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Ciprofloxacin as Treatment for Genitourinary Tract Infection
0022-534 7/89/1411-0001$02,0G/0 ~,fol. 141, Januar; Printed in U.S.A.
THE JOURNAL OF UROLDGY
Copyright© 1989 by The Williams & Wilkins Co.
Review Article CIPROFLOXACIN AS TREATMENT FOR GENITOURINARY TRACT INFECTION STACY J. CHILDS*
AND
ELLIE J. C. GOLDSTEIN
From the Southeastern Research Foundation, Birmingham and Department of Surgery, Community Health Sciences, University of Alabama, Tuscaloosa, Alabama, and R. M. Alden Research Laboratory, Santa Monica and Department of Medicine, University of California, Los Angeles, California
Ciprofloxacin is a member of the new fluoroquinolone class of antibacterials. It possesses a wide spectrum of activity and increased potency against almost all potential uropathogens. 1 - 7 The oral preparation has been studied, and shown to be safe and efficacious in the therapy of gonorrhea and complicated and uncomplicated urinary tract infections. Consequently, it may descrease the need for and the cost of conventional parenteral antibiotic therapies.
RESISTANCE
Because ciprofloxacin and the other fluoroquinolones have a novel mechanism of action, there is little cross-resistance between the fluoroquinolones and different classes of antibiotics. addition, transferrable plasmid mediated resistance, or jumpmg genes, do not affect bacterial susceptibility to the fluoroquinolones. However, concern about the development of resistance to ciprofloxacin has been voiced. Compared to older analogues the rate of spontaneous bacterial resistance to ciprofloxacin is markedly less frequent (approximately 1 X 10-12 ). 9 Resistance can be selected or induced by serial passage of organisms on drug-containing media, especially with subinhibitory concentrations. When resistance does appear it occurs because of either mutations of the A-subunit target of DNA gyrase or by alteration in outer membrane protein (OmpF) drug permeability.9
!n
STRUCTURE AND ACTIVITY
The term quinolone is applied loosely to a variety of similar synthetic antibacterial agents that have a bicyclic, heteroaromatic system (see figure). The basic antibacterial activity is derived from the carboxylic acid ring (A ring). Particularly important is the relationship between the ketone moiety at position 4 and the carboxylic acid side chain at position 3. A variety of substituted ring systems may be used for the second ring (Bring). These ring(s) and side chains can further augment the activity of the compound. More than 10,000 variants have been synthesized but only a few have come to clinical use. However, the addition of a fluorine atom to position 6, therefore the name fluoroquinolone, has extended the spectrum of activity to aerobic gram-positive and gram-negative bacteria, and has increased the antibacterial activity of these compounds 100-fold when compared to older quinolone compounds, such as nalidixic acid, cinoxacin and oxalinic acid. 6 • 8 No other halogen at position 6 provides a similar increase in activity. The addition of a piperazinyl group at position 7 increased the antibacterial activity of the fluo:roquinolones, especially against Pseudomonas aeruginosa, and may facilitate transport and increase bioavailability. 6 · 8 The addition of a cyclopropyl group attached to position 1 distinguishes ciprofloxacin from other fluoroqui~olones, most of which have an ethyl group at the 1 position. The stearic configuration of the cyclopropyl group is believed to be responsible for the additional 2 to 4-fold potency of ciprofloxacin against most pathogens, including P. aeruginosa, compared to other fluoroquinolones. Ciprofloxacin is bactericidal and believed to work by inhibiting the A-subunit of the essential bacterial enzyme deoxyribonucleic acid (DNA) gyrase. The enzyme is composed of 2 Asubunits and 2 B-subunits in equal amounts. It is not present in mammalian cells but is essential for DNA replication in bacterial cells. The fluoroquinolones inhibit reactions, such as supercoiling, relaxation, catenation and decatenation, that require the breaking and rebonding of the DNA strands. Ciprofloxacin may have additional activities leading to its increased bactericidal activity. 9 However, the exact mechanism of bacterial cell death remains undefined.
ANTIBACTERIAL SPECTRUM
Ciprofloxacin possesses a broad spectrum of antibacterial activity that includes most potential aerobic gram-positive and gram-negative uropathogens. Strains of Escherichia coli, Klebsiella pneumoniae, Enterobacter species, Serratia marcescens Proteus mirabilis, P. vulgaris, Morganella morgagnii, Providen~ cia rettgeri, P. aeruginosa, enterococci and gonococci have minimal inhibitory concentration 90s of 0.004 to 2 µg./ml. 1 - 7 Most Enterobacteriaceae have minimal inhibitory concentration 90s that range between 0.015 and 1.0 µg./ml. On a weight basis it is more active than other oral agents, such as trimethoprim-sulfamethoxazole and cefaclor. Ciprofloxacin also is highly active against gentamicin-susceptible and gentamicin-resistant strains of P. aeruginosa with minimal inhibitory concentration 90s in most studies of 2.0 µg./ml. or less. 1- 3 • 5 - 7 Nonaeruginosa Pseudomonas species usually are resistant to the current fluoroquinolones. Ciprofloxacin is relatively less active against gram-positive cocci than gramnegative bacteria. However, it has shown good activity against Staphylococcus aureus, including methicillin-resistant strains and coagulase-negative staphylococci, such as Staph. saprophyticus with minimal inhibitory concentration 90s of 0.8 µg./ml. or less for most strains. 4 • 7 Streptococci, including enterococci, generally are less susceptible than staphylococci but the minimal inhibitory concentration 90s (6 µg./ml. or less) are well within the range of the levels achieved in the urinary tract.'· 2 None of the fluoroquinolones is active against most anaerobic bacteria and, consequently, they have little disturbing effect on the normal anaerobic vaginal and fecal flora. 10 Gonococci, including penicillinase-producing strains, are susceptible to ciprofloxacin with minimal inhibitory concentration 90s of less than 0.008 and 0.004 µg./ml., respectively. 1 · 11 The in vitro activity of ciprofloxacin against Chlamydia trachomatis
* Requests for reprints: Alabama Urology Associates, P.C., P.O. Box 985, Alabaster, Alabama 35007. 1
2
CHILDS AND GOLDSTEIN
Structure of quinolones
was studied by Schacter and Moncada, and included fresh cervir:al isolates and serovars L2 (LGV-434) and D (IC-Cal8).12 Each had minimal inhibitory concentrations of 1.56 µ,g./ ml. and similar minimal bactericidal concentrations. They concluded that ciprofloxacin "may prove to be a useful antichlamydia agent". PHARMACOKINETICS
