County Medical Center, Minneapolis, Minnesota; and School of Medicine and College of Pharmacy, University of Minnesota, Minneapolis, Minnesota. Work was performed at Hennepin County Medical Center, Minneapolis, Minnesota and affiliated Extended-Care Program nursing homes.
Supported by a grant-in-aid from Miles, Inc., West Haven, Connecticut. Presented in part at the Third International Symposium on New Quinolones, Vancouver, Canada, July 1990. Address correspondence and reprint requests to Cheryl HirataDulas, PharmD, The Drug Evaluation Unit, Division of Nephrology, Hennepin County Medical Center, 701 Park Avenue South, Minneapolis, MN 55415.
Q 1991 by the American Geriatrics Societv
0002-8614/91/$3.50
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the study drugs; (3) serum creatinine greater than 3.0 mg/dL; (4) contraindication to intramuscular therapy; (5) designation as supportive care only status; or (6) previous study enrollment. The study was approved by the Human Subjects Research Committee at Hennepin County Medical Center, and written, informed consent was obtained from the patient or from his/her surrogate before entry into the study. Patients were randomized to receive a 14-day total course of either ciprofloxacin (200 mg administered intravenously every 12 hours, followed by 750 mg administered orally every 12 hours) or ceftriaxone (2 g administered intravenously every 24 hours, followed by 1 g administered intramuscularly every 24 hours). Intravenous therapy was administered for a minimum of 2 days. In April 1989, the dose of intravenous ciprofloxacin was increased from 200 mg to 400 mg every 12 hours. Pharmacokinetic assessments revealed that at steady state, serum concentrations achieved after multiple intravenous doses of 200 mg were approximately 50% of those achieved after multiple oral doses of 750 mg." Consequently, 19 patients received initial therapy with intravenous ciprofloxacin at a dose of 200 mg every 12 hours, and five patients received 400 mg every 12 hours. Twenty-six patients received ceftriaxone. Ceftriaxone for intramuscular injection was reconstituted in 1%lidocaine to reduce injection pain. During ciprofloxacin therapy, antacids and sucralfate were avoided, and theophylline serum concentrations were monitored. On admission to the hospital, all patients underwent a thorough history and physical examination. Baseline laboratory studies included hematology, serum chemistries, urinalysis, chest roentgenography, and sputum and blood cultures. Hematology, serum chemistries, and urinalysis were performed weekly during drug administration and at the end of therapy. Abnormal laboratory values were repeated at appropriate intervals until resolution. METHODS Sputum samples for microscopic analysis and culture From January 1988 to March 1990, 50 elderly (de- were obtained by expectoration. Sputum was collected fined as age 60 years or older) nursing home residents by a respiratory therapist, and, if necessary, was inin the Extended Care P r ~ g r a m ' ~at, ' Hennepin ~ County duced by saline nebulization or recovered by nasotraMedical Center, who were admitted to the hospital for cheal suction. Sputum specimens were Gram-stained, treatment of lower respiratory tract infections, were and specimens were considered satisfactory if there enrolled in the study. The criteria for the diagnosis of were greater than 25 white blood cells and less than pneumonia were (1) at least one of the following: 10 squamous epithelial cells per low power field. Spucough, oral temperature greater than 37.2OC, dyspnea, tum and blood cultures were processed in a routine peripheral white blood cell count greater than lO,OOO/ manner, and initial susceptibility studies were permm,3 and (2) the presence of new infiltrates on chest formed on all bacterial isolates based on the standard roentgenogram interpreted as compatible with the di- disk testing method using 5-pg disks of ciprofloxac~ agnosis. Acute bronchitis was defined as previously and 30-pg disks of ceftriaxone." Subsequently, the minimum inhibitory concentrations(MICs)of the study de~cribed.'~ Patients were excluded for the following reasons: (1) drugs were determined at concentration ranges of documented allergy to ciprofloxacin, ceftriaxone or re- 0.125 to 128 pg/mL using a microdilution technique in lated compounds; (2) concomitant antimicrobial ther- Mueller-Hinton agar. The following breakpoints were apy with an agent similar in antibacterial spectrum to used to define susceptibility to ciprofloxacin: 1.0 pg/
