MINIREVIEWS. hominis. Fluoroquinolones are less active against Ureaplasma

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1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, OCt. 1989, p Vol. 33, No /89/ $02.00/0 Copyright 1989, American Society for Microbiology MINIREVIEWS Treatment of Genitourinary Tract Infections with Fluoroquinolones: Activity In Vitro, Pharmacokinetics, and Clinical Efficacy in Urinary Tract Infections and Prostatitis JOHN S. WOLFSON* AND DAVID C. HOOPER Infectious Disease Unit, Medical Services, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts INTRODUCTION There has been a recent dramatic growth in information on the use of fluoroquinolone antimicrobial agents for the oral treatment of bacterial infections of the genitourinary tract. The fluoroquinolones, which include norfloxacin, ciprofloxacin, ofloxacin, pefloxacin, enoxacin, fleroxacin, and many others, are analogs of the nonfluorinated agent nalidixic acid, which was first released for the treatment of urinary tract infections in Like nalidixic acid, fluoroquinolones have as their target the essential bacterial enzyme DNA gyrase, the antagonism of which disrupts DNA replication and aspects of transcription, DNA repair, and recombination, ultimately resulting in killing of bacteria. In contrast to nalidixic acid, the fluoroquinolones are more potent in vitro against a broader spectrum of bacterial species, are less prone to selection of resistant bacteria, and exhibit more favorable pharmacokinetic properties. This minireview summarizes recent data on the use of fluoroquinolones to treat genitourinary tract infections, considering potency in vitro, pharmacokinetics, and treatment of urinary tract infections and prostatitis. In the second minireview (37), treatment of genital infections and adverse effects are reviewed. More detailed discussions can be found in recent reviews on the use of fluoroquinolones for the treatment of urinary tract infections (47, 54), prostatitis (47, 54; K. G. Naber, Rev. Infect. Dis., in press), and sexually transmitted diseases (20) and in larger overviews (3, 12, 22, 36, 42, 49, 50, 66, 80, 81). Referencing has been selective because of space limitations. ACTIVITY IN VITRO Considering bacterial urinary tract pathogens, fluoroquinolones exhibit excellent potency in vitro against most members of the family Enterobacteriaceae and in most cases good activity against Serratia marcescens and Providencia spp. (Table 1) (25, 82). Notably, fluoroquinolones have good activity against Pseudomonas aeruginosa, but potency is lower against other Pseudomonas species. Staphylococcus saprophyticus and group B streptococci are susceptible, but Enterococcus spp. are less so. The drugs have excellent activity against multiply antibiotic-resistant gram-negative bacilli. Considering genital pathogens, fluoroquinolones have excellent activity against penicillin-susceptible and penicillinresistant Neisseria gonorrhoeae and Haemophilus ducreyi. * Corresponding author Ciprofloxacin, ofloxacin, and fleroxacin also exhibit good activity against Chlamydia trachomatis and Mycoplasma hominis. Fluoroquinolones are less active against Ureaplasma urealyticum and Gardnerella vaginalis and exhibit poor or no activity against many anaerobic species and Candida albicans. The activity of many fluoroquinolones in vitro is antagonized by the presence of urine, because of the acidic ph and an increased concentration of magnesium ions (59, 82). This decreased potency, however, is unlikely to be of clinical importance for the therapy of urinary tract infections, because of the high drug concentrations achieved with most agents in the urinary tract. A minimal decrease in the potency of fluoroquinolones occurs with increased inocula with most bacterial species (81). PHARMACOKINETIC PROPERTIES Representative pharmacokinetic properties of fluoroquinolones (reviewed in references 6, 12, 23, 36, 42, 49, 52, 70, and 82) administered orally to healthy volunteers are presented in Table 2. The drugs are well absorbed and have terminal half-lives of elimination which allow twice-daily dosing for