- Email: [email protected]
ORAL CIPROFLOXACIN THERAPY OF INFECTIONS DUE TO PSEUDOMONAS AERUGINOSA
819
microorganism in the lesion makes it seem likely that MS is caused by an immunological defect. A commensal bacterium with growth favoured by the conditions in a diseased sinus might elicit an immune reaction against central nervous system antigens due to cross-reacting antigenic groups. An acquired allergy of this type, however, is not consistent with the differences between the seasonal behaviour offirst attacks and of exacerbations, and despite many years of intensive effort the efficacy of immunosuppression remains in doubt. 15 Although sinus infection may extend to the CNS by retrograde venous spread, no microorganisms likely to be present in a diseased sinus would be capable of causing MS by direct invasion. However, though the original observations of spirochaetes in acute plaques by Steiner 16 are no longer taken seriously, Steere 17 has found that spirochaetes can cause the immunological and pathological changes peculiar to MS. In Lyme disease" spirochaetes cause a chronic relapsing and remitting lymphocytic inflammation of the joints and CNS and, as in MS, oligoclonal antibodies are found in the cerebrospinal fluid, immune complexes are present in the lesions, and T-lymphopenia occurs, with pronounced killerT-cell depression. Susceptibility is associated with the DW2 B-cell alloantigen. Organisms have not been seen in the lesions and are rarely cultured, but the disease is cured by large doses of parenteral penicillin, and only modified by corticosteroids. Because of the complete failure to discover the cause ofMS we believe it could be worthwhile to reinvestigate the
ORAL CIPROFLOXACIN THERAPY OF INFECTIONS DUE TO PSEUDOMONAS AERUGINOSA BRIAN E. SCULLY1 MICHAEL F. PARRY2
HAROLD C. NEU1 WILLIAM MANDELL1
Division of Infectious Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, USA;1 and Division of Infectious Diseases, Stamford Hospital, Stamford, Connecticut2
The efficacy and safety of oral ciprofloxacin, a fluoroquinolone, were evaluated in the treatment of infection due to Pseudomonas aeruginosa. 96 infections in 71 patients were treated. Substantial underlying disease was present in most of the patients, and 25 (35%) were seriously ill. 52% of pseudomonas isolates were carbenicillinresistant, and 31% gentamicin-resistant. The overall clinical response rate was 77% - 28 of 35 exacerbations of cystic fibrosis respiratory disease, 17 of 19 urinary infections, 4 of 6 osteomyelitis, and 11 of 15 soft tissue infections. The bacteriological cure rate was 34% - 0 of 35 cystic fibrosis, 4 of 17 respiratory infections, 17 of 19 urinary infections, 4 of6 osteomyelitis, and 8 of 15 soft tissue infections. Ps aeruginosa developed resistance to ciprofloxacin in 25 of 96 infections. Side-effects were generally slight with nausea in 14 (15%) the most common, and there were only two substantial
Summary
superinfections.
spirochaetal theory. We thank Dr S. Marshall, Dr A. Bush, Dr J. Sanderson, Dr A. Googe, Dr A. Kerr, DrN. Paros,DrJ. Tomlinson, Dr C. Hall, DrJ. Owen, DrJ. Weston, Dr
G. Hey, and their partners for making the records oftheit patients available. This work was supported by the Department of Health and Social Security granting a period of sabbatical leave to D. G.
Correspondence should be addressed to D. G., Green Storthe, 68 Coast Road, West Mersea, Essex C05 8LS, from whom a typescript of the relevant data on the 92 patients and 184 controls from which table was prepared and details of statistical calculations may be obtained
on
request.
REFERENCES
Spidel E, Inoue YK, Nishibe Y. Isolation of virus from the spinal fluid of three patients with multiple sclerosis and one with amyotrophic lateral sclerosis.
1. Melnick JL,
Lancet 1982; i: 830-33. 2. Inoue YK, Nishibe Y, Nakamura Y. Virus associated with SMON in Japan. Lancet 1971; i: 853-54. 3. McAlpine D. Course and prognosis of multiple sclerosis. In: McAlpine D, Lumsden C-E, Acheson ED, eds. Multiple sclerosis: a reappraisal. Edinburgh: Churchill Livingstone, 1972: 202. 4. Sibley WA, Bamford CR, Clark K. In: Poser C, ed. The diagnosis of multiple sclerosis. New York: Thieme-Stratton Inc, 1984. 5 Sibley WA, Foley JM. Infection and immunisation in multiple sclerosis. Ann NY Acad Sci 1965; 122: 457-68. 6 Poser S. Multiple sclerosis. An analysis of 812 cases by means of electronic data processing. Berlin: Springer-Verlag, 1978: 27. 7. Fry J In Fry J, ed. Trends in general practice 1977. London: Royal College of General Practitioners, 1977: 20. 8. Sibley WA, Bamford CR, Clark K. Clinical viral infections and multiple sclerosis. Lancet 1985; i: 1313-15. 9. Acheson ED. The epidemiology of multiple sclerosis. In: Matthews WB, Acheson ED, Batchelor JR, Weller RO, eds. McAlpine’s multiple sclerosis. Edinburgh: Churchill Livingstone, 1985: 28. 10. Brody JA. Epidemiology of multiple sclerosis and a possible virus aetiology. Lancet 1972; ii: 173-76. 1 1. Formby ML. The maxillary sinus. Proc R Soc Med 1959; 53: 1-6. 12. Jaffe L Sinusitis in tropical climates. Zeitschurfur Laringol, rhinol otol und grenz 1951; 30: 295-301. 13 Manson-Bahr P. Tropical diseases affecting the throat, nose and ear. J Laryngol Otol
1956; 70: 175-95. Martin JAM. Diseases of the ear, nose and throat in tropical Africa. A Uganda survey. J Laryngol Otol 1967; 81: 1079-98. 15 Hallpike JF. New treatments for multiple sclerosis. Br J Hosp Med 1980; 23: 63-66. 16. Steiner G. Acute plaques in multiple sclerosis; their pathogenic significance and the role of spirochaetes as etiological factor. J Neuropathol Exp Neurol 1952; 11: 14
343-72. 17 Steere AC. First International Symposium on Lyme
445-711.