Ciprofloxacin is absorbed rapidly after oral administration. After a single 250 or 500 mg. dose peak serum concentrations of 1. 7 ± 0.6 (standard deviation) and 2.3 ± 0.9 µ,g./ml., respectively, were achieved within 1 to 1.5 hours."'- 15 Simultaneous administration of food or antacids may delay and decrease the absorption of ciprofloxacin. rn In patients with normal renal and hepatic function the half-life of ciprofloxacin is 3.5 to 4.5 hours."· 1" · " Renal clearance of ciprofloxacin is higher than glomerular filtration, which suggests active tubular secretion of ciprofloxacin into the urine."' Probenecid apparently blocks the active tubular secretion of ciprofloxacin. 17 In patients with normal renal function approximately a third to half of the orally ingested dose will be excreted into the urine. 10 • 18 Consequently, peak levels of more than 500 µ,g./ml. are achieved in the urine after a 250 or 500 mg. oral dose, and remain at concentrations of 40 to 60 µ,g./ml. for up to 12 hours and 5 to 20 µ,g./ml. at 24 hours.'4,1s, 19 Ciprofloxacin has shown good diffusion into prostatic tissue achieving levels 1.5 to 14.2 times greater than serum levels. 20· 21 Gombert and associates showed that after 3, 500 mg. doses patients undergoing trans urethral resection of the prostate had prostatic levels of 1.5 to 14.2 µg,/gm. tissue. 21 Grabe and associates studied 12 men and found an average prostatic tissue level of 3.03 ± 0.38 µ,g./gm. tissue (range 1.1 to 7.2 µ,g,/gm. tissue). 20 Patients with renal insufficiency have a prolonged half-life (7 to 10 hours) and require dosage adjustments. 1 :i, 22 • 2 " However, 2 other mechanisms of elimination, intestinal (fecal) and metabolic (biliary), may at least partially compensate for decreased renal excretion. In patients with impaired renal function, if the creatinine clearance is greater than 50 ml. per minute the usual dosage would apply. If the creatinine clearance is between 30 and 50 ml. per minute the dose would be 250 to 500 mg. every 12 hours and if between 5 and 29 ml. per minute the dose should be adjusted to 250 to 500 mg. every 18 hours. Further decreases in the dosage would be prudent if renal and hepatic insufficiency is present. ADVERSE EFFECTS
Adverse effects from nalidixic acid and older quinolone agents were frequent and sometimes severe. Ciprofloxacin does not appear to cause these reactions with the same frequency or severity. In review of the worldwide experience with ciprofloxacin, adverse effects were reported in 3 per cent of the European patients, 6.5 per cent of the Japanese patients and 13.4 per cent
of patients in the United States. 24 The higher rate reported in the United States may have been related to use of higher dosages or to the fact that the investigators were encouraged to report side effects, even if they were judged to be only possibly related to the drug. The table lists the type of side effects encountered and their incidence. Gastrointestinal side effects, especially nausea, vomiting, diarrhea and abdominal discomfort, were the most frequently reported (2 to 8 per cent). 24 ' 25 Central nervous system effects, such as headache and restlessness, also were reported. Hypersensitivity reactions, such as skin rash and pruritis, were infrequent (less than 1 per cent). Some patients had Candida vaginitis and others reported a bad taste. Serious toxicity was reported in only 3 of 6,500 patients in that series and included 1 patient each with pseudomembranous colitis and interstitial nephritis with crystalluria renal failure, and seizure in a patient who was also receiving theophylline. Laboratory abnormalities were infrequent but included transaminemia and eosinophilia. DRUG INTERACTIONS
Drug interactions between ciprofloxacin and theophylline, warfarin and caffeine may occur, since they compete for the same metabolic hepatic enzyme systems (cytochrome P450 system). In 1 series the concomitant use of ciprofloxacin and theophylline caused elevated theophylline levels. 26 Consequently, decreased theophylline doses should be used and levels monitored frequently should patients receive both drugs. There are scant clinical data on the use of ciprofloxacin in either pregnant women or children. In addition, animal studies with nalidixic acid have noted cartilage toxicity. 6 While nothing similar has been reported in the studies of ciprofloxacin in the treatment of pulmonary infections in children with cystic fibrosis, it would be prudent to avoid its use in children and pregnant women until definitive studies have been performed. 24 CLINICAL APPLICATION
Effective antibiotic therapy depends upon adequate tissue penetration in appropriate sites. Inflamed tissues are more easily penetrated by most antibiotics but several physicochemical characteristics of ciprofloxacin, such as low serum protein binding and small molecular size, provide favorable conditions for tissue penetration despite the drug being poorly lipophilic. A single 100 mg. intravenous dose achieves levels of 0.93 to 4.66 µ,g./gm. kidney tissue from 1 to 8 hours after administration. Serum levels during that same period were 0.13 to 0.85 µ,g./ml. and perirenal fat levels were 0.05 to 0.45 µ,g./gm. Since the minimal inhibitory concentration 90 of ciprofloxacin for Enterobacteriaceae is equal to or less than 0.25 µ,g./ml. this implies the drug at a relatively low dosing to be able to inhibit strains causing urological infections for 5 to 8 hours. 27 Other studies have shown similar results with consistent levels of 4.2 to 5.2 mg./kg. in kidney tissue. 28 The penetration of single doses of 500 mg. ciprofloxacin Reported incidences (per cent) of adverse reactions probably or possibly due to ciprofloxacin in Europe, Japan and the United States 24 Europe/ United States (1,693 pts,) Total reactions Total pts. affected Gastrointestinal: Nausea Diarrhea Pain/dyspepsia Nervous system: Dizziness
Headache Skin (allergy): Rash Pruritis
8.0 6,5 4.5 2,1
Japan (2,578 pts,)
United States (1,241 pts.)
3.6 3,0 2.1
22,5 13.4 8.1 3.0 2,0
0.4
4.4
0.4
1.9 0.7
1.4
0.6 1.1 0.6 0.4 1.0 0.6 0.4
CIPROFLOX_ACH\J AS TREAT:VKE?,"JT FOR GENITOURINARY TRACT iNFECTI01>J
has resulted in prostatic tissue levels of twice the serum levels for as much as up to 12 hours after dosing. An important implication is drawn here because this is noninflamed prostate tissue, and the results in several studies have shown sustained levels exceeding the minimal inhibitory concentration of virtually all Enterobacteriaceae and organisms important to the urinary tract for up to 12 hours. 20 • 29 Other reports have shown adequate penetration into the male and female genital tract, peritoneal fluid, uterus and fallopian tubes. 29 In summary, we can say that relatively low doses of ciprofloxacin achieve adequate to high tissue and serum levels for treatment of almost all infections commonly seen in the genitourinary tract of male or female patients. Although, seemingly overkill, ciprofloxacin has been used successfully to treat uncomplicated urinary tract infections. In a prospective randomized double blind study comparing 250 mg. ciprofloxacin twice daily for 10 days with 160 mg./800 mg. cotri:noxazole twice daily for 10 days, the ciprofloxacin group had a 100 per cent clinical and bacteriological cure rate compared to a 94 per cent bacteriological and 91 per cent clinical cure rate for cotrimoxazole. A bacteriological cure is the absence of the original pathogen at the 5 to 9-day post-treatment culture. A clinical cure is the absence of the original symptoms referable to the urinary tract infection at the 5 to 9-day posttherapy visit. A statistically significant increase in adverse side effects was noted in the cotrimoxazole group. As expected, 28 of the 31 women receiving ciprofloxacin had E. coli isolated from the urine. One patient had Staph. saprophyticus, 1 had coagulase negative staphylococcus and 1 had P. mirabilis.'30 Additionally, ciprofloxacin compares favorably with cinoxacin in the treatment of uncomplicated urinary tract infections." 1 There have been numerous reports on the use of ciprofloxacin in complicated urinary tract infections. Williams and Gruneberg reported on 75 evaluable patients showing a 5 to 9day bacteriological cure rate of 88 to 94 per cent (2 dosing regimens), compared to an 87 per cent cure rate of trimethoprim-sulfamethoxazole-treated patients.'1' In noncomparative studies, Guibert and associates reported on 56 patients with a 92 per cent cure rate,8·1 whereas Gasser and associates produced an 84 to 87 per cent cure rate in 110 patients with complicated urinary tract infections treated with ciprofloxacin034 Peters compared ciprofloxacin with mezlocillin in 40 patients and found 5 to 9-day cure rates of 90 and 74 per cent, respectively. 