at risk for lower respiratory tract infection including compromised immune defense^.^,' associated medical conditions,' and oropharyngeal colonization with Gram-negative bacilli.' The absence of classical clinical signs and symptoms of lower respiratory tract infection often results in delayed diagnosis and treatment,' and this factor may also play a role in the increased morbidity and mortality reported in elderly patient^.^ The bacteria that cause lower respiratory tract infections in nursing home patients are often difficult to identify. The replacement of normal oropharyngeal bacterial flora by Gram-negative bacteria in the respiratory tract' supports the need for empiric treatment with broad spectrum antibiotics. Ciprofloxacin, a fluoroquinolone antibiotic, has been proposed as a treatment for lower respiratory tract infections because of its activity against a wide variety of Gram-negative and Gram-positive aerobic bacteria," high degree of penetration into lung tissue and sputum,",'* and low incidence of adverse effect^.'^ Lower respiratory tract infections in elderly nursing home patients have been examined in only a few clinical studies. We recently demonstrated that oral ciprofloxacin therapy was as safe and effective as intramuscular cefamandole in treating patients with relatively mild lower respiratory tract infections acquired in the nursing home.14 The present study was conducted in elderly nursing home patients with moderate to severe lower respiratory tract infections requiring hospitalization for initial intravenous antimicrobial therapy. The purpose of this clinical trial was to evaluate the safety and efficacy of ciprofloxacin administered in an intravenous followed by an oral dosage regimen sequence. Ceftriaxone, administered in an intravenous followed by an intramuscular dosage regimen sequence, was selected as a comparative agent because of its similar spectrum of activity and convenient once a day dosage.
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TABLE 1. CHARACTERISTICS OF PATIENTS AT STUDY ENTRY*
Number of Cases (Percent) Characteristic Number in study Mean age, years (range)
Sex Mean number of medications (range)** Type of Infection:
Pneumonia Bronchitis Underlying diseases Chronic obstructive pulmonary disease Chronic heart disease Dementia 21 Cerebral vascular accident
Ciprofloxacin
Ceftriaxone
24 79.3 (65-101) 13M, 11F 3.9 (0-11)
26 79.4 (64-97) 18M, 8F 3.1 (0-13)
20 (83) 4 (17)
24 (92) 2 (8)
11 (46) 12 (50) 8 (33) 12 (50)
10 (38) 14 (59) 15 (58) 6 (23)
* N o significant differences were observed between the treatment groups. ** Medications prescribed in the nursing home exclusive of pro re nata, vitamins, bowel medications, and topical, otic, and ophthalmic preparations.
TABLE 2. INITIAL CULTURE ISOLATES mL or less, susceptible; 2 pg/mL, intermediately susAND OUTCOME* ceptible; and 4 pg/mL or more, resistant. Breakpoints Number of Cases. for defining susceptibility to ceftriaxone were the fol(% Successful Outcome**) lowing: 8 pg/mL or less, susceptible; 64 pg/mL or more, Specimen Type and resistant. Strains were considered intermediate in susOrganism Ciprofloxacin Ceftriaxone ceptibility when the MICs of ceftriaxone were greater Sputum*** than 8 pg/mL but less than 64 pg/mL. S. pneumoniae 3 (67) 3 (33) S. aureus In selected patients randomized to receive ciproflox1(0) 1 (0) H. influenzae 4 (50)# 1 (0) acin, pharmacokinetic studies at steady-state after inl(lO0) 0 K. pneumoniae travenous and oral dosing were performed; the results l(lO0) 0 E. cloacae have been reported.I6 P. aeruginosa 1 (0) 0 Three categories were established for clinical out9 (44)# 8 (38) Normal oral flora come: success, failure, and indeterminate outcome. Blood S. pneumoniae 0 2 (O)## Success was defined as marked improvement or resolution of the clinical signs and symptoms of lower * N o significant differences were observed between the treatment groups. respiratory tract infection upon completion of the 14- **Marked improvement or resolution of symptoms and clinical signs of day treatment course. Failure was defined as death lower respiratory tract infection on completion of a 14-day course of ciprofloxacin or ceftriaxone therapy. during the study regardless of whether or not it was *** Only sputum specimens with >25 white blood cells and 25 white blood cells and ( 1 0 epithelial cells per low power field (n = 11) were evaluated. More than one organism was isolated in seven sputum specimens. *'* Includes S. pneurnoniae isolates in sputum and blood from one patient during ciprofloxacin therapy. # Unable to obtain minimum inhibitory concentration data for some isolates due to technical problems.