Disease. Yale J Biol Med 1984; 57:
Introduction
Pseudomonas
aeruginosa is an important pathogen, particularly as a cause of nosocomial infections and of the chronic pulmonary disease associated with cystic fibrosis. Because this organism is resistant to antibiotics that can be taken orally, effective therapy has required admission to hospital, which is expensive and inconvenient. If treatment must be long term or repeated, there is a risk of aminoglycosides causing toxic effects on the central nervous system or kidneys and of further nosocomial infection. There is, therefore, a need for a safe and effective agent that could be
given orally to treat infections caused by Ps aeruginosa and other multiply resistant Enterobacteriaceae. Ciprofloxacin is a fluorinated carboxyquinolone with a broad antibacterial spectrum that includes Ps aeruginosa; 90% of strains are inhibited by 0’55 mg/1.’°2 Blood levels of 2-3 mg/l are attained after 500 mg taken orally and interstitial fluid levels of 1 -4 mg/1 can be achieved.3,4 We have studied the efficacy and safety of ciprofloxacin in the treatment of various infections due to Ps aeruginosa. Although the interpretation of open, non-comparative studies is difficult, we chose this design because of the lack of alternative oral agents and because we wished to use ciprofloxacin in infections caused by Ps aeruginosa resistant to even the available parenteral antibiotics. Patients and Methods Patients were seen at the Presbyterian Hospital in New York or the Stamford Hospital. All had Ps aeruginosa as a sole or major contributing pathogen. They were part of a larger study of ciprofloxacin in the treatment of infections due to multiply resistant organisms. Reasons for exclusion were having received an effective antibiotic within the previous 72 h, serious liver disease, pregnancy, or a history of an adverse reaction to nalidixic acid or other quinolones. Also excluded were patients under the age of 18, with the exception of two patients with cystic fibrosis aged 15 and 12
820 years whose other therapy had failed and who were seriously ill. All or an immediate family member gave informed, written consent in accordance with the guidelines of the institutional committee on human investigation. The clinical diagnosis was confirmed in each case by appropriate cultures, X-ray examination, and diagnostic tests appropriate to the infection. For patients with cystic fibrosis, bronchopneumonia, or bronchitis, cultures of expectorated sputum, tracheal aspirates (intubated patients only), or bronchoscopy specimens grew Ps aeruginosa as the sole or predominant pathogen. Patients with sinusitis had X-ray findings consistent with sinusitis and cultures of sinus aspirates grew Ps aeruginosa. Patients with osteomyelitis had positive X-rays and cultures of bone tissue biopsy samples. Patients with soft tissue infections had positive cultures ofpus or aspirates of appropriate body fluid (for example, empyema fluid). Patients with urinary tract infection had >105 colony-forming units (cfu) per ml of urine in two consecutive samples. Response to therapy was evaluated from clinical, radiological, and bacteriological aspects by the investigators and the primary physicians. Patients were considered to have responded clinically if satisfactory improvement in signs and symptoms of infection occurred - for example, complete resolution of fever, pronounced reduction in respiratory symptoms in pulmonary infections, clearing of pus and signs of infection in soft tissue and bone infections, and complete clearing of urinary symptoms in urinary tract infections. Bacteriological cure required elimination of Ps aeruginosa from culture sites during treatment and at follow-up at 5 to 9 days for urinary tract infection, and more than 24 h after therapy for infections outside the urinary tract. Inpatients were observed daily by one of the investigators for a response to therapy and signs of toxicity. Outpatients were seen weekly. The eyes were fully examined (with funduscopy, visual acuity, and colour vision) before, during, and after treatment. Blood chemistry, complete blood count, prothrombin time, and urinalysis were also followed. Ciprofloxacin was given orally, usually 1 h before or 2 h after a meal. The dose ranged from 750 mg to 2250 mg daily. Most patients received either 500 mg or 750 mg every 12 h (28% and 38%, respectively) or 750 mg every 8 h (28%). All but 3 patients received ciprofloxacin as sole therapy. Initial susceptibility to ciprofloxacin was determined for clinical isolates by the Kirby-Bauer disc method with 5 lag ciprofloxacin discs at the Presbyterian Hospital and by microdilution at the Stamford Hospital. Minimum inhibitory concentrations (MIC) were determined by applying 104cfu to Mueller-Hinton agar or by inoculating 5 x 105 cfu into Mueller-Hinton broth containing twofold increasing concentrations of antibiotic. Susceptibility to other antibiotics was determined by the microtube dilution method with the Microscan system (Mahwah, New Jersey). Concentrations of ciprofloxacin in serum and body fluids were measured by the agar-well diffusion method with a susceptible strain of Klebsiella pneumoniae as the test organism.3Peak serum samples were drawn 1-4 h after a dose. Trough samples were drawn during the 30 min before a dose. Urine levels were determined on a sample from a 6-12 h collection.
TABLE I-OVERALL RESPONSE TO CIPROFLOXACIN THERAPY
patients
_
Results 96 infections due to Ps aeruginosa in 71 patients (36 male, 35 female) were treated with ciprofloxacin. The patients’ mean age was 49 years (range 12-85 years), mean duration of therapy 24 days (range 4-180 days), and mean daily dose 1500 mg (range 750-2250 mg). All but 3 patients had severe underlying disorders (12 cardiovascular, 12 pulmonary, 16 cystic fibrosis, 2 renal, 1 hepatic, 10 neurological, 8 diabetes mellitus, 8 malignant, and 1 acquired immunodeficiency syndrome). 10 patients had recently undergone operations. 6 patients were receiving corticosteroids and 6 were malnourished. The condition of the patient was serious at the start of 25 of the treatment courses, fair for 45 courses, and good for 25 courses. The range of MIC for ciprofloxacin of the Ps aeruginosa
TABLE II-RESPIRATORY TRACT INFECTION RESULTS
*1
patient was treated three times. tpatient was treated twice.