10 Long-term followup cultures were available on some of these studies but they are largely meaningless because of the lesions involved in the urinary tract that could be corrected surgically. Those not corrected surgically could be expected to have relapse anyway. Five to 9-day bacteriological cure rates of 84 to 95 per cent are excellent for this disease. When one considers urinary tract infections caused from troublesome organisms, such as P. aeruginosa or multipleresistant bacteria, equally favorable results can be seen. Five to 9-day bacteriological cure rates following vuuA,auu have been reported by Cox (95 per cent, 53 patients), and Ryan per cent, 30 patients)," Preheim (84 per cent, 25 patients),'3 8 Saavedra (90 per cent, 28 patients)19 and Leigh (89 per cent, 28 patients) 40 and their associates. Since these bacteria are difficult to eradicate even with the aminoglycosides, cure rates of 90 per cent or better seem to offer promise for these pathogens. Van Poppel and Wegge evaluated 29 patients with multiple sclerosis and/or neurogenic bladder and found no patient clinical failures after treatment with ciprofloxacin.4 1 The 14-day bacteriological eradication rate was 48 per cent and the 35-day rate was 36 per cent. The large persistence was because of the majority of the patients having indwelling Foley urethral catheters. The drug was well tolerated in these patients with neurological disease. The geriatric population also has been evaluated by Newsom and associates in a comparative study of 32 patients. Cure rates of 94 per cent were obtained in both groups, ciprofloxacin
3
versus trimethoprim.4" Cassiers and associates treated 40 patients and received a 78 per cent bacteriological cure rate.4'3 Interesting points from these 2 studies were that there was no abundance of Candida overgrowth on these antibiotic-treated patients nor was resistance found even in the patients with relapse or persistence of the bacteria. It is noteworthy that in patients who must receive either long-term antibiotics or antibiotics frequently because of recurrent disease that ciprofloxacin evidently has a low incidence of resistance. In 2 elderly patients who we treated with ciprofloxacin and who had complicated urinary tract infections we did notice Candida overgrowth in the urine. Of these patients 1 had chronic prostatitis and received 1 month of therapy, whereas 1 was a diabetic with recurrent infections and received 14 days of therapy. In both patients candiduria resolved without treatment upon stopping the antibiotics. Of special interest is the use of ciprofloxacin in the treatment of chronic bacterial prostatitis. Weidner and associates treated patients with chronic bacterial prostatitis with ciprofloxacin for 2 weeks and the followup for most of these patients was 1 year. The 1-year cure rate for E. coli prostatitis was 64 per cent. Although the data are small, Enterococcus and Enterobacter aerogenes were not as successful in the long term.4 4 Another study showed a long-term cure rate of 78 per cent bacteriologically and 77 per cent clinically among 39 evaluable male patients. 4 " Ciprofloxacin has been shown to be effective in the treatment of gonococcal and nongonococcal urethritis. Oriel reported final cure rates similar for ciprofloxacin and doxycycline.4" Fong and associates randomized in a double blind manner 225 men with nongonococcal urethritis.4 7 Patients either received 750 mg. ciprofloxacin twice daily for 7 days or 100 mg. doxycycline twice daily for 7 days. Results were similar with over-all cure rates of 52.1 per cent for ciprofloxacin and 60.8 per cent for doxycycline. In patients with Chlamydia! infections alone ciprofloxacin was less effective than doxycycline (45.5 versus 75 per cent) but in patients with U reaplasma urealyticum ciprofloxacin was more effective than doxycycline (69.2 versus 45 per cent). Data on file at Bayer Laboratories in West Germany show that many pathogens implicated in sexually transmitted diseases were treated with ciprofloxacin. Of 250 patients with Neisseria gonorrhea a 100 per cent eradication rate was obtained. For C. trachomatis 64 per cent eradication and for U. urealyticum 91 per cent eradication were observed:rn Somewhat poorer results were observed Fong and associates for all forms of nongonococcal urethritis.4° Dosing studies of Cox do not indicate any statistically significant differences at 250, 500 or 750 mg. for the treatment of urinary tract infections."' His personal experience would indicate a better success rate in treating Pseudomonas urinary tract infections with 500 mg. ciprofloxacin twice daily over the lower regimen. For most infections, however, it would appear that 250 mg. twice for 3 or more would be adequate. CONCLUSION
Ciprofloxacin appears to be an appropriate antibacterial for the treatment of uncomplicated and complicated urinary tract infections. It seemingly is appropriately substituted for aminoglycosides for the treatment of troublesome resistant bacteria, such as P. aeruginosa. It also may allow for outpatient treatment of enterococcus urinary tract infections in addition to common Enterobacteriaceae. The adverse events and side effects associated with use of ciprofloxacin are minimal as of this writing. Previously, difficult infections to eradicate, such as chronic bacterial prostatitis, may show some promise using this drug as treatment since ciprofloxacin achieves excellent tissue levels as well as serum and urine levels when orally administered. The treatment of nonspecific urethritis caused by organisms, such as Chlamydia or Ureaplasma, may be more difficult and conventional therapy with drugs, such as doxycycline, may
4
CHILDS AND GOLDSTEIN
be more appropriate. Although resistance has been rare, it certainly can occur and should be expected should this drug be overused or used inappropriately. REFERENCES 1. Barry, A. L., Jones, R. N., Thornsberry, C., Ayers, L. W., Gerlach, E. H. and Sommers, H. M.: Antibacterial activities of ciprofloxacin, norfloxacin, oxolinic acid, cinoxacin, and nalidixic acid. Antimicrob. Agents Chemother., 25: 633, 1984. 2. Chin, N. X. and Neu, H. C.: Ciprofloxacin, a quinolone carboxylic acid compound active against aerobic and anaerobic bacteria. Antimicrob. Agents Chemother., 25: 319, 1984. 3. Fass, R. J.: In vitro activity of ciprofloxacin (Bay 09867). Antimicrob. Agents Chemother., 24: 568, 1983. 4. Smith, S. M. and Eng, R. H. K.: Activity of ciprofloxacin against methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother., 27: 688, 1985. 5. Wise, R., Andrews, M. J. and Edwards, L. M.: In vitro activity of Bay 09867, a new quinolone derivative, compared with those of other antimicrobial agents. Antimicrob. Agents Chemother., 23: 559, 1983. 6. Wolfson, J. S. and Hooper, D. C.: The fluoroquinolones: structures, mechanisms of action and resistance, and spectra of activity in vitro. Antimicrob. Agents Chemother., 28: 581, 1985. 7. Zeiler, H. J. and Grohe, K.: The in vitro and in vivo activity of ciprofloxacin. Eur. J. Clin. Microbial., 3: 339, 1984. 8. Shentag, J. J. and Domagala, J. M.: Structure-activity relationships with the quinolone antibiotics. Res. Clin. Forums, 7: 9, 1985. 9. Hooper, D. C., Wolfson, J. S., Ng, E. Y. and Swartz, M. N.: Mechanisms of action of and resistance to ciprofloxacin. Amer. J. Med., suppl. 4A, 82: 12, 1987. 10. Goldstein, E. J. C. and Citron, D. M.: Comparative activity of the quinolones against anaerobic bacteria isolated at community hospitals. Antimicrob. Agents Chemother., 27: 657, 1985. 