TABLE 4. TREATMENT OUTCOMES* Number of Cases (Percent) -~
Outcome
Death during therapy Therapy outcome Success** Failure*** Indeterminate# Mean number of days hospitalized (range) Mean number of days of intravenous therapy (range)
Ciprofloxacin 2 (8) 12 (50) 10 (42) 2 (8) 5.8 (2-13) 3.4 ( 2 - 6 )
Ceftriaxone 2 (8) 14 (54) 10 (38) 2 (8) 4.5 (2-11) 3.9 (2-10)
* No significant differences were observed between the treatment groups. **Marked improvement or resolution of symptoms and clinical signs of lower respiratory tract infection on completion of a 14-day course of ciprofloxacin or ceftriaxone therapy. *** Early termination due to death, lack of improvement, adverse event, or superinfection. # Early termination due to protocol specification or to factors unrelated to study drug administration.
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S. pneumoniae pneumonia with bacteremia (superinfection) that occurred during ciprofloxacin therapy was the cause of treatment failure in one patient. The patient, a 74-year-old Caucasian male with chronic obstructive pulmonary disease, presented with increasing dyspnea, fever, lethargy, and hypertension. He was intubated and later required a dopamine infusion for blood pressure support. Left lower lobe and lingular infiltrates were observed on initial chest roentgenogram. The patient was randomized to receive intravenous ciprofloxacin 200 mg every 1 2 hours, and he defervesced and remained afebrile during the first 3 days of admission. Initial blood and urine cultures were negative, and normal oral flora was isolated in sputum culture. The patient was extubated on day three, and he was switched to oral ciprofloxacin. After four doses of oral therapy, reinstitution of intravenous ciprofloxacin was required due to increasing dyspnea, persistently elevated white blood cell count, and spiking temperatures. A chest roentgenogram on day six showed worsening of the left lung infiltrates and new right basilar infiltrates. S. pneurnoniae was isolated from sputum and blood cultures on day eight. The MICs of ciprofloxacin to these isolates were 4 pg/mL and 2 wg/ mL, respectively. A pharmacokinetic assessment, performed after the fifth intravenous dose of ciprofloxacin 200 mg, revealed that the serum ciprofloxacin concentrations at the end of a 1-hour infusion and at the end of the dosing interval were 3.54 &mL and 0.27 pg/ mL, respectively. On day eight, the patient was switched to intravenous penicillin G with eventual resolution of the pneumonia. Of the seven patients from whom S. pneumoniae was isolated on hospital admission in sputum and/or blood, outcomes were successful in two of the three patients who received ciprofloxacin (all three patients received initial therapy with intravenous ciprofloxacin 200 mg every 12 hours) and in one of four patients who received ceftriaxone. Although one failure to ceftriaxone was attributed to an adverse event (intramuscular pain), two were attributed to primary antibiotic failure. Reasons for early withdrawal from the study for the four patients categorized as indeterminate in outcome were: H. influenzae resistant to study drugs on initial disk susceptibility testing, enterococcus isolated in urine resistant to ceftriaxone, inadvertent withdrawal from study due to pharmacy error, and physician request despite patient improvement. Adverse drug reactions regarded as possibly or probably due to the study drugs were infrequent in both groups. In patients receiving ciprofloxacin, laboratory abnormalities included transient elevations in serum aspartate aminotransferase (n = 2), serum alanine aminotransferase (n = 2), alkaline phosphatase (n = l), lactate dehydrogenase ( n = l), and eosinophil count ( n = 1). Six ciprofloxacin-treated patients received con-
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comitant theophylline therapy; no signs or symptoms of theophylline toxicity were observed. Laboratory abnormalities observed during ceftriaxone therapy included transient elevations in serum aspartate aminotransferase (n = l), alkaline phosphatase (n = l), and eosinophil count ( n = 1). Diarrhea was reported in four patients during ceftriaxone therapy. Pseudomembranous colitis was diagnosed in one patient after completion of ceftriaxone therapy. One patient was discontinued from ceftriaxone therapy due to presumed drug fever, and one patient withdrew secondary to intolerable intramuscular injection pain. Three patients in each group developed candiduria during antimicrobiaI therapy.