isolated before therapy was 0 -. 06-20 mg/1 (geometric mean 0 -3 mg/1). The organism was resistant to carbenicillin in 52% of infections (MIC >128 mg/1), to gentamicin in 31% (MIC >8 mg/1), to amikacin in 27% (MIC >16 mg/1), and to tobramycin in 15% (MIC >6 mg/1). The overall results of therapy are summarised in table I. There was a 77% clinical response rate and a 34% bacteriological cure rate (54% if cystic fibrosis patients are excluded). Of the patients who had a clinical response to ciprofloxacin, 14 had not responded to a standard beta-lactam and aminoglycoside regimen. Of the patients who did not respond clinically to ciprofloxacin, 4 did not respond to subsequent therapy, and 6 responded to betalactam and aminoglycoside therapy. Table II shows the results of ciprofloxacin therapy in lower respiratory tract and sinus and ear infections. 8 patients had pneumonia. In 3 patients pulmonary infiltrates had developed in a setting of chronic lung disease and ongoing colonisation of the respiratory tract with pseudomonas. In 2 pseudomonas pneumonia had developed during mechanical ventilation. The other underlying disorders were Alzheimer’s disease, lung carcinoma, and AIDS. Although the pseudomonas was eradicated in only 2 patients, 7 had clinical responses. The clinical failure was a man with lung carcinoma complicated by right upper and middle lobe pneumonia. He also did not respond to ticarcillin and tobramycin and later died. The remaining respiratory infections were exacerbations of chronic and well-established infection. Bacteriological cure was achieved in only 2 of 13 patients. Good clinical responses were observed in 7 patients. 16 patients (6 male, 10 female) with cystic fibrosis received ciprofloxacin as therapy for 35 exacerbations of their chronic lung disease (table III). In 11 of these exacerbations the patient was severely ill with a high temperature, severe respiratory distress, and low exercise tolerance; in 17 the patient was in fair condition, and in 7 good condition. The patients ranged
821 TABLE III-THERAPY OF EXACERBATIONS OF PULMONARY INFECTION IN PATIENTS WITH CYSTIC FIBROSIS LUNG DISEASE I
I
I
fever). Bacteriological cure was achieved in only 8 of the patients, however. The clinical failures occurred in a diabetic with neurovascular disease whose foot infection cleared during ciprofloxacin therapy but recurred immediately afterwards; an elderly woman with a chronic draining lesion of the thigh of unknown aetiology; a young man with extensive postoperative osteomyelitis and a pseudomonas superinfection of his thigh wound; and a young man with a severe neuromuscular injury of the ankle in whom pseudomonas was eliminated but a superinfection with group D streptococcus and Bacillus subtilis occurred. 4 of 6 patients with osteomyelitis due to Ps aeruginosa responded to ciprofloxacin therapy (table IV). 3 patients had other pathogens which were susceptible to ciprofloxacin and 1 of these also had concomitant anaerobic streptococcus for which amoxicillin was prescribed. The duration of therapy ranged from 16 to 65 days (mean 42). None of the 4 responders has relapsed during follow-up of 9-18 months (mean 13 months). The 2 patients who did not respond both had extensive chronic osteomyelitis of the femur and adequate surgical debridement was not possible. The mean peak serum levels of ciprofloxacin were 2 -9mg/l after 500 mg and 3’6mg/l after 750 mg. Mean trough values were 0 - 54 mg/l and 1 - 0 mg/1. The urinary ciprofloxacin level in 13 patients 6-12 h after a dose was >50 mg/1. A significant fall in susceptibility of pseudomonas to ciprofloxacin, defined as a greater than four-fold rise in MIC, was observed in 32 of 96 treatment courses. In 7 the MIC rose but remained within the susceptible range (eg, from 0’25to 1 -0 mg/1). In the remaining 25, however, the pseudomonas became resistant (MIC >2 mg/1).5 Resistance occurred in infections of the respiratory tract, soft tissue, and bone but not of the urinary tract. Typically the pseudomonas persisted at the infection site and could be isolated throughout the treatment course. In contrast, if the infected site had been sterilised during therapy but a subsequent microbiological relapse occurred, the organism isolated was usually susceptible to ciprofloxacin with little or no rise in MIC. 9 isolates of pseudomonas became more susceptible (MIC four times less than pre-treatment value) to beta-lactams or aminoglycosides, and 8 became less susceptible (MIC four times greater than pre-treatment value). In the remaining infections the pseudomonas showed no changes in betalactam or aminoglycoside MIC during ciprofloxacin therapy. Nausea and epigastric pain were the only adverse reactions noted with any frequency (14 of 96 courses of treatment). The mean daily dose per kg body weight of patients experiencing nausea was slightly less than for those patients without nausea. Lowering the dose, however, did reduce the discomfort in several patients. In 3 patients fluid retention was a possible adverse reaction; in 2 peripheral oedema without any change in cardiac or renal function occurred, and 1 patient with cor pulmonale deterioriated without a clear inciting event. Other side-effects noted were diarrhoea (3 patients), raised aminotransferases (2), pruritus without rash (1), and sleep disturbance (1). Only 1 patient stopped therapy because of nausea. There were 2 substantial superinfections. The first was in a patient with a wound infection of the ankle. The Ps aeruginosa was eradicated by ciprofloxacin, but the skin graft became superinfected with group D streptococcus and Bacillus subtilis. The second occurred in a patient with an exacerbation of pseudomonas bronchitis who also had lymphoma and neutropenia after chemotherapy. 12 days into therapy a cavitary lung lesion developed. The sputum became more purulent and ciprofloxacin-resistant man
in age from 12 to 36 years (mean 23 years), the duration of therapy from 12 to 58 days (mean 20 days), and the time between courses of therapy from 14 to 220 days (mean 95 days). The ciprofloxacin dose varied according to severity of illness, body size, and susceptibility of the pseudomonas from 750 mg to 2250 mg daily (mean 1860 mg). 8 patients received one course and 8 repeated courses of ciprofloxacin. At least 1 strain of Ps aeruginosa was isolated in each patient, and in 12 patients other pathogens susceptible to ciprofloxacin were present. The overall clinical response rate was 80%. The clinical failures occurred in patients being retreated with ciprofloxacin who were moderately to severely ill and had large volumes of sputum. Failure to respond correlated poorly with pretreatment MIC (0’6 mg/1 for failures v 04 mg/1 for responders). Pseudomonas could not be eradicated from the sputum of the patients, although there was substantial reduction in sputum purulence. All but 1 of the 18 patients with urinary tract infections (19 infections) had acquired the infection in association with bladder instrumentation or catheterisation. 3 patients had superficial bladder neoplasms, and 6 patients required further intermittent catheterisation during therapy with ciprofloxacin (neurogenic bladder 5, Koch pouch 2). No
patients required indwelling catheters while receiving ciprofloxacin. In 2 patients, both with neurogenic bladders, a second pathogen was cultured (Proteus mirabilis, Providencia stuartiz). In all 19 infections the urine was sterilised during therapy. In 17 the urine was sterile at 5-9 day follow-up. For 15 of the 17 cured patients cultures were done 3-6 weeks later; all were negative for Ps aeruginosa. 1 of the 2 patients who relapsed was cured by a second, longer, course of ciprofloxacin (30 days) and was clear at 1 week and 6 weeks of follow-up. In 11of the 15 soft tissue infections (table IV) there were good clinical responses to ciprofloxacin (ie, progressive healing, substantial reduction of purulence, and lowering of TABLE IV-SOFT TISSUE INFECTION AND OSTEOMYELITIS RESULTS
*Other pathogens cultured Enterobacter cloacae 1, Serratia marcescens 1, Proteus mirablhs 1. tOther pathogens cultured S marcescens 2; E cloacae 1, and P mlrabilis 1. femur 1, tibia 2: chronic in all 3. 5Chronlc in both.
822 aureus and Ps aeruginosa (MÍC 4 mg/1) were cultured from the sputum. 4 patients had mild candidal skin or vaginal infections, which responded to topical therapy.