norfloxacin, ciprofloxacin, ofloxacin, and enoxacin and once- or twice-daily dosing for pefloxacin and fleroxacin. Elimination is both renal and nonrenal for norfloxacin, ciprofloxacin, enoxacin, and fleroxacin, primarily renal for ofloxacin, and primarily nonrenal for pefloxacin. Fluoroquinolones penetrate well into fluids and tissues of the genitourinary tract. Peak concentrations in urine are 25- to many-hundred-fold above peak concentrations in serum after oral dosing. Concentrations of fluoroquinolones achieved in urine in patients with decreased renal function are likely to be adequate for the treatment of urinary tract infections. Concentrations in kidney tissue are usually 2- to 10-fold concentrations in serum. Concentrations in prostatic tissue are usually 0.9- to 2.3-fold concentrations in serum. In prostatic fluid, however, concentrations are only 0.1- to 0.3-fold concentrations in serum for norfloxacin, ciprofloxacin, and fleroxacin but are 1.2-fold concentrations in serum for ofloxacin. Concentrations in gynecologic tissues are typically 0.7- to 2.0-fold concentrations in serum. Concentrations of fluoroquinolones in feces after oral administration are high, in the range of 50 to thousands of micrograms of drug per gram of feces (24). Thus, potency in vitro against enteric gram-negative bacilli, P. aeruginosa, N. gonorrhoeae, H. ducreyi, and C. trachomatis combined with pharmacokinetic properties and concentrations achieved in urine, feces, kidney, and prostate

2 1656 MINIREVIEWS TABLE 1. Activity in vitro of fluoroquinolones against genitourinary tract pathogensa ANTIMICROB. AGENTS CHEMOTHER. Microbial species NAL NFX CFX OFX PFX ENX FLX Escherichia coli Klebsiella pneumoniae Enterobacter aerogenes E. cloacae Citrobacterfreundii C. diversus Proteus mirabilis P. vulgaris Providencia stuartii P. rettgeri Morganella morganii Serratia marcescens > Pseudomonas aeruginosa P. maltophilia P. cepacia Acinetobacter calcoaceticus subsp. anitratus A. calcoaceticus subsp. Iwoffii Staphylococcus saprophyticus > Streptococcus agalactiae (group B) > Enterococcus faecalis > E. faecium > Corynebacterium sp. strain D Neisseria gonorrhoeae Haemophilus ducreyi Gardnerella vaginalis Bacteroides fragilis 512 > Mobiluncus spp. > Chlamydia trachomatis Ureaplasma urealyticum Mycoplasma hominis > Candida albicans >100 >100 a Data are modified from reference 82. b MICgo, MIC for 90%o of isolates; NAL, nalidixic acid; NFX, norfloxacin; CFX, ciprofloxacin; OFX, ofloxacin; PFX, pefloxacin; ENX, enoxacin; FLX, fleroxacin. suggests the potential usefulness of fluoroquinolones in the therapy of urinary tract infections, prostatitis, gonorrhea, chancroid, and certain genital infections caused by chlamydiae. CLINICAL EFFICACY Urinary tract infections. (i) Uncomplicated cystitis. Norfloxacin and ciprofloxacin were compared with trimetho- TABLE 2. Pharmacokinetic propertiesa of a single 400-mg oral dose of fluoroquinolone administered to healthy volunteers Fluoroquinolone C x Tma t1m2 AUC V CL Renal (reference) (mtg -h/ (liters) (ml/min) excre- (pg/mi) ~liter) tionb (reference) (,ug/ml) (h) (h) Norfloxacin (1) c 27 Ciprofloxacin (10) Ofloxacin (10) Pefloxacin (5) d Enoxacin (53) e Fleroxacin (56) Ye a Cm.x, Peak concentration in serum; Tm., time to peak; tl/2,3, terminal half-life of elimination; AUC, area under the curve; V, volume of distribution; CLR, renal clearance. b Cumulative percentage of dose in urine after 24 h. From reference 4. d Cumulative percentage of dose in urine after 84 h. e Cumulative percentage of dose in urine after 72 h. prim-sulfamethoxazole (TMP-SMX) for the therapy of uncomplicated urinary tract infections in prospective, randomized, double-blind trials (Table 3). Pathogens were eliminated from urine in 98 to 99% of patients treated with norfloxacin or TMP-SMX (74). For ciprofloxacin as compared with TMP-SMX, bacteria were eradicated in 31 of 31 patients receiving ciprofloxacin and in 32 of 34 patients (94%) receiving TMP-SMX (35). Combining data from similar studies of uncomplicated and complicated urinary tract infections, pathogens were eliminated from urine in 145 of 149 patients (97%) treated