DISCUSSION Our understanding of the pathophysiology, bacteriology, and clinical features of lower respiratory tract infection acquired in the nursing home has improved significantly over the past d e ~ a d e . ' ~ ~However, ~ ' * ~ ' ~ the treatment of this infectious disease entity has been examined in only a few prospective, randomized clinical trials. Two recent comparative studies combined nursing home-acquired lower respiratory tract infections with community-acquired and/or hospital-acquired pneumonia,z0*21and, thus, potentially overlooked important characteristics of elderly nursing home patients such as differences in etiology and preexisting medical conditions. In the present study, the microbiologic findings in expectorated sputum were consistent with previous ~ t u d i e s ~supporting ,'~ the importance of S. pneumoniae and Gram-negative organisms as etiologic agents of lower respiratory tract infection acquired in the nursing home. Unfortunately, satisfactory sputum specimens for diagnosis were not obtainable in all patients. Invasive procedures for procuring more reliable specimens for culture were not practical in this acutely ill, medically fragile nursing home population. The bacteriologic etiology of pneumonia was established by positive blood cultures in only two patients. Other investigators have also noted a low frequency of bacteremia in elderly patients with p n e ~ m o n i a . ' ~ ~ ~ ~ ~ ~ ~ Most isolated pathogens were susceptible to both study drugs. Discrepancies between the disk sensitivity and microdilution tests were few. The occurrence of in vifro test differences has been noted previouslyz4and may be caused by subtle technical variables in testing such as inoculum size and end-point determinations. The implications of these differences as they influence the selection of antimicrobial agents is unknown. The clinical success rate in the present study of approximately 50% in both groups is lower than that reported in our previous study (76%).14 In addition, patients required hospitalization for a slightly longer duration than in our previous study (mean of 4 days).I4
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These differences possibly reflect the greater severity of illness among patients enrolled in the present study. The lower mortality rates observed in the present study (8%) and our previous study (6.5%),14compared to other may be attributed to early recognition of the frequently atypical presentation of bronchopulmonary infection in the elderly nursing home patient. Identifyinginfection early in its course was made possible by the structure of our Extended Care Program.'4*'5 Aspiration of oropharyngeail contents is the predominant pathophysiological mechanism of lower respiratory tract infection in nursing home patient^.'^ Over 50% of the treatment failures were patients who experienced recurrent episodes of clinically evident oropharyngeal aspiration. In some of these patients, normal oral flora was isolated in sputum culture. Normal oral flora isolated in sputum has unknown significance but may be pathogenic in the context of aspiration pneumonia.26Evidence exists that ciprofloxacin may be active against oropharyngeal flora,27but it is possible that treatment failures were (duein part to its relative lack of antianaerobic activity." Another major reservation regarding the use of ciprofloxacin in patients such as those reported here is its modest in vitro activity against S. pneumoniae. The case of S. pneumoniae pneumonia (including bacteremia) during therapy with ciprofloxacin was instructive. Although this infection was considered a superinfection, it is possible that the organism was present initially but not isolated in either blood or sputum. Alternatively, administration of ciprofloxacin could have allowed colonization and subsequent infection of the respiratory tract to occur with S. pneumoniae as suspected in a recent case report.28 Some investigators believe that a useful predictor of bacterial eradication in patients with nosocomial lower respiratory tract infections is the length of time that the serum concentration of the antimicrobial agent remains above the MIC.29*30 Our patient received intravenous ciprofloxacin 200 mg every 12 hours during the acute phase of infection., which achieved a peak serum concentration of ciprofloxacin that was below the MIC for the strain of S. pneumoniae isolated in the sputum. Although data from other clinical studies indicate that the high MICs of ciprofloxacin to s. pneumoniae do not impair its effectiveness, probably because concentrations in sputum and lung tissue are several times greater than those achieved in initial therapy with a higher dose of ciprofloxacin may have circumvented this complication. In the small number of ]patients with probable S. pneumoniae infection in the present series, no significant difference in outcome between the ciprofloxacinand ceftriaxone-treated patients was observed. Other studies in which ciprofloxacin was used to treat S.