11. Lyon, M. D., Smith, K. R., Saag, M. S. and Cobbs, C. G.: Brief report: in vitro activity of ciprofloxacin against Neisseria gonorrhoeae. Amer. J. Med., suppl. 4A, 82: 40, 1987. 12. Schachter, J. and Moncada, J.: In vitro activity of ciprofloxacin against Chlamydia trachomatis .. Amer. J. Med., suppl. 4A, 82: 42, 1987. 13. Bergan, T., Thorsteinsson, S. B., Solberg, R., Bjornskau, L., Kolstad, I. M. and Johnsen, S.: Pharmacokinetics of ciprofloxacin: intravenous and increasing oral doses. Amer. J. Med., suppl. 4A, 82: 97, 1987. 14. Borner, K., Hoffken, G., Lode, H., Koeppe, P., Prinzing, C., Glatzel, P., Wiley, R., Olschewski, P., Sievers, B. and Reinitz, D.: Pharmacokinetics of ciprofloxacin in healthy volunteers after oral and intravenous administration. Eur. J. Clin. Microbial., 5: 179, 1986. 15. Wingender, W., Graefe, K. H., Gau, W., Forster, D., Beermann, D. and Schacht, P.: Pharmacokinetics of ciprofloxacin after oral and intravenous administration in healthy volunteers. Eur. J. Clin. Microbial., 3: 355, 1984. 16. Ledergerber, B., Bettex, J. D., Joos, B., Flepp, M. and Luthy, R.: Effect of standard breakfast on drug absorption and multipledose pharmacokinetics of ciprofloxacin. Antimicrob. Agents Chemother., 27: 350, 1985. 17. Wingender, W., Beermann, D., Foerster, D., Graefe, K. H., Schacht, P. and Scharbrodt, V.: Mechanism of renal excretion of ciprofloxacin, a new quinolone carboxylic acid derivative, in humans. Chemotherapia, suppl. 2, 4: 403, 1985. 18. Wise, R. and Donovan, I. A.: Tissue penetration and metabolism of ciprofloxacin. Amer. J. Med., suppl. 4A, 82: 103, 1987. 19. Smith, J, T.: The mode of action of 4-quinolones and possible mechanisms of resistance. J. Antimicrob. Chemother, suppl. D, 18: 21, 1986. 20. Grabe, M., Forsgren, A. and Bjork, T.: Concentrations of ciprofloxacin in serum and prostatic tissue in patients undergoing transurethral resection. Eur. J. Clin. Microbial., 5: 211, 1986. 21. Gombert, M. E., duBouchet, L., Aulicino, T. M., Berkowitz, L. B. and Macchia, R. J.: Brief report: prostatic tissue concentrations of ciprofloxacin after oral administration. Amer. J. Med., suppl. 4A, 82: 130, 1987. 22. Boelaert, J., Valcke, Y., Schugers, M., Daneels, R., Rosseneu, M., Rosseel, M. T. and Bogaert, M. G.: The pharmacokinetics of ciprofloxacin in patients with impaired renal function. J. Anti-
microb. Chemother., 16: 87, 1985. 23. Gasser, T. C., Ebert, S. C., Graversen, P. H. and Madsen, P. 0.: Pharmacokinetic study of ciprofloxacin in patients with impaired renal function. Amer. J. Med., suppl. 4A, 82: 139, 1987. 24. Ball, P.: Ciprofloxacin: an overview of adverse experiences. J. Antimicrob. Chemother., suppl. D, 18: 187, 1986. 25. Arcieri, G., Griffith, E., Gruenwaldt, G., Heyd, A., O'Brien, B., Becker, N. and August, R.: Ciprofloxacin: an update on clinical experience. Amer. J. Med., suppl. 4A, 82: 381, 1987. 26. Raoof, S., Wollschlager, C. and Khan, F. A.: Ciprofloxacin increases serum levels oftheophylline. Amer. J. Med., suppl. 4A, 82: 115, 1987. 27. Daschner, F. D., Westenfelder, M. and Dalhoff, A.: Penetration of ciprofloxacin into kidney, fat, muscle and skin tissue. Eur. J. Clin. Microbial., 5: 212, 1986. 28. Daschner, F. D., Westenfelder, M., Dalhoff, A. and Becker, Ch.: Penetration of ciprofloxacin into kidney, fat, muscle and skin of patients undergoing urologic operations. In: 14th International Congress of Chemotherapy, Kyoto, Japan, p. 182, abstract S-428, 1985. 29. Bergogne-Berezin, E.: Penetration of ciprofloxacin into tissue: a review. Excerpta Med. Curr. Clin. Pract., 34: 183, 1985. 30. Henry, N. K., Schultz, H. J., Grubbs, N. C., Muller, S. M., Ilstrup, D. M. and Wilson, W. R.: Comparison of ciprofloxacin and cotrimoxazole in the treatment of uncomplicated urinary tract infection in women. J. Antimicrob. Chemother., suppl. D, 18: 103, 1986. 31. Goldstein, E. J. C., Kahn, R. M., Alpert, M. L., Ginsberg, B. P., Greenway, F. L. and Citron, D. M.: Ciprofloxacin versus cinoxacin in therapy of urinary tract infections. Amer. J. Med., suppl. 4A, 82: 284, 1987. 32. Williams, A. H. and Gruneberg, R. N.: Ciprofloxacin and cotrimoxazole in urinary tract infection. J. Antimicrob. Chemother., suppl. D, 18: 107, 1986. 33. Guibert, J., Destree, D., Konopka, C. and Acar, J.: Ciprofloxacin in the treatment of urinary tract infection due to enterobacteria. Eur. J. Clin. Microbial., 5: 247, 1986. 34. Gasser, T. C., Graversen, P.H. and Madsen, P. 0.: Treatment of complicated urinary tract infections with ciprofloxacin. Amer. J. Med., suppl. 4A, 82: 278, 1987. 35. Peters, H.J.: Comparison of intravenous ciprofloxacin and mezlocillin in treatment of complicated urinary tract infection. Eur. J. Clin. Microbial., 5: 253, 1986. 36. Cox, C.: Brief report: ciprofloxacin in the treatment of urinary tract infections caused by Pseudomonas species and organisms resistant to trimethoprim/sulfamethoxazole. Amer. J. Med., suppl. 4A, 82: 288, 1987. 37. Ryan, J. L., Berenson, C. S., Greco, T. P., Mangi, R. J., Sims, M., Thornton, G. F. and Andriole, V. T.: Oral ciprofloxacin in resistant urinary tract infections. Amer. J. Med., suppl. 4A, 82: 303, 1987. 38. Preheim, L. C., Cuevas, T. A., Roccaforte, J. S., Mellencamp, M. A. and Bittner, M. J.: Oral ciprofloxacin in the treatment of elderly patients with complicated urinary tract infections due to trimethoprim/ sulfamethoxazole-resistant bacteria. Amer. J. Med., suppl. 4A, 82: 295, 1987. 39. Saavedra, S., Ramirez-Ronda, C. and Nevarez, M.: Ciprofloxacin in the treatment of urinary tract infections caused by Pseudomonas aeruginosa and multiresistant bacteria. Eur. J. Clin. Microbial., 5: 255, 1986. 40. Leigh, D. A., Emmanuel, F. X. S. and Petch, V. J.: Ciprofloxacin therapy in complicated urinary tract infections caused by Pseudomonas aeruginosa and other resistant bacteria. J. Antimicrob. Chemother., suppl. D, 18: 117, 1986. 41. van Poppel, H. and Wegge, M.: Efficacy of ciprofloxacin in urinary tract infection in multiple sclerosis and neurogenic bladder patients. Excerpta Med. Curr. Clin. Pract., 34: 297, 1985. 42. Newsom, S. W. B., Murphy, P. and Matthews, J.: A comparative study of ciprofloxacin and trimethoprim in the treatment of urinary tract infections in geriatric patients. J. Antimicrob. Chemother., suppl. D, 18: 111, 1986. 43. Cassiers, J., Chysky, V. and Dammekens, H.: Efficacy of ciprofloxacin in urinary tract infections in geriatric patients. Excerpta Med. Curr. Clin. Pract., 34: 300, 1985. 44. Weidner, W., Schiefer, H. G. and Dalhoff, A.: Treatment of chronic bacterial prostatitis with ciprofloxacin: results of a one-year follow-up study. Amer. J. Med., suppl. 4A, 82: 280, 1987. 45. Childs, S. J.: Treatment of chronic bacterial prostatitis with cip-
D
:rofkixacin. Infect. 6: 649, 1987. 46. Oriel 1 J,. Cip:rofioxaci::1 the t:reatn1ent of gono:r:rhoea and nongonococcal urethritis. J. Antirnicrob. Chemother., suppl. D, 18: 129, 1986. 47. Fong, I. W., Linton, W., Simbul, M., McLaughlin, B. and Rahm, V.: Clinical efficacy of ciprofloxacin versus doxycycline in nongonococcal urethritis: a preliminary report. Excerpta Med. Curr. Clin. Pract., 34: 333, 1985. 48. Schacht, P., Arcieri, G., Bnmolte, J., Bruck, H., Chysky, V., Griffith, E., Hullmann, R., Konopka, C., O'Brien, B., Rahm, V.,
Ryoki, T., A. and Weuta, H.: 'Worldwide Clinical Data on Efficacy Safety of Ciprofloxacin. Data on file at Bayer A.G., Wuppertal, West Germany, p. 7, 1987. 49. Fong, I. W., Linton, W., Simbul, M., Thornp, R., McLaughlin, B., Rahm, V. and Quinn, P. A .. Treatment of nongonococcal urethritis with ciprofloxacin. Amer. J. Med., suppl. 4A, 82: 311, 1987. 50. Cox, C. E.: Comparative study of three dosage regimens of ciprofloxacin in the treatment of urinai,r tract infections. Excerpta Med. Curr. Clin. P:ract., 34: 291, 1985.