with ciprofloxacin and in 125 of 140 patients (89%) treated with TMP-SMX (P = 0.005) (66). For ofloxacin as compared with TMP-SMX, bacteriologic cure was documented in 89 of 97 patients (92%) treated with ofloxacin and in 81 of 92 patients (88%) treated with TMP- SMX (7). In prospective nonblind comparative trials, fluoroquinolones were equal in efficacy to most nonfluoroquinolones (Table 3) and superior in efficacy to nalidixic acid (60) and nitrofurantion (46). The efficacy of single doses of fluoroquinolones in the treatment of uncomplicated urinary tract infections was evaluated in a limited number of studies. Ciprofloxacin was efficacious at 100 or 250 mg, curing 16 of 19 (84%) and 17 of 19 (89%) patients, respectively (26). A single dose of ofloxacin (100 mg) as compared with TMP-SMX given for 3 or 7 days eliminated pathogens from urine of 44 of 60 patients (73%), while TMP-SMX 55 of 59 patients (93%) (P = 0.007) (55). In a study comparing a single 100-mg dose of

3 VOL. 33, 1989 TABLE 3. Results of selected comparative studies of fluoroquinolones for the treatment of uncomplicated urinary tract infections No. No. (%) Refer- Du'Oral dose patoft bacterio- Reencee- Drga (mg x days) evaluable logically 74c NFX 200 BID x (98) NFX 400 BID x (98) TMP-SMX 160/800 BID x (98) 27 NFX 200 BID x (94) TMP-SMX 80/400 BID x (96) 77 NFX 400 BID x (94) TMP-SMX 160/800 BID x (92) 60 NFX 400 BID x (89) NAL 660 TID x (67) 75 NFX 400 BID x (82) AMOX 250 TID x (74) 67 NFX 400 BID x (100) TMP-SMX 160/800 BID x (100) 28 NFX 400 BID x (91) TMP-SMX 160/800 BID x (86) 65 NFX 400 BID x (99) TMP-SMX 160/800 x (90) 29 NFX 400 BID x (86) TMP-SMX 160/800 BID x (90) 71 NFX 400 BID x (96) TMP-SMX 160/800 BID x (100) 35c CFX 250 BID x (100) TMP-SMX 160/800 BID x (94) 51 CFX 100 BID x (94) TMP 200 BID x (94) 7c OFX 100 BID x (92) TMP-SMX 160/800 BID x (88) 17 OFX 200 BID x (91) OFX 300 BID x (93) TMP-SMX 160/800 BID x (96) 55 OFX lood (73) TMP-SMX 160/800 BID x (93) 46 OFX 100 BID x (81) NFT 100 TID x (66) 40 FLX 60d (100) AMOX 3,0d 10 10(100) a NFX, Norfloxacin; CFX, ciprofloxacin; OFX, ofloxacin; FLX, fleroxacin; NAL, nalidixic acid; TMP, trimethoprim; NFT, nitrofurantoin; AMOX, amoxicillin. b BID, Two times daily; TID, three times daily. c Double-blind study. d One dose. ofloxacin with 100 mg twice daily for 3 days, bacteriologic cure occurred in 25 of 29 (86%) and 27 of 30 (90%) patients, respectively (46). In two noncomparative studies, ofloxacin (100 mg) achieved bacteriologic cure in 30 of 37 (81%) and 89 of 95 (94%) patients (8). The low efficacy of ofloxacin in two of these studies (8, 55) might reflect the relatively low dose used. For fleroxacin, bacteriologic cure occurred in 17 of 19 patients (89%) receiving either a single 200-mg dose or a single 400-mg dose (48) and in 10 of 10 patients receiving a single 600-mg dose (40). Additional studies are needed. The emergence of bacterial resistance during the therapy of uncomplicated urinary tract infections with fluoroquinolones has been uncommon (47). Decreased susceptibility occurred in strains isolated from only 3 of 492 patients (0.6%) in a large double-blind study with norfloxacin (74). In three studies (26, 38, 55), there was a suggestion that courses of fluoroquinolone therapy of 3 days or less may be less effective in the treatment of S. saprophyticus infections. Fecal and vaginal flora are reservoirs for colonization of the urethra and bladder prior to recurrent urinary tract MINIREVIEWS 1657 TABLE 4. Results of selected comparative studies of fluoroquinolones for the treatment of uncomplicated pyelonephritis Nof No. (% Refer- Drg rlds ains bacterioence (mg x days) evaluable logically 65 NFX 400 BID x 10c (94) TMP-SMX 160/800 BID x 10c (91) 30 NFX 400 BID x (86) TMP-SMX 160/800 BID x (90) 34 NFX 400 BID x (91) TMP-SMX 160/800 BID x (100) 8 OFX 200 BID x (82) TMP-SMX 160/800 BID x (80) 46 OFX 200 BID x (85) TMP-SMX 160/800 BID x (69) a NFX, Norfloxacin; OFX, ofloxacin. b BID, Two times daily. c Mean number of days. infections (69). Fluoroquinolones achieve high concentrations in feces and effectively suppress Escherichia coli and other members