Staphylococcus
Discussion The in-vitro and pharmacokinetic characteristics of the first quinolone antimicrobial, nalidixic acid, are such that concentrations adequate to inhibit many species of gramnegative bacteria are reached in urine but not in blood or body tissues. Furthermore, in the treatment of lower urinary tract infections the emergence of resistance curtailed its use. Owing to toxic effects on the central nervous system and eyes, larger doses and parenteral administration of nalidixic acid are not safe. Subsequent agents of this class, cinoxacin and oxolinic acid, did not enlarge the antibacterial spectrum and did not have superior pharmacological properties. In the past 5 years many new quinolones have been developed with greatly improved in-vitro activity, especially against gram-negative bacteria.1,2,6,7 Of these new agents, ciprofloxacin is the most active, against both a broad range of enteric gram-negative bacteria and Ps aeruginosa. Many studies have shown that ciprofloxacin will inhibit the majority of the Enterobacteriaceae at concentrations below 0 . 25 mg/1.1,2,6 Though less active against Ps aeruginosa, it will inhibit 90% of strains at 0 -5mg/l. Activity is also good against staphylococci, including methicillin-resistant isolates (MIC9o 0’8 mg/1), but only fair against streptococci (MIC9o 2-4 mg/1), and bacteroides are resistant (MIC9o >8 mg/1). Pharmacokinetic studies of ciprofloxacin in healthy volunteers have shown peak blood levels of 2-0-2-9 mg/1 after 500 mg and 2-9-3-55 mg/l after 750 mg.3,4,STaken orally, the plasma elimination half-life is 3-4 h, and blood levels at 8 h and 12 h after 750 mg are 0 -7 mg/1 and 0 -4 mg/1, respectively. Levels are slightly lower after 500 mg doses. Both hepatic metabolism and renal excretion occur. 50% of an administered dose is excreted in the urine as intact drug or active metabolites. The volume of distribution is very high (2 - 0-2 - 6 1/kg), corroborated by preliminary data that suggest good penetration into interstitial fluid, sputum, bone, and prostate.4,IO-12 Our overall clinical and bacteriological response rates were 77% and 34%, respectively. In roughly comparable groups of patients treated with aztreonam or ceftazidime for Ps aeruginosa infections the clinical response rates were 83% and 80% and bacteriological response rates 37% and 50%.13,14 The results of ciprofloxacin therapy of urinary tract infections and exacerbations of cystic fibrosis, particularly the first course of treatment, were excellent, although the tendency for resistance to develop may have impaired efficacy in retreatment of cystic fibrosis patients. Generally favourable responses were also noted in soft tissue, bone, and other pulmonary infections. Ciprofloxacin was often effective where earlier therapies had failed owing to the resistance of pseudomonas to other drugs. It should also be noted that in some of the cases for which ciprofloxacin failed other therapy also failed. Development of resistance to ciprofloxacin in Ps aeruginosa isolates during therapy is a major difficulty. The mechanism of resistance may be related to the presence at the infected site of subinhibitory or barely inhibitory concentrations of antibiotic, encouraging the growth of more resistant strains within a population of bacteria. It is possible in vitro with repeated subculture to select isolates resistant to ciprofloxacin, even though the frequency of spontaneous resistance is low (<10-9).2 The development of resistance may
have little effect upon the course of the infection being treated. In soft tissue infections, a surface culture of a healing wound often grew a resistant pseudomonas during or at the end of therapy as the wound continued to heal uneventfully. In cystic fibrosis patients, a less susceptible or resistant strain was usually isolated during or at the end of therapy. Clinical improvement occurred and persisted for a variable time. At the subsequent relapse the isolate was usually less susceptible than the pretherapy isolate but more susceptible than the post-therapy isolate. This course was not predictable, however, and resistance sometimes persisted. In bone infections we usually observed initial modest clinical improvement, but subsequent deterioration if drug resistance occurred. These organisms retained their resistance for at least 2-3 months. Thus, the implications of the development of resistance to ciprofloxacin vary between infections and between patients. Certainly, the resistant strains are capable of causing disease. We plan studies of whether the combination of ciprofloxacin with a second agent will prevent the emergence of resistance. Ciprofloxacin was very well tolerated. We did not encounter central nervous system toxicity, but 1 elderly patient experienced insomnia throughout a 3-week course of therapy. We also did not find joint pains or myalgias which have been linked with some agents of this class. None of the patients had crystalluria or reduced renal function. Ciprofloxacin makes it possible to treat patients infected with Ps aeruginosa at home. It will be particularly important in the treatment of urinary infections, osteomyelitis, and respiratory infections in patients with cystic fibrosis. There are worries about the development of resistance, however. Results of comparative studies are awaited to determine its efficacy and safety relative to the standard beta-lactam and
aminoglycoside regimens. Correspondence should be addressed to H. C. N., Division of Infectious Diseases, Department of Medicine, College of Physicians and Surgeons of Columbia University, 630 West 168th Street, New York, NY 10032, USA. REFERENCES 1. Wise
R, Andrews JM, Edwards LJ. In vitro activity of Bay-0-9867, a new quinolone derivative, compared with other antimicrobial agents. Antimicrob Ag Chemother 1983; 23: 559-64. 2. Chin NX, Neu HC. Ciprofloxacin, a quinolone carboxylic acid compound active against aerobic and anaerobic bacteria. Antimicrob Ag Chemother 1984; 25: 319-32. 3. Brittain DC, Scully BE, McElrath MJ, Steinman R, Labthavikul P, Neu HC The
pharmacokinetics and serum and urine bacterical activity of ciprofloxacin. JClin Pharmacol 1984; 25: 82-85. 4. Crump BR, Wise R, Dent J. Pharmacokinetics and tissue penetration of ciprofloxacin. Antimicrob Ag Chemother 1983; 24: 784-86. 5. Barry AL, Fass RJ, Anhalt JP, et al. Ciprofloxacin disk susceptibility tests: interpretive zone size standards for 5µg disks J Clin Microbial 1985; 21: 880-83. 6. Bauerfeind A, Petermuller C. In vitro activity of ciprofloxacin, norfloxacin and nalidixic acid. Eur J Clin Microbiol 1983; 2: 111-15. 7. Chin NX, Neu HC In vitro activity of enoxacin, a quinolone carboxylic acid, compared with those of norfloxacin, new beta-lactams, aminoglycosides, and trimethoprim. Antimicrob Ag Chemother 1983; 24: 754-63. 8. Gonzalez MA, Uribe F, Moisen SD, et al. Multiple-dose pharmacokinetics and safety of ciprofloxacin in normal volunteers. Antimicrob Ag Chemother 1984; 26: 741-44 9. Gonzalez MA, Moranchel AA, Duran S, et al. Multiple-dose pharmacokinetics of ciprofloxacin administered intravenously to normal volunteers. Antimicrob Ag Chemother 1985; 28: 235-39. 10. Blumer JL, Stern RC, Myers CM, Klinger JD, Reed MD. Pharmacokinetics and pharmacodynamics of ciprofloxacin in cystic fibrosis. 14th International Congress on Chemotherapy. Kyoto, Japan, 1985: abstr no S-40-14. 11. Fong IW, Ledbetter W, Vandenbroncke A, Sunbal M, Rahan U. The penetration of ciprofloxacin after single oral doses in normal and infected bones. 14th International Congress on Chemotherapy. Kyoto, Japan, 1985: abstr no S-40-8. 12. Schalkauser K, Adam D, Dalhoff A. Diffusion of ciprofloxacin into human prostatic tissue after oral intravenous application. 14th International Congress on Chemotherapy, Kyoto, Japan, 1985: abstr no S-40-9. 13. Scully BE, Neu HC. Use of aztreonam in the treatment of serious infections due to multiresistant gram-negative organisms, including Pseudomonas auruginosa. Am J Med 1984; 78: 251-261. 14. Scully BE, Neu HC. Clinical efficacy of ceftazidime. Treatment of serious infection due to multiresistant Pseudomonas and other gram-negative bacteria. Arch Intern Med 1984; 144: 57-62.