THE JOURNAL OF UROLDGY
Copyright© 1989 by The Williams & Wilkins Co.
Review Article CIPROFLOXACIN AS TREATMENT FOR GENITOURINARY TRACT INFECTION STACY J. CHILDS*
AND
ELLIE J. C. GOLDSTEIN
From the Southeastern Research Foundation, Birmingham and Department of Surgery, Community Health Sciences, University of Alabama, Tuscaloosa, Alabama, and R. M. Alden Research Laboratory, Santa Monica and Department of Medicine, University of California, Los Angeles, California
Ciprofloxacin is a member of the new fluoroquinolone class of antibacterials. It possesses a wide spectrum of activity and increased potency against almost all potential uropathogens. 1 - 7 The oral preparation has been studied, and shown to be safe and efficacious in the therapy of gonorrhea and complicated and uncomplicated urinary tract infections. Consequently, it may descrease the need for and the cost of conventional parenteral antibiotic therapies.
RESISTANCE
Because ciprofloxacin and the other fluoroquinolones have a novel mechanism of action, there is little cross-resistance between the fluoroquinolones and different classes of antibiotics. addition, transferrable plasmid mediated resistance, or jumpmg genes, do not affect bacterial susceptibility to the fluoroquinolones. However, concern about the development of resistance to ciprofloxacin has been voiced. Compared to older analogues the rate of spontaneous bacterial resistance to ciprofloxacin is markedly less frequent (approximately 1 X 10-12 ). 9 Resistance can be selected or induced by serial passage of organisms on drug-containing media, especially with subinhibitory concentrations. When resistance does appear it occurs because of either mutations of the A-subunit target of DNA gyrase or by alteration in outer membrane protein (OmpF) drug permeability.9
!n
STRUCTURE AND ACTIVITY
The term quinolone is applied loosely to a variety of similar synthetic antibacterial agents that have a bicyclic, heteroaromatic system (see figure). The basic antibacterial activity is derived from the carboxylic acid ring (A ring). Particularly important is the relationship between the ketone moiety at position 4 and the carboxylic acid side chain at position 3. A variety of substituted ring systems may be used for the second ring (Bring). These ring(s) and side chains can further augment the activity of the compound. More than 10,000 variants have been synthesized but only a few have come to clinical use. However, the addition of a fluorine atom to position 6, therefore the name fluoroquinolone, has extended the spectrum of activity to aerobic gram-positive and gram-negative bacteria, and has increased the antibacterial activity of these compounds 100-fold when compared to older quinolone compounds, such as nalidixic acid, cinoxacin and oxalinic acid. 6 • 8 No other halogen at position 6 provides a similar increase in activity. The addition of a piperazinyl group at position 7 increased the antibacterial activity of the fluo:roquinolones, especially against Pseudomonas aeruginosa, and may facilitate transport and increase bioavailability. 6 · 8 The addition of a cyclopropyl group attached to position 1 distinguishes ciprofloxacin from other fluoroqui~olones, most of which have an ethyl group at the 1 position. The stearic configuration of the cyclopropyl group is believed to be responsible for the additional 2 to 4-fold potency of ciprofloxacin against most pathogens, including P. aeruginosa, compared to other fluoroquinolones. Ciprofloxacin is bactericidal and believed to work by inhibiting the A-subunit of the essential bacterial enzyme deoxyribonucleic acid (DNA) gyrase. The enzyme is composed of 2 Asubunits and 2 B-subunits in equal amounts. It is not present in mammalian cells but is essential for DNA replication in bacterial cells. The fluoroquinolones inhibit reactions, such as supercoiling, relaxation, catenation and decatenation, that require the breaking and rebonding of the DNA strands. Ciprofloxacin may have additional activities leading to its increased bactericidal activity. 9 However, the exact mechanism of bacterial cell death remains undefined.
ANTIBACTERIAL SPECTRUM
Ciprofloxacin possesses a broad spectrum of antibacterial activity that includes most potential aerobic gram-positive and gram-negative uropathogens. Strains of Escherichia coli, Klebsiella pneumoniae, Enterobacter species, Serratia marcescens Proteus mirabilis, P. vulgaris, Morganella morgagnii, Providen~ cia rettgeri, P. aeruginosa, enterococci and gonococci have minimal inhibitory concentration 90s of 0.004 to 2 µg./ml. 1 - 7 Most Enterobacteriaceae have minimal inhibitory concentration 90s that range between 0.015 and 1.0 µg./ml. On a weight basis it is more active than other oral agents, such as trimethoprim-sulfamethoxazole and cefaclor. Ciprofloxacin also is highly active against gentamicin-susceptible and gentamicin-resistant strains of P. aeruginosa with minimal inhibitory concentration 90s in most studies of 2.0 µg./ml. or less. 1- 3 • 5 - 7 Nonaeruginosa Pseudomonas species usually are resistant to the current fluoroquinolones. Ciprofloxacin is relatively less active against gram-positive cocci than gramnegative bacteria. However, it has shown good activity against Staphylococcus aureus, including methicillin-resistant strains and coagulase-negative staphylococci, such as Staph. saprophyticus with minimal inhibitory concentration 90s of 0.8 µg./ml. or less for most strains. 4 • 7 Streptococci, including enterococci, generally are less susceptible than staphylococci but the minimal inhibitory concentration 90s (6 µg./ml. or less) are well within the range of the levels achieved in the urinary tract.'· 2 None of the fluoroquinolones is active against most anaerobic bacteria and, consequently, they have little disturbing effect on the normal anaerobic vaginal and fecal flora. 10 Gonococci, including penicillinase-producing strains, are susceptible to ciprofloxacin with minimal inhibitory concentration 90s of less than 0.008 and 0.004 µg./ml., respectively. 1 · 11 The in vitro activity of ciprofloxacin against Chlamydia trachomatis
* Requests for reprints: Alabama Urology Associates, P.C., P.O. Box 985, Alabaster, Alabama 35007. 1
2
CHILDS AND GOLDSTEIN
Structure of quinolones
was studied by Schacter and Moncada, and included fresh cervir:al isolates and serovars L2 (LGV-434) and D (IC-Cal8).12 Each had minimal inhibitory concentrations of 1.56 µ,g./ ml. and similar minimal bactericidal concentrations. They concluded that ciprofloxacin "may prove to be a useful antichlamydia agent". PHARMACOKINETICS