of the family Enterobacteriaceae during the therapy of acute cystitis (19, 24, 34, 67). Ofloxacin (73) and norfloxacin (34, 67) also suppress vaginal and periurethral flora. These findings suggest that therapy with a fluoroquinolone may reduce the risk of early recurrences of urinary tract infections (73). (ii) Uncomplicated pyelonephritis. For comparative trials, treatment of acute pyelonephritis with norfloxacin as compared with TMP-SMX for 10 days eliminated pathogens from urine in 12 of 14 patients (86%) receiving norfloxacin and in 9 of 10 patients (90%) receiving TMP-SMX (30) and, in a similar study, in 10 of 11 patients (91%) receiving norfloxacin and in 5 of 5 patients receiving TMP-SMX (34) (Table 4). For data combined from different centers, bacteriologic cure occurred in 30 of 32 patients (94%) treated with norfloxacin and in 29 of 32 patients (91%) treated with TMP-SMX (65). Ofloxacin therapy for 7 days was compared with TMP-SMX in several studies, with combined results showing bacteriologic cure in 182 of 223 patients (82%) receiving ofloxacin and in 161 of 202 patients (80%) receiving TMP-SMX (8). These few trials suggest the usefulness of fluoroquinolones for the therapy of acute uncomplicated pyelonephritis. Studies are needed to define the optimal dosage and duration of therapy. (iii) Complicated urinary tract infections. Definitions of complicated urinary tract infections have differed among studies but in general have included patients with structural or functional abnormalities of the urinary tract. In three comparative trials (13, 18, 45), pathogens were eliminated from the urine in 95 to 100% of patients treated with norfloxacin and in 75 to 100% of patients treated with comparative agents (Table 5). In a double-blind study (2), ciprofloxacin eliminated pathogens from urine in 18 of 22 patients (82%) in comparison with 12 of 23 patients (52%) for TMP-SMX (P = 0.035) 5 to 9 days after the completion of therapy; both treatment groups had similar eradication rates of 60 and 63% 4 to 6 weeks after therapy. In a large double-blind trial ofloxacin eliminated pathogens from 102 of 115 patients (89%) in comparison with pipemidic acid, an older quinolone analog, which 81 of 113 patients (72%) (P = 0.001) (39). In a nonblind trial, enoxacin had efficacy similar to that of TMP-SMX (16). Thus, in comparative trials, oral therapy with fluoroquinolones was similar or in

4 1658 MINIREVIEWS TABLE 5. Results of selected comparative studies of fluoroquinolones for the treatment of complicated urinary tract infections ReferD-ug Oral dose No. of N.(o Refer- Drg rlds ains bacterioence (mg x days)b patlents eaube logically 45 NFX 400 BID x (95) AMOX 250 TID x (75) 13 NFX 400 BID x (100) Parenteral agent 7-46c (88) 18 NFX 400 BID x lod (100) Parenteral agent 12' (%) 62 NFX 400 BID x (53) OFX 200 QD x (80) 68f NFX 400 BID x (88) NFX, placebo 400 BID x 84, (14) 57 CFX 100 BID (90) Mezlocillin 2,000 BID (74) 19 CFX 500 BID x (94) P-Lactams 10 3 (30) 2" CFX 250 BID x 7d (82) TMP-SMX 160/800 BID x 7d (52) 79 CFX 100 BID x (94) CFX 250 BID x (88) TMP-SMX 160/800 BID x (87) 41f CFX 250 BID x (63) OFX 100 BID x (63) 39f OFX 200 BID x (89) PIP 500 QID x (72) 17 OFX 200 BID x (100) TMP-SMX 160/800 BID x (88) 16 ENX 400 BID x (87) TMP-SMX 160/800 BID x (100) a NFX, Norfloxacin; CFX, ciprofloxacin; OFX, ofloxacin; ENX, enoxacin; AMOX, amoxicillin; PIP, pipemidic acid. b BID, Two times daily; TID, three times daily; QD, once daily; QID, four times daily. c Parenteral dose given for the indicated number of days. d Mean number of days. e Parenteral dose given for the indicated mean number of days. f Double-blind study. g The duration of therapy was not stated; ciprofloxacin and mezlocillin were administered intravenously. some instances superior in efficacy to oral therapy with the comparative agents. In an open study of therapy of urinary tract infections in renal transplant recipients, ofloxacin eradicated pathogens in 31 of 39 patients (79%) (76). ANTIMICROB. AGENTS CHEMOTHER. Prolonged therapy of complicated urinary tract infections with norfloxacin for 24 weeks was compared in a doubleblind