microorganism in the lesion makes it seem likely that MS is caused by an immunological defect. A commensal bacterium with growth favoured by the conditions in a diseased sinus might elicit an immune reaction against central nervous system antigens due to cross-reacting antigenic groups. An acquired allergy of this type, however, is not consistent with the differences between the seasonal behaviour offirst attacks and of exacerbations, and despite many years of intensive effort the efficacy of immunosuppression remains in doubt. 15 Although sinus infection may extend to the CNS by retrograde venous spread, no microorganisms likely to be present in a diseased sinus would be capable of causing MS by direct invasion. However, though the original observations of spirochaetes in acute plaques by Steiner 16 are no longer taken seriously, Steere 17 has found that spirochaetes can cause the immunological and pathological changes peculiar to MS. In Lyme disease" spirochaetes cause a chronic relapsing and remitting lymphocytic inflammation of the joints and CNS and, as in MS, oligoclonal antibodies are found in the cerebrospinal fluid, immune complexes are present in the lesions, and T-lymphopenia occurs, with pronounced killerT-cell depression. Susceptibility is associated with the DW2 B-cell alloantigen. Organisms have not been seen in the lesions and are rarely cultured, but the disease is cured by large doses of parenteral penicillin, and only modified by corticosteroids. Because of the complete failure to discover the cause ofMS we believe it could be worthwhile to reinvestigate the
ORAL CIPROFLOXACIN THERAPY OF INFECTIONS DUE TO PSEUDOMONAS AERUGINOSA BRIAN E. SCULLY1 MICHAEL F. PARRY2
HAROLD C. NEU1 WILLIAM MANDELL1
Division of Infectious Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, USA;1 and Division of Infectious Diseases, Stamford Hospital, Stamford, Connecticut2
The efficacy and safety of oral ciprofloxacin, a fluoroquinolone, were evaluated in the treatment of infection due to Pseudomonas aeruginosa. 96 infections in 71 patients were treated. Substantial underlying disease was present in most of the patients, and 25 (35%) were seriously ill. 52% of pseudomonas isolates were carbenicillinresistant, and 31% gentamicin-resistant. The overall clinical response rate was 77% - 28 of 35 exacerbations of cystic fibrosis respiratory disease, 17 of 19 urinary infections, 4 of 6 osteomyelitis, and 11 of 15 soft tissue infections. The bacteriological cure rate was 34% - 0 of 35 cystic fibrosis, 4 of 17 respiratory infections, 17 of 19 urinary infections, 4 of6 osteomyelitis, and 8 of 15 soft tissue infections. Ps aeruginosa developed resistance to ciprofloxacin in 25 of 96 infections. Side-effects were generally slight with nausea in 14 (15%) the most common, and there were only two substantial
Summary
superinfections.
spirochaetal theory. We thank Dr S. Marshall, Dr A. Bush, Dr J. Sanderson, Dr A. Googe, Dr A. Kerr, DrN. Paros,DrJ. Tomlinson, Dr C. Hall, DrJ. Owen, DrJ. Weston, Dr
G. Hey, and their partners for making the records oftheit patients available. This work was supported by the Department of Health and Social Security granting a period of sabbatical leave to D. G.
Correspondence should be addressed to D. G., Green Storthe, 68 Coast Road, West Mersea, Essex C05 8LS, from whom a typescript of the relevant data on the 92 patients and 184 controls from which table was prepared and details of statistical calculations may be obtained
on
request.
REFERENCES
Spidel E, Inoue YK, Nishibe Y. Isolation of virus from the spinal fluid of three patients with multiple sclerosis and one with amyotrophic lateral sclerosis.
1. Melnick JL,
Lancet 1982; i: 830-33. 2. Inoue YK, Nishibe Y, Nakamura Y. Virus associated with SMON in Japan. Lancet 1971; i: 853-54. 3. McAlpine D. Course and prognosis of multiple sclerosis. In: McAlpine D, Lumsden C-E, Acheson ED, eds. Multiple sclerosis: a reappraisal. Edinburgh: Churchill Livingstone, 1972: 202. 4. Sibley WA, Bamford CR, Clark K. In: Poser C, ed. The diagnosis of multiple sclerosis. New York: Thieme-Stratton Inc, 1984. 5 Sibley WA, Foley JM. Infection and immunisation in multiple sclerosis. Ann NY Acad Sci 1965; 122: 457-68. 6 Poser S. Multiple sclerosis. An analysis of 812 cases by means of electronic data processing. Berlin: Springer-Verlag, 1978: 27. 7. Fry J In Fry J, ed. Trends in general practice 1977. London: Royal College of General Practitioners, 1977: 20. 8. Sibley WA, Bamford CR, Clark K. Clinical viral infections and multiple sclerosis. Lancet 1985; i: 1313-15. 9. Acheson ED. The epidemiology of multiple sclerosis. In: Matthews WB, Acheson ED, Batchelor JR, Weller RO, eds. McAlpine’s multiple sclerosis. Edinburgh: Churchill Livingstone, 1985: 28. 10. Brody JA. Epidemiology of multiple sclerosis and a possible virus aetiology. Lancet 1972; ii: 173-76. 1 1. Formby ML. The maxillary sinus. Proc R Soc Med 1959; 53: 1-6. 12. Jaffe L Sinusitis in tropical climates. Zeitschurfur Laringol, rhinol otol und grenz 1951; 30: 295-301. 13 Manson-Bahr P. Tropical diseases affecting the throat, nose and ear. J Laryngol Otol
1956; 70: 175-95. Martin JAM. Diseases of the ear, nose and throat in tropical Africa. A Uganda survey. J Laryngol Otol 1967; 81: 1079-98. 15 Hallpike JF. New treatments for multiple sclerosis. Br J Hosp Med 1980; 23: 63-66. 16. Steiner G. Acute plaques in multiple sclerosis; their pathogenic significance and the role of spirochaetes as etiological factor. J Neuropathol Exp Neurol 1952; 11: 14
343-72. 17 Steere AC. First International Symposium on Lyme
445-711.