Ciprofloxacin is absorbed rapidly after oral administration. After a single 250 or 500 mg. dose peak serum concentrations of 1. 7 ± 0.6 (standard deviation) and 2.3 ± 0.9 µ,g./ml., respectively, were achieved within 1 to 1.5 hours."'- 15 Simultaneous administration of food or antacids may delay and decrease the absorption of ciprofloxacin. rn In patients with normal renal and hepatic function the half-life of ciprofloxacin is 3.5 to 4.5 hours."· 1" · " Renal clearance of ciprofloxacin is higher than glomerular filtration, which suggests active tubular secretion of ciprofloxacin into the urine."' Probenecid apparently blocks the active tubular secretion of ciprofloxacin. 17 In patients with normal renal function approximately a third to half of the orally ingested dose will be excreted into the urine. 10 • 18 Consequently, peak levels of more than 500 µ,g./ml. are achieved in the urine after a 250 or 500 mg. oral dose, and remain at concentrations of 40 to 60 µ,g./ml. for up to 12 hours and 5 to 20 µ,g./ml. at 24 hours.'4,1s, 19 Ciprofloxacin has shown good diffusion into prostatic tissue achieving levels 1.5 to 14.2 times greater than serum levels. 20· 21 Gombert and associates showed that after 3, 500 mg. doses patients undergoing trans urethral resection of the prostate had prostatic levels of 1.5 to 14.2 µg,/gm. tissue. 21 Grabe and associates studied 12 men and found an average prostatic tissue level of 3.03 ± 0.38 µ,g./gm. tissue (range 1.1 to 7.2 µ,g,/gm. tissue). 20 Patients with renal insufficiency have a prolonged half-life (7 to 10 hours) and require dosage adjustments. 1 :i, 22 • 2 " However, 2 other mechanisms of elimination, intestinal (fecal) and metabolic (biliary), may at least partially compensate for decreased renal excretion. In patients with impaired renal function, if the creatinine clearance is greater than 50 ml. per minute the usual dosage would apply. If the creatinine clearance is between 30 and 50 ml. per minute the dose would be 250 to 500 mg. every 12 hours and if between 5 and 29 ml. per minute the dose should be adjusted to 250 to 500 mg. every 18 hours. Further decreases in the dosage would be prudent if renal and hepatic insufficiency is present. ADVERSE EFFECTS
Adverse effects from nalidixic acid and older quinolone agents were frequent and sometimes severe. Ciprofloxacin does not appear to cause these reactions with the same frequency or severity. In review of the worldwide experience with ciprofloxacin, adverse effects were reported in 3 per cent of the European patients, 6.5 per cent of the Japanese patients and 13.4 per cent
of patients in the United States. 24 The higher rate reported in the United States may have been related to use of higher dosages or to the fact that the investigators were encouraged to report side effects, even if they were judged to be only possibly related to the drug. The table lists the type of side effects encountered and their incidence. Gastrointestinal side effects, especially nausea, vomiting, diarrhea and abdominal discomfort, were the most frequently reported (2 to 8 per cent). 24 ' 25 Central nervous system effects, such as headache and restlessness, also were reported. Hypersensitivity reactions, such as skin rash and pruritis, were infrequent (less than 1 per cent). Some patients had Candida vaginitis and others reported a bad taste. Serious toxicity was reported in only 3 of 6,500 patients in that series and included 1 patient each with pseudomembranous colitis and interstitial nephritis with crystalluria renal failure, and seizure in a patient who was also receiving theophylline. Laboratory abnormalities were infrequent but included transaminemia and eosinophilia. DRUG INTERACTIONS
Drug interactions between ciprofloxacin and theophylline, warfarin and caffeine may occur, since they compete for the same metabolic hepatic enzyme systems (cytochrome P450 system). In 1 series the concomitant use of ciprofloxacin and theophylline caused elevated theophylline levels. 26 Consequently, decreased theophylline doses should be used and levels monitored frequently should patients receive both drugs. There are scant clinical data on the use of ciprofloxacin in either pregnant women or children. In addition, animal studies with nalidixic acid have noted cartilage toxicity. 6 While nothing similar has been reported in the studies of ciprofloxacin in the treatment of pulmonary infections in children with cystic fibrosis, it would be prudent to avoid its use in children and pregnant women until definitive studies have been performed. 24 CLINICAL APPLICATION
Effective antibiotic therapy depends upon adequate tissue penetration in appropriate sites. Inflamed tissues are more easily penetrated by most antibiotics but several physicochemical characteristics of ciprofloxacin, such as low serum protein binding and small molecular size, provide favorable conditions for tissue penetration despite the drug being poorly lipophilic. A single 100 mg. intravenous dose achieves levels of 0.93 to 4.66 µ,g./gm. kidney tissue from 1 to 8 hours after administration. Serum levels during that same period were 0.13 to 0.85 µ,g./ml. and perirenal fat levels were 0.05 to 0.45 µ,g./gm. Since the minimal inhibitory concentration 90 of ciprofloxacin for Enterobacteriaceae is equal to or less than 0.25 µ,g./ml. this implies the drug at a relatively low dosing to be able to inhibit strains causing urological infections for 5 to 8 hours. 27 Other studies have shown similar results with consistent levels of 4.2 to 5.2 mg./kg. in kidney tissue. 28 The penetration of single doses of 500 mg. ciprofloxacin Reported incidences (per cent) of adverse reactions probably or possibly due to ciprofloxacin in Europe, Japan and the United States 24 Europe/ United States (1,693 pts,) Total reactions Total pts. affected Gastrointestinal: Nausea Diarrhea Pain/dyspepsia Nervous system: Dizziness
Headache Skin (allergy): Rash Pruritis
8.0 6,5 4.5 2,1
Japan (2,578 pts,)
United States (1,241 pts.)
3.6 3,0 2.1
22,5 13.4 8.1 3.0 2,0
0.4
4.4
0.4
1.9 0.7
1.4
0.6 1.1 0.6 0.4 1.0 0.6 0.4
CIPROFLOX_ACH\J AS TREAT:VKE?,"JT FOR GENITOURINARY TRACT iNFECTI01>J
has resulted in prostatic tissue levels of twice the serum levels for as much as up to 12 hours after dosing. An important implication is drawn here because this is noninflamed prostate tissue, and the results in several studies have shown sustained levels exceeding the minimal inhibitory concentration of virtually all Enterobacteriaceae and organisms important to the urinary tract for up to 12 hours. 20 • 29 Other reports have shown adequate penetration into the male and female genital tract, peritoneal fluid, uterus and fallopian tubes. 29 In summary, we can say that relatively low doses of ciprofloxacin achieve adequate to high tissue and serum levels for treatment of almost all infections commonly seen in the genitourinary tract of male or female patients. Although, seemingly overkill, ciprofloxacin has been used successfully to treat uncomplicated urinary tract infections. In a prospective randomized double blind study comparing 250 mg. ciprofloxacin twice daily for 10 days with 160 mg./800 mg. cotri:noxazole twice daily for 10 days, the ciprofloxacin group had a 100 per cent clinical and bacteriological cure rate compared to a 94 per cent bacteriological and 91 per cent clinical cure rate for cotrimoxazole. A bacteriological cure is the absence of the original pathogen at the 5 to 9-day post-treatment culture. A clinical cure is the absence of the original symptoms referable to the urinary tract infection at the 5 to 9-day posttherapy visit. A statistically significant increase in adverse side effects was noted in the cotrimoxazole group. As expected, 28 of the 31 women receiving ciprofloxacin had E. coli isolated from the urine. One patient had Staph. saprophyticus, 1 had coagulase negative staphylococcus and 1 had P. mirabilis.'30 Additionally, ciprofloxacin compares favorably with cinoxacin in the treatment of uncomplicated urinary tract infections." 1 There have been numerous reports on the use of ciprofloxacin in complicated urinary tract infections. Williams and Gruneberg reported on 75 evaluable patients showing a 5 to 9day bacteriological cure rate of 88 to 94 per cent (2 dosing regimens), compared to an 87 per cent cure rate of trimethoprim-sulfamethoxazole-treated patients.'1' In noncomparative studies, Guibert and associates reported on 56 patients with a 92 per cent cure rate,8·1 whereas Gasser and associates produced an 84 to 87 per cent cure rate in 110 patients with complicated urinary tract infections treated with ciprofloxacin034 Peters compared ciprofloxacin with mezlocillin in 40 patients and found 5 to 9-day cure rates of 90 and 74 per cent, respectively. 