fashion with therapy with norfloxacin for 12 weeks followed by 12 weeks of administration of placebo (68). During the second 12 weeks of the study, bacteriuria was suppressed in seven of eight patients (88%) receiving norfloxacin and in one of seven patients (14%) receiving placebo (P < 0.05). Thus, the fluoroquinolones may have efficacy as suppressive therapy, but with more prolonged use toxicities may be higher (37). Fluoroquinolones were directly compared with each other in two trials. In a double-blind study, ciprofloxacin and ofloxacin each eliminated pathogens in 19 of 30 patients (63%) (41). In a nonblind study, norfloxacin (400 mg) administered orally twice daily for 10 days eliminated pathogens in 8 of 15 patients (53%), while ofloxacin (200 mg) administered orally once daily for 10 days 12 of 15 patients (80%) (62). Fluoroquinolones have been efficacious in the treatment of infections caused by P. aeruginosa or multiply antibioticresistant bacteria. In a comparative study (18), pathogens were eliminated from urine in 51 of 51 patients treated with norfloxacin and in 43 of 45 patients (96%) treated with parenteral agents, with a cure of 17 of 17 patients infected with P. aeruginosa and treated with norfloxacin. In other open trials (14, 43), norfloxacin eradicated Pseudomonas spp. from 34 of 42 patients (81%), and ciprofloxacin infections caused predominantly by P. aeruginosa and other TMP-SMX-resistant pathogens in 143 of 184 patients (78%) (11, 15, 44, 58, 63). The emergence of bacterial resistance to nalidixic acid, in many instances with E. coli, has been problematic in certain settings, occurring in 6 to 26% of patients (reviewed in reference 81). The development of resistance to fluoroquinolones appears to be less common. Resistance occurred in 19 of 1,130 patients (1.7%) in 17 studies of complicated and uncomplicated infections treated with norfloxacin (80) and in 15 of 526 patients (2.9%) in 17 studies of infections treated with ciprofloxacin (82). Resistance appears to occur more often in patients with complicated urinary tract infections, particularly those caused by P. aeruginosa (11, 21, 44, 58, 82). As yet, there are no data indicating whether combinations of fluoroquinolones with other agents will diminish the frequency of the development of resistance in P. aeruginosa infections in predisposed patients with complicated urinary tract infections. TABLE 6. Results of studies on fluoroquinolones for the treatment of bacterial prostatitis Oral dose No. of patients No. (%) Follow-up Type of Reference Druga (mg x days)' evaluable bacteriologically (MO) prostatitis 64 NFX 400 BID x (92) 1 Chronic TMP-SMX 160/800 BID x (67) 1 Chronic 9 NFX 400 BID x (85) 1 Chronic 32 CFX 500 BID x (67) 3 P. aeruginosa 33 CFX 500 BID x 28 or (77) 1 78 CFX 500 BID x (54) 12 Chronic 31 OFX 200 BID x (79) OFX 200 BID x 60c (91) 7-12 Acute, chronic 72 OFX TID x (82) Acute, chronic 21 PFX 400 BIDd (65) 3 a NFX, Norfloxacin; CFX, ciprofloxacin; OFX, ofloxacin; PFX, pefloxacin. b BID, Two times daily; TID, three times daily. c Mean number of days. d The duration was not specified.

5 VOL. 33, 1989 Prostatitis. In a single comparative trial (64), treatment with norfloxacin for 4 to 6 weeks eliminated pathogens in 23 of 25 patients (92%) with chronic prostatitis, while therapy with TMP-SMX eliminated pathogens in 10 of 15 patients (67%) (P = 0.055), but the follow-up after the completion of therapy was only at 1 month (Table 6). In studies of ciprofloxacin administered for 1 or 3 months (32, 33), pathogens were eliminated in 10 of 15 patients (67%) and 20 of 26 patients (77%) 1 to 3 months after the completion of therapy. With a shorter duration of therapy (2 weeks), ciprofloxacin eradicated pathogens in only 7 of 13 patients (54%) with chronic prostatitis at follow-up at 1 year (78), with failures occurring in 3 patients infected with Enterococcus faecalis. In two open trials (31, 61), bacteriologic cure occurred in 11 of 14 patients (79%) and in 21 of 23 patients (91%) treated with ofloxacin for.40 days at follow-up at 3 to 13 months. 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