Disease. Yale J Biol Med 1984; 57:
Introduction
Pseudomonas
aeruginosa is an important pathogen, particularly as a cause of nosocomial infections and of the chronic pulmonary disease associated with cystic fibrosis. Because this organism is resistant to antibiotics that can be taken orally, effective therapy has required admission to hospital, which is expensive and inconvenient. If treatment must be long term or repeated, there is a risk of aminoglycosides causing toxic effects on the central nervous system or kidneys and of further nosocomial infection. There is, therefore, a need for a safe and effective agent that could be
given orally to treat infections caused by Ps aeruginosa and other multiply resistant Enterobacteriaceae. Ciprofloxacin is a fluorinated carboxyquinolone with a broad antibacterial spectrum that includes Ps aeruginosa; 90% of strains are inhibited by 0’55 mg/1.’°2 Blood levels of 2-3 mg/l are attained after 500 mg taken orally and interstitial fluid levels of 1 -4 mg/1 can be achieved.3,4 We have studied the efficacy and safety of ciprofloxacin in the treatment of various infections due to Ps aeruginosa. Although the interpretation of open, non-comparative studies is difficult, we chose this design because of the lack of alternative oral agents and because we wished to use ciprofloxacin in infections caused by Ps aeruginosa resistant to even the available parenteral antibiotics. Patients and Methods Patients were seen at the Presbyterian Hospital in New York or the Stamford Hospital. All had Ps aeruginosa as a sole or major contributing pathogen. They were part of a larger study of ciprofloxacin in the treatment of infections due to multiply resistant organisms. Reasons for exclusion were having received an effective antibiotic within the previous 72 h, serious liver disease, pregnancy, or a history of an adverse reaction to nalidixic acid or other quinolones. Also excluded were patients under the age of 18, with the exception of two patients with cystic fibrosis aged 15 and 12
820 years whose other therapy had failed and who were seriously ill. All or an immediate family member gave informed, written consent in accordance with the guidelines of the institutional committee on human investigation. The clinical diagnosis was confirmed in each case by appropriate cultures, X-ray examination, and diagnostic tests appropriate to the infection. For patients with cystic fibrosis, bronchopneumonia, or bronchitis, cultures of expectorated sputum, tracheal aspirates (intubated patients only), or bronchoscopy specimens grew Ps aeruginosa as the sole or predominant pathogen. Patients with sinusitis had X-ray findings consistent with sinusitis and cultures of sinus aspirates grew Ps aeruginosa. Patients with osteomyelitis had positive X-rays and cultures of bone tissue biopsy samples. Patients with soft tissue infections had positive cultures ofpus or aspirates of appropriate body fluid (for example, empyema fluid). Patients with urinary tract infection had >105 colony-forming units (cfu) per ml of urine in two consecutive samples. Response to therapy was evaluated from clinical, radiological, and bacteriological aspects by the investigators and the primary physicians. Patients were considered to have responded clinically if satisfactory improvement in signs and symptoms of infection occurred - for example, complete resolution of fever, pronounced reduction in respiratory symptoms in pulmonary infections, clearing of pus and signs of infection in soft tissue and bone infections, and complete clearing of urinary symptoms in urinary tract infections. Bacteriological cure required elimination of Ps aeruginosa from culture sites during treatment and at follow-up at 5 to 9 days for urinary tract infection, and more than 24 h after therapy for infections outside the urinary tract. Inpatients were observed daily by one of the investigators for a response to therapy and signs of toxicity. Outpatients were seen weekly. The eyes were fully examined (with funduscopy, visual acuity, and colour vision) before, during, and after treatment. Blood chemistry, complete blood count, prothrombin time, and urinalysis were also followed. Ciprofloxacin was given orally, usually 1 h before or 2 h after a meal. The dose ranged from 750 mg to 2250 mg daily. Most patients received either 500 mg or 750 mg every 12 h (28% and 38%, respectively) or 750 mg every 8 h (28%). All but 3 patients received ciprofloxacin as sole therapy. Initial susceptibility to ciprofloxacin was determined for clinical isolates by the Kirby-Bauer disc method with 5 lag ciprofloxacin discs at the Presbyterian Hospital and by microdilution at the Stamford Hospital. Minimum inhibitory concentrations (MIC) were determined by applying 104cfu to Mueller-Hinton agar or by inoculating 5 x 105 cfu into Mueller-Hinton broth containing twofold increasing concentrations of antibiotic. Susceptibility to other antibiotics was determined by the microtube dilution method with the Microscan system (Mahwah, New Jersey). Concentrations of ciprofloxacin in serum and body fluids were measured by the agar-well diffusion method with a susceptible strain of Klebsiella pneumoniae as the test organism.3Peak serum samples were drawn 1-4 h after a dose. Trough samples were drawn during the 30 min before a dose. Urine levels were determined on a sample from a 6-12 h collection.
TABLE I-OVERALL RESPONSE TO CIPROFLOXACIN THERAPY
patients
_
Results 96 infections due to Ps aeruginosa in 71 patients (36 male, 35 female) were treated with ciprofloxacin. The patients’ mean age was 49 years (range 12-85 years), mean duration of therapy 24 days (range 4-180 days), and mean daily dose 1500 mg (range 750-2250 mg). All but 3 patients had severe underlying disorders (12 cardiovascular, 12 pulmonary, 16 cystic fibrosis, 2 renal, 1 hepatic, 10 neurological, 8 diabetes mellitus, 8 malignant, and 1 acquired immunodeficiency syndrome). 10 patients had recently undergone operations. 6 patients were receiving corticosteroids and 6 were malnourished. The condition of the patient was serious at the start of 25 of the treatment courses, fair for 45 courses, and good for 25 courses. The range of MIC for ciprofloxacin of the Ps aeruginosa
TABLE II-RESPIRATORY TRACT INFECTION RESULTS
*1
patient was treated three times. tpatient was treated twice.