10 Long-term followup cultures were available on some of these studies but they are largely meaningless because of the lesions involved in the urinary tract that could be corrected surgically. Those not corrected surgically could be expected to have relapse anyway. Five to 9-day bacteriological cure rates of 84 to 95 per cent are excellent for this disease. When one considers urinary tract infections caused from troublesome organisms, such as P. aeruginosa or multipleresistant bacteria, equally favorable results can be seen. Five to 9-day bacteriological cure rates following vuuA,auu have been reported by Cox (95 per cent, 53 patients), and Ryan per cent, 30 patients)," Preheim (84 per cent, 25 patients),'3 8 Saavedra (90 per cent, 28 patients)19 and Leigh (89 per cent, 28 patients) 40 and their associates. Since these bacteria are difficult to eradicate even with the aminoglycosides, cure rates of 90 per cent or better seem to offer promise for these pathogens. Van Poppel and Wegge evaluated 29 patients with multiple sclerosis and/or neurogenic bladder and found no patient clinical failures after treatment with ciprofloxacin.4 1 The 14-day bacteriological eradication rate was 48 per cent and the 35-day rate was 36 per cent. The large persistence was because of the majority of the patients having indwelling Foley urethral catheters. The drug was well tolerated in these patients with neurological disease. The geriatric population also has been evaluated by Newsom and associates in a comparative study of 32 patients. Cure rates of 94 per cent were obtained in both groups, ciprofloxacin
3
versus trimethoprim.4" Cassiers and associates treated 40 patients and received a 78 per cent bacteriological cure rate.4'3 Interesting points from these 2 studies were that there was no abundance of Candida overgrowth on these antibiotic-treated patients nor was resistance found even in the patients with relapse or persistence of the bacteria. It is noteworthy that in patients who must receive either long-term antibiotics or antibiotics frequently because of recurrent disease that ciprofloxacin evidently has a low incidence of resistance. In 2 elderly patients who we treated with ciprofloxacin and who had complicated urinary tract infections we did notice Candida overgrowth in the urine. Of these patients 1 had chronic prostatitis and received 1 month of therapy, whereas 1 was a diabetic with recurrent infections and received 14 days of therapy. In both patients candiduria resolved without treatment upon stopping the antibiotics. Of special interest is the use of ciprofloxacin in the treatment of chronic bacterial prostatitis. Weidner and associates treated patients with chronic bacterial prostatitis with ciprofloxacin for 2 weeks and the followup for most of these patients was 1 year. The 1-year cure rate for E. coli prostatitis was 64 per cent. Although the data are small, Enterococcus and Enterobacter aerogenes were not as successful in the long term.4 4 Another study showed a long-term cure rate of 78 per cent bacteriologically and 77 per cent clinically among 39 evaluable male patients. 4 " Ciprofloxacin has been shown to be effective in the treatment of gonococcal and nongonococcal urethritis. Oriel reported final cure rates similar for ciprofloxacin and doxycycline.4" Fong and associates randomized in a double blind manner 225 men with nongonococcal urethritis.4 7 Patients either received 750 mg. ciprofloxacin twice daily for 7 days or 100 mg. doxycycline twice daily for 7 days. Results were similar with over-all cure rates of 52.1 per cent for ciprofloxacin and 60.8 per cent for doxycycline. In patients with Chlamydia! infections alone ciprofloxacin was less effective than doxycycline (45.5 versus 75 per cent) but in patients with U reaplasma urealyticum ciprofloxacin was more effective than doxycycline (69.2 versus 45 per cent). Data on file at Bayer Laboratories in West Germany show that many pathogens implicated in sexually transmitted diseases were treated with ciprofloxacin. Of 250 patients with Neisseria gonorrhea a 100 per cent eradication rate was obtained. For C. trachomatis 64 per cent eradication and for U. urealyticum 91 per cent eradication were observed:rn Somewhat poorer results were observed Fong and associates for all forms of nongonococcal urethritis.4° Dosing studies of Cox do not indicate any statistically significant differences at 250, 500 or 750 mg. for the treatment of urinary tract infections."' His personal experience would indicate a better success rate in treating Pseudomonas urinary tract infections with 500 mg. ciprofloxacin twice daily over the lower regimen. For most infections, however, it would appear that 250 mg. twice for 3 or more would be adequate. CONCLUSION
Ciprofloxacin appears to be an appropriate antibacterial for the treatment of uncomplicated and complicated urinary tract infections. It seemingly is appropriately substituted for aminoglycosides for the treatment of troublesome resistant bacteria, such as P. aeruginosa. It also may allow for outpatient treatment of enterococcus urinary tract infections in addition to common Enterobacteriaceae. The adverse events and side effects associated with use of ciprofloxacin are minimal as of this writing. Previously, difficult infections to eradicate, such as chronic bacterial prostatitis, may show some promise using this drug as treatment since ciprofloxacin achieves excellent tissue levels as well as serum and urine levels when orally administered. The treatment of nonspecific urethritis caused by organisms, such as Chlamydia or Ureaplasma, may be more difficult and conventional therapy with drugs, such as doxycycline, may
4
CHILDS AND GOLDSTEIN
be more appropriate. Although resistance has been rare, it certainly can occur and should be expected should this drug be overused or used inappropriately. REFERENCES 1. Barry, A. L., Jones, R. N., Thornsberry, C., Ayers, L. W., Gerlach, E. H. and Sommers, H. M.: Antibacterial activities of ciprofloxacin, norfloxacin, oxolinic acid, cinoxacin, and nalidixic acid. Antimicrob. Agents Chemother., 25: 633, 1984. 2. Chin, N. X. and Neu, H. C.: Ciprofloxacin, a quinolone carboxylic acid compound active against aerobic and anaerobic bacteria. Antimicrob. Agents Chemother., 25: 319, 1984. 3. Fass, R. J.: In vitro activity of ciprofloxacin (Bay 09867). Antimicrob. Agents Chemother., 24: 568, 1983. 4. Smith, S. M. and Eng, R. H. K.: Activity of ciprofloxacin against methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother., 27: 688, 1985. 5. Wise, R., Andrews, M. J. and Edwards, L. M.: In vitro activity of Bay 09867, a new quinolone derivative, compared with those of other antimicrobial agents. Antimicrob. Agents Chemother., 23: 559, 1983. 6. Wolfson, J. S. and Hooper, D. C.: The fluoroquinolones: structures, mechanisms of action and resistance, and spectra of activity in vitro. Antimicrob. Agents Chemother., 28: 581, 1985. 7. Zeiler, H. J. and Grohe, K.: The in vitro and in vivo activity of ciprofloxacin. Eur. J. Clin. Microbial., 3: 339, 1984. 8. Shentag, J. J. and Domagala, J. M.: Structure-activity relationships with the quinolone antibiotics. Res. Clin. Forums, 7: 9, 1985. 9. Hooper, D. C., Wolfson, J. S., Ng, E. Y. and Swartz, M. N.: Mechanisms of action of and resistance to ciprofloxacin. Amer. J. Med., suppl. 4A, 82: 12, 1987. 10. Goldstein, E. J. C. and Citron, D. M.: Comparative activity of the quinolones against anaerobic bacteria isolated at community hospitals. Antimicrob. Agents Chemother., 27: 657, 1985. 11. Lyon, M. D., Smith, K. R., Saag, M. S. and Cobbs, C. G.: Brief report: in vitro activity of ciprofloxacin against Neisseria gonorrhoeae. Amer. J. Med., suppl. 