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pneumoniae isolated in the respiratory tract reported favorable overall clinical cure In only one study37was an unfavorable clinical outcome reported (9/26 patients improved, and 17/26 patients failed therapy); the reason for the discrepancy in results between this study and others is not clear. Ciprofloxacin 400 mg administered intravenously every 12 hours would theoretically provide better coverage against S. pneumoniae and appears to be the standard dose for these patients assuming that creatinine clearance exceeds 25 mL/min. However, clinical and pharmacokinetic studies of this regimen have not yet been performed in elderly patients, and it is not known whether significant accumulation occurs with multiple dosing regimens. While ciprofloxacin should not be the sole or preferred therapy when S. pneumoniae infection is documented, empiric therapy with ciprofloxacin is appropriate when infection with any of a variety of bacterial pathogens is likely, such as in nursing homeacquired pneumonia. In cases when sputum Gramstrains are suggestive of s. pneumoniae infection, the addition of penicillin may be appropriate. Intravenous ciprofloxacin has only recently been approved for commercial use, and a cost comparison of the intravenous regimens is not currently available. Upon hospital discharge, switching to an oral agent, such as ciprofloxacin, is more cost effective than changing to intramuscular ceftriaxone. In addition to the lower cost of ciprofloxacin itself ($9/day for two 750 mg ciprofloxacin tablets compared with $37/day for ceftriaxone 1 g at our institution), other expenses associated with parenteral therapy including preparation time, administration, and potential complications must be considered. In the minority of cases in which the pathogen is established by positive blood culture, therapy can be individualized based on sensitivity patterns of the organism isolated, as well as cost considerations. The results of the present study indicate the ciprofloxacin is as safe and effectiveas ceftriaxone in treating elderly patients with nursing home-acquired lower respiratory tract infections requiring initial hospitalization. Both agents can be administered intravenously in the hospital, then changed to the same drug for administation by the oral (ciprofloxacin) or intramuscular (ceftriaxone) route to complete therapy in the nursing home. Oral ciprofloxacin offers significant advantages over intramuscular ceftriaxone, such as convenience and cost savings. However, neither drug may be the antimicrobial agent of choice for treating nursing home patients who have a history of recurrent aspiration. With the development of newer broad spectrum agents, it is likely that in the future other agents will provide similar or superior safety and efficacy profiles compared to those of ciprofloxacin and ceftriaxone. Additional studies are also warranted to evaluate whether clinically stable patients with nursing home-
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TREATMENT OF NURSING HOME-ACQUIRED PNEUMONIA
acquired lower respiratory tract infections can safely and effectively be treated in the nursing home without initial hospitalization.
ACKNOWLEDGMENTS We are deeply grateful to the Extended Care Program nurses and internal medicine residents who assisted with the conduct of this study.
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