isolated before therapy was 0 -. 06-20 mg/1 (geometric mean 0 -3 mg/1). The organism was resistant to carbenicillin in 52% of infections (MIC >128 mg/1), to gentamicin in 31% (MIC >8 mg/1), to amikacin in 27% (MIC >16 mg/1), and to tobramycin in 15% (MIC >6 mg/1). The overall results of therapy are summarised in table I. There was a 77% clinical response rate and a 34% bacteriological cure rate (54% if cystic fibrosis patients are excluded). Of the patients who had a clinical response to ciprofloxacin, 14 had not responded to a standard beta-lactam and aminoglycoside regimen. Of the patients who did not respond clinically to ciprofloxacin, 4 did not respond to subsequent therapy, and 6 responded to betalactam and aminoglycoside therapy. Table II shows the results of ciprofloxacin therapy in lower respiratory tract and sinus and ear infections. 8 patients had pneumonia. In 3 patients pulmonary infiltrates had developed in a setting of chronic lung disease and ongoing colonisation of the respiratory tract with pseudomonas. In 2 pseudomonas pneumonia had developed during mechanical ventilation. The other underlying disorders were Alzheimer’s disease, lung carcinoma, and AIDS. Although the pseudomonas was eradicated in only 2 patients, 7 had clinical responses. The clinical failure was a man with lung carcinoma complicated by right upper and middle lobe pneumonia. He also did not respond to ticarcillin and tobramycin and later died. The remaining respiratory infections were exacerbations of chronic and well-established infection. Bacteriological cure was achieved in only 2 of 13 patients. Good clinical responses were observed in 7 patients. 16 patients (6 male, 10 female) with cystic fibrosis received ciprofloxacin as therapy for 35 exacerbations of their chronic lung disease (table III). In 11 of these exacerbations the patient was severely ill with a high temperature, severe respiratory distress, and low exercise tolerance; in 17 the patient was in fair condition, and in 7 good condition. The patients ranged
821 TABLE III-THERAPY OF EXACERBATIONS OF PULMONARY INFECTION IN PATIENTS WITH CYSTIC FIBROSIS LUNG DISEASE I
I
I
fever). Bacteriological cure was achieved in only 8 of the patients, however. The clinical failures occurred in a diabetic with neurovascular disease whose foot infection cleared during ciprofloxacin therapy but recurred immediately afterwards; an elderly woman with a chronic draining lesion of the thigh of unknown aetiology; a young man with extensive postoperative osteomyelitis and a pseudomonas superinfection of his thigh wound; and a young man with a severe neuromuscular injury of the ankle in whom pseudomonas was eliminated but a superinfection with group D streptococcus and Bacillus subtilis occurred. 4 of 6 patients with osteomyelitis due to Ps aeruginosa responded to ciprofloxacin therapy (table IV). 3 patients had other pathogens which were susceptible to ciprofloxacin and 1 of these also had concomitant anaerobic streptococcus for which amoxicillin was prescribed. The duration of therapy ranged from 16 to 65 days (mean 42). None of the 4 responders has relapsed during follow-up of 9-18 months (mean 13 months). The 2 patients who did not respond both had extensive chronic osteomyelitis of the femur and adequate surgical debridement was not possible. The mean peak serum levels of ciprofloxacin were 2 -9mg/l after 500 mg and 3’6mg/l after 750 mg. Mean trough values were 0 - 54 mg/l and 1 - 0 mg/1. The urinary ciprofloxacin level in 13 patients 6-12 h after a dose was >50 mg/1. A significant fall in susceptibility of pseudomonas to ciprofloxacin, defined as a greater than four-fold rise in MIC, was observed in 32 of 96 treatment courses. In 7 the MIC rose but remained within the susceptible range (eg, from 0’25to 1 -0 mg/1). In the remaining 25, however, the pseudomonas became resistant (MIC >2 mg/1).5 Resistance occurred in infections of the respiratory tract, soft tissue, and bone but not of the urinary tract. Typically the pseudomonas persisted at the infection site and could be isolated throughout the treatment course. In contrast, if the infected site had been sterilised during therapy but a subsequent microbiological relapse occurred, the organism isolated was usually susceptible to ciprofloxacin with little or no rise in MIC. 9 isolates of pseudomonas became more susceptible (MIC four times less than pre-treatment value) to beta-lactams or aminoglycosides, and 8 became less susceptible (MIC four times greater than pre-treatment value). In the remaining infections the pseudomonas showed no changes in betalactam or aminoglycoside MIC during ciprofloxacin therapy. Nausea and epigastric pain were the only adverse reactions noted with any frequency (14 of 96 courses of treatment). The mean daily dose per kg body weight of patients experiencing nausea was slightly less than for those patients without nausea. Lowering the dose, however, did reduce the discomfort in several patients. In 3 patients fluid retention was a possible adverse reaction; in 2 peripheral oedema without any change in cardiac or renal function occurred, and 1 patient with cor pulmonale deterioriated without a clear inciting event. Other side-effects noted were diarrhoea (3 patients), raised aminotransferases (2), pruritus without rash (1), and sleep disturbance (1). Only 1 patient stopped therapy because of nausea. There were 2 substantial superinfections. The first was in a patient with a wound infection of the ankle. The Ps aeruginosa was eradicated by ciprofloxacin, but the skin graft became superinfected with group D streptococcus and Bacillus subtilis. The second occurred in a patient with an exacerbation of pseudomonas bronchitis who also had lymphoma and neutropenia after chemotherapy. 12 days into therapy a cavitary lung lesion developed. The sputum became more purulent and ciprofloxacin-resistant man
in age from 12 to 36 years (mean 23 years), the duration of therapy from 12 to 58 days (mean 20 days), and the time between courses of therapy from 14 to 220 days (mean 95 days). The ciprofloxacin dose varied according to severity of illness, body size, and susceptibility of the pseudomonas from 750 mg to 2250 mg daily (mean 1860 mg). 8 patients received one course and 8 repeated courses of ciprofloxacin. At least 1 strain of Ps aeruginosa was isolated in each patient, and in 12 patients other pathogens susceptible to ciprofloxacin were present. The overall clinical response rate was 80%. The clinical failures occurred in patients being retreated with ciprofloxacin who were moderately to severely ill and had large volumes of sputum. Failure to respond correlated poorly with pretreatment MIC (0’6 mg/1 for failures v 04 mg/1 for responders). Pseudomonas could not be eradicated from the sputum of the patients, although there was substantial reduction in sputum purulence. All but 1 of the 18 patients with urinary tract infections (19 infections) had acquired the infection in association with bladder instrumentation or catheterisation. 3 patients had superficial bladder neoplasms, and 6 patients required further intermittent catheterisation during therapy with ciprofloxacin (neurogenic bladder 5, Koch pouch 2). No
patients required indwelling catheters while receiving ciprofloxacin. In 2 patients, both with neurogenic bladders, a second pathogen was cultured (Proteus mirabilis, Providencia stuartiz). In all 19 infections the urine was sterilised during therapy. In 17 the urine was sterile at 5-9 day follow-up. For 15 of the 17 cured patients cultures were done 3-6 weeks later; all were negative for Ps aeruginosa. 1 of the 2 patients who relapsed was cured by a second, longer, course of ciprofloxacin (30 days) and was clear at 1 week and 6 weeks of follow-up. In 11of the 15 soft tissue infections (table IV) there were good clinical responses to ciprofloxacin (ie, progressive healing, substantial reduction of purulence, and lowering of TABLE IV-SOFT TISSUE INFECTION AND OSTEOMYELITIS RESULTS
*Other pathogens cultured Enterobacter cloacae 1, Serratia marcescens 1, Proteus mirablhs 1. tOther pathogens cultured S marcescens 2; E cloacae 1, and P mlrabilis 1. femur 1, tibia 2: chronic in all 3. 5Chronlc in both.
822 aureus and Ps aeruginosa (MÍC 4 mg/1) were cultured from the sputum. 4 patients had mild candidal skin or vaginal infections, which responded to topical therapy.