4A, 82: 40, 1987. 12. Schachter, J. and Moncada, J.: In vitro activity of ciprofloxacin against Chlamydia trachomatis .. Amer. J. Med., suppl. 4A, 82: 42, 1987. 13. Bergan, T., Thorsteinsson, S. B., Solberg, R., Bjornskau, L., Kolstad, I. M. and Johnsen, S.: Pharmacokinetics of ciprofloxacin: intravenous and increasing oral doses. Amer. J. Med., suppl. 4A, 82: 97, 1987. 14. Borner, K., Hoffken, G., Lode, H., Koeppe, P., Prinzing, C., Glatzel, P., Wiley, R., Olschewski, P., Sievers, B. and Reinitz, D.: Pharmacokinetics of ciprofloxacin in healthy volunteers after oral and intravenous administration. Eur. J. Clin. Microbial., 5: 179, 1986. 15. Wingender, W., Graefe, K. H., Gau, W., Forster, D., Beermann, D. and Schacht, P.: Pharmacokinetics of ciprofloxacin after oral and intravenous administration in healthy volunteers. Eur. J. Clin. Microbial., 3: 355, 1984. 16. Ledergerber, B., Bettex, J. D., Joos, B., Flepp, M. and Luthy, R.: Effect of standard breakfast on drug absorption and multipledose pharmacokinetics of ciprofloxacin. Antimicrob. Agents Chemother., 27: 350, 1985. 17. Wingender, W., Beermann, D., Foerster, D., Graefe, K. H., Schacht, P. and Scharbrodt, V.: Mechanism of renal excretion of ciprofloxacin, a new quinolone carboxylic acid derivative, in humans. Chemotherapia, suppl. 2, 4: 403, 1985. 18. Wise, R. and Donovan, I. A.: Tissue penetration and metabolism of ciprofloxacin. Amer. J. Med., suppl. 4A, 82: 103, 1987. 19. Smith, J, T.: The mode of action of 4-quinolones and possible mechanisms of resistance. J. Antimicrob. Chemother, suppl. D, 18: 21, 1986. 20. Grabe, M., Forsgren, A. and Bjork, T.: Concentrations of ciprofloxacin in serum and prostatic tissue in patients undergoing transurethral resection. Eur. J. Clin. Microbial., 5: 211, 1986. 21. Gombert, M. E., duBouchet, L., Aulicino, T. M., Berkowitz, L. B. and Macchia, R. J.: Brief report: prostatic tissue concentrations of ciprofloxacin after oral administration. Amer. J. Med., suppl. 4A, 82: 130, 1987. 22. Boelaert, J., Valcke, Y., Schugers, M., Daneels, R., Rosseneu, M., Rosseel, M. T. and Bogaert, M. G.: The pharmacokinetics of ciprofloxacin in patients with impaired renal function. J. Anti-
microb. Chemother., 16: 87, 1985. 23. Gasser, T. C., Ebert, S. C., Graversen, P. H. and Madsen, P. 0.: Pharmacokinetic study of ciprofloxacin in patients with impaired renal function. Amer. J. Med., suppl. 4A, 82: 139, 1987. 24. Ball, P.: Ciprofloxacin: an overview of adverse experiences. J. Antimicrob. Chemother., suppl. D, 18: 187, 1986. 25. Arcieri, G., Griffith, E., Gruenwaldt, G., Heyd, A., O'Brien, B., Becker, N. and August, R.: Ciprofloxacin: an update on clinical experience. Amer. J. Med., suppl. 4A, 82: 381, 1987. 26. Raoof, S., Wollschlager, C. and Khan, F. A.: Ciprofloxacin increases serum levels oftheophylline. Amer. J. Med., suppl. 4A, 82: 115, 1987. 27. Daschner, F. D., Westenfelder, M. and Dalhoff, A.: Penetration of ciprofloxacin into kidney, fat, muscle and skin tissue. Eur. J. Clin. Microbial., 5: 212, 1986. 28. Daschner, F. D., Westenfelder, M., Dalhoff, A. and Becker, Ch.: Penetration of ciprofloxacin into kidney, fat, muscle and skin of patients undergoing urologic operations. In: 14th International Congress of Chemotherapy, Kyoto, Japan, p. 182, abstract S-428, 1985. 29. Bergogne-Berezin, E.: Penetration of ciprofloxacin into tissue: a review. Excerpta Med. Curr. Clin. Pract., 34: 183, 1985. 30. Henry, N. K., Schultz, H. J., Grubbs, N. C., Muller, S. M., Ilstrup, D. M. and Wilson, W. R.: Comparison of ciprofloxacin and cotrimoxazole in the treatment of uncomplicated urinary tract infection in women. J. Antimicrob. Chemother., suppl. D, 18: 103, 1986. 31. Goldstein, E. J. C., Kahn, R. M., Alpert, M. L., Ginsberg, B. P., Greenway, F. L. and Citron, D. M.: Ciprofloxacin versus cinoxacin in therapy of urinary tract infections. Amer. J. Med., suppl. 4A, 82: 284, 1987. 32. Williams, A. H. and Gruneberg, R. N.: Ciprofloxacin and cotrimoxazole in urinary tract infection. J. Antimicrob. Chemother., suppl. D, 18: 107, 1986. 33. Guibert, J., Destree, D., Konopka, C. and Acar, J.: Ciprofloxacin in the treatment of urinary tract infection due to enterobacteria. Eur. J. Clin. Microbial., 5: 247, 1986. 34. Gasser, T. C., Graversen, P.H. and Madsen, P. 0.: Treatment of complicated urinary tract infections with ciprofloxacin. Amer. J. Med., suppl. 4A, 82: 278, 1987. 35. Peters, H.J.: Comparison of intravenous ciprofloxacin and mezlocillin in treatment of complicated urinary tract infection. Eur. J. Clin. Microbial., 5: 253, 1986. 36. Cox, C.: Brief report: ciprofloxacin in the treatment of urinary tract infections caused by Pseudomonas species and organisms resistant to trimethoprim/sulfamethoxazole. Amer. J. Med., suppl. 4A, 82: 288, 1987. 37. Ryan, J. L., Berenson, C. S., Greco, T. P., Mangi, R. J., Sims, M., Thornton, G. F. and Andriole, V. T.: Oral ciprofloxacin in resistant urinary tract infections. Amer. J. Med., suppl. 4A, 82: 303, 1987. 38. Preheim, L. C., Cuevas, T. A., Roccaforte, J. S., Mellencamp, M. A. and Bittner, M. J.: Oral ciprofloxacin in the treatment of elderly patients with complicated urinary tract infections due to trimethoprim/ sulfamethoxazole-resistant bacteria. Amer. J. Med., suppl. 4A, 82: 295, 1987. 39. Saavedra, S., Ramirez-Ronda, C. and Nevarez, M.: Ciprofloxacin in the treatment of urinary tract infections caused by Pseudomonas aeruginosa and multiresistant bacteria. Eur. J. Clin. Microbial., 5: 255, 1986. 40. Leigh, D. A., Emmanuel, F. X. S. and Petch, V. J.: Ciprofloxacin therapy in complicated urinary tract infections caused by Pseudomonas aeruginosa and other resistant bacteria. J. Antimicrob. Chemother., suppl. D, 18: 117, 1986. 41. van Poppel, H. and Wegge, M.: Efficacy of ciprofloxacin in urinary tract infection in multiple sclerosis and neurogenic bladder patients. Excerpta Med. Curr. Clin. Pract., 34: 297, 1985. 42. Newsom, S. W. B., Murphy, P. and Matthews, J.: A comparative study of ciprofloxacin and trimethoprim in the treatment of urinary tract infections in geriatric patients. J. Antimicrob. Chemother., suppl. D, 18: 111, 1986. 43. Cassiers, J., Chysky, V. and Dammekens, H.: Efficacy of ciprofloxacin in urinary tract infections in geriatric patients. Excerpta Med. Curr. Clin. Pract., 34: 300, 1985. 44. Weidner, W., Schiefer, H. G. and Dalhoff, A.: Treatment of chronic bacterial prostatitis with ciprofloxacin: results of a one-year follow-up study. Amer. J. Med., suppl. 4A, 82: 280, 1987. 45. Childs, S. J.: Treatment of chronic bacterial prostatitis with cip-
D
:rofkixacin. Infect. 6: 649, 1987. 46. Oriel 1 J,. Cip:rofioxaci::1 the t:reatn1ent of gono:r:rhoea and nongonococcal urethritis. J. Antirnicrob. Chemother., suppl. D, 18: 129, 1986. 47. Fong, I. W., Linton, W., Simbul, M., McLaughlin, B. and Rahm, V.: Clinical efficacy of ciprofloxacin versus doxycycline in nongonococcal urethritis: a preliminary report. Excerpta Med. Curr. Clin. Pract., 34: 333, 1985. 48. Schacht, P., Arcieri, G., Bnmolte, J., Bruck, H., Chysky, V., Griffith, E., Hullmann, R., Konopka, C., O'Brien, B., Rahm, V.,
Ryoki, T., A. and Weuta, H.: 'Worldwide Clinical Data on Efficacy Safety of Ciprofloxacin. Data on file at Bayer A.G., Wuppertal, West Germany, p. 7, 1987. 49. Fong, I. W., Linton, W., Simbul, M., Thornp, R., McLaughlin, B., Rahm, V. and Quinn, P. A .. Treatment of nongonococcal urethritis with ciprofloxacin. Amer. J. Med., suppl. 4A, 82: 311, 1987. 50. Cox, C. E.: Comparative study of three dosage regimens of ciprofloxacin in the treatment of urinai,r tract infections. Excerpta Med. Curr. Clin. P:ract., 34: 291, 1985.