Staphylococcus
Discussion The in-vitro and pharmacokinetic characteristics of the first quinolone antimicrobial, nalidixic acid, are such that concentrations adequate to inhibit many species of gramnegative bacteria are reached in urine but not in blood or body tissues. Furthermore, in the treatment of lower urinary tract infections the emergence of resistance curtailed its use. Owing to toxic effects on the central nervous system and eyes, larger doses and parenteral administration of nalidixic acid are not safe. Subsequent agents of this class, cinoxacin and oxolinic acid, did not enlarge the antibacterial spectrum and did not have superior pharmacological properties. In the past 5 years many new quinolones have been developed with greatly improved in-vitro activity, especially against gram-negative bacteria.1,2,6,7 Of these new agents, ciprofloxacin is the most active, against both a broad range of enteric gram-negative bacteria and Ps aeruginosa. Many studies have shown that ciprofloxacin will inhibit the majority of the Enterobacteriaceae at concentrations below 0 . 25 mg/1.1,2,6 Though less active against Ps aeruginosa, it will inhibit 90% of strains at 0 -5mg/l. Activity is also good against staphylococci, including methicillin-resistant isolates (MIC9o 0’8 mg/1), but only fair against streptococci (MIC9o 2-4 mg/1), and bacteroides are resistant (MIC9o >8 mg/1). Pharmacokinetic studies of ciprofloxacin in healthy volunteers have shown peak blood levels of 2-0-2-9 mg/1 after 500 mg and 2-9-3-55 mg/l after 750 mg.3,4,STaken orally, the plasma elimination half-life is 3-4 h, and blood levels at 8 h and 12 h after 750 mg are 0 -7 mg/1 and 0 -4 mg/1, respectively. Levels are slightly lower after 500 mg doses. Both hepatic metabolism and renal excretion occur. 50% of an administered dose is excreted in the urine as intact drug or active metabolites. The volume of distribution is very high (2 - 0-2 - 6 1/kg), corroborated by preliminary data that suggest good penetration into interstitial fluid, sputum, bone, and prostate.4,IO-12 Our overall clinical and bacteriological response rates were 77% and 34%, respectively. In roughly comparable groups of patients treated with aztreonam or ceftazidime for Ps aeruginosa infections the clinical response rates were 83% and 80% and bacteriological response rates 37% and 50%.13,14 The results of ciprofloxacin therapy of urinary tract infections and exacerbations of cystic fibrosis, particularly the first course of treatment, were excellent, although the tendency for resistance to develop may have impaired efficacy in retreatment of cystic fibrosis patients. Generally favourable responses were also noted in soft tissue, bone, and other pulmonary infections. Ciprofloxacin was often effective where earlier therapies had failed owing to the resistance of pseudomonas to other drugs. It should also be noted that in some of the cases for which ciprofloxacin failed other therapy also failed. Development of resistance to ciprofloxacin in Ps aeruginosa isolates during therapy is a major difficulty. The mechanism of resistance may be related to the presence at the infected site of subinhibitory or barely inhibitory concentrations of antibiotic, encouraging the growth of more resistant strains within a population of bacteria. It is possible in vitro with repeated subculture to select isolates resistant to ciprofloxacin, even though the frequency of spontaneous resistance is low (<10-9).2 The development of resistance may
have little effect upon the course of the infection being treated. In soft tissue infections, a surface culture of a healing wound often grew a resistant pseudomonas during or at the end of therapy as the wound continued to heal uneventfully. In cystic fibrosis patients, a less susceptible or resistant strain was usually isolated during or at the end of therapy. Clinical improvement occurred and persisted for a variable time. At the subsequent relapse the isolate was usually less susceptible than the pretherapy isolate but more susceptible than the post-therapy isolate. This course was not predictable, however, and resistance sometimes persisted. In bone infections we usually observed initial modest clinical improvement, but subsequent deterioration if drug resistance occurred. These organisms retained their resistance for at least 2-3 months. Thus, the implications of the development of resistance to ciprofloxacin vary between infections and between patients. Certainly, the resistant strains are capable of causing disease. We plan studies of whether the combination of ciprofloxacin with a second agent will prevent the emergence of resistance. Ciprofloxacin was very well tolerated. We did not encounter central nervous system toxicity, but 1 elderly patient experienced insomnia throughout a 3-week course of therapy. We also did not find joint pains or myalgias which have been linked with some agents of this class. None of the patients had crystalluria or reduced renal function. Ciprofloxacin makes it possible to treat patients infected with Ps aeruginosa at home. It will be particularly important in the treatment of urinary infections, osteomyelitis, and respiratory infections in patients with cystic fibrosis. There are worries about the development of resistance, however. Results of comparative studies are awaited to determine its efficacy and safety relative to the standard beta-lactam and
aminoglycoside regimens. Correspondence should be addressed to H. C. N., Division of Infectious Diseases, Department of Medicine, College of Physicians and Surgeons of Columbia University, 630 West 168th Street, New York, NY 10032, USA. REFERENCES 1. Wise
R, Andrews JM, Edwards LJ. In vitro activity of Bay-0-9867, a new quinolone derivative, compared with other antimicrobial agents. Antimicrob Ag Chemother 1983; 23: 559-64. 2. Chin NX, Neu HC. Ciprofloxacin, a quinolone carboxylic acid compound active against aerobic and anaerobic bacteria. Antimicrob Ag Chemother 1984; 25: 319-32. 3. Brittain DC, Scully BE, McElrath MJ, Steinman R, Labthavikul P, Neu HC The
pharmacokinetics and serum and urine bacterical activity of ciprofloxacin. JClin Pharmacol 1984; 25: 82-85. 4. Crump BR, Wise R, Dent J. Pharmacokinetics and tissue penetration of ciprofloxacin. Antimicrob Ag Chemother 1983; 24: 784-86. 5. Barry AL, Fass RJ, Anhalt JP, et al. Ciprofloxacin disk susceptibility tests: interpretive zone size standards for 5µg disks J Clin Microbial 1985; 21: 880-83. 6. Bauerfeind A, Petermuller C. In vitro activity of ciprofloxacin, norfloxacin and nalidixic acid. Eur J Clin Microbiol 1983; 2: 111-15. 7. Chin NX, Neu HC In vitro activity of enoxacin, a quinolone carboxylic acid, compared with those of norfloxacin, new beta-lactams, aminoglycosides, and trimethoprim. Antimicrob Ag Chemother 1983; 24: 754-63. 8. Gonzalez MA, Uribe F, Moisen SD, et al. Multiple-dose pharmacokinetics and safety of ciprofloxacin in normal volunteers. Antimicrob Ag Chemother 1984; 26: 741-44 9. Gonzalez MA, Moranchel AA, Duran S, et al. Multiple-dose pharmacokinetics of ciprofloxacin administered intravenously to normal volunteers. Antimicrob Ag Chemother 1985; 28: 235-39. 10. Blumer JL, Stern RC, Myers CM, Klinger JD, Reed MD. Pharmacokinetics and pharmacodynamics of ciprofloxacin in cystic fibrosis. 14th International Congress on Chemotherapy. Kyoto, Japan, 1985: abstr no S-40-14. 11. Fong IW, Ledbetter W, Vandenbroncke A, Sunbal M, Rahan U. The penetration of ciprofloxacin after single oral doses in normal and infected bones. 14th International Congress on Chemotherapy. Kyoto, Japan, 1985: abstr no S-40-8. 12. Schalkauser K, Adam D, Dalhoff A. Diffusion of ciprofloxacin into human prostatic tissue after oral intravenous application. 14th International Congress on Chemotherapy, Kyoto, Japan, 1985: abstr no S-40-9. 13. Scully BE, Neu HC. Use of aztreonam in the treatment of serious infections due to multiresistant gram-negative organisms, including Pseudomonas auruginosa. Am J Med 1984; 78: 251-261. 14. Scully BE, Neu HC. Clinical efficacy of ceftazidime. Treatment of serious infection due to multiresistant Pseudomonas and other gram-negative bacteria. Arch Intern Med 1984; 144: 57-62.