Cinoxacin A Review of its Pharmacological Properties and Therapeutic Efficacy in the Treatment of Urinary Tract Infections

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Abstract
Synopsis: Cinoxacin1 is a urinary antibacterial drug closely related structurally to nalidixic acid. It has a spectrum of in vitro antibacterial activity which qualitatively resembles that of the latter agent, covering most common Gram-negative pathogens, excluding Pseudomonas. In acute or recurrent urinary tract infections it has been shown to be at least as effective as nalidixic acid or co-trimoxazole, and in a few studies was as effective as amoxycillin or nitrofurantoin. Cinoxacin appears to be well tolerated and may have a low propensity to induce bacterial resistance during clinical use, although the latter needs further confirmation. Thus, cinoxacin is an effective alternative for treating urinary tract infections due to common Gram-negative pathogens, and its apparently low incidence of adverse effects may offer worthwhile advantages over the related compounds nalidixic and oxolinic acids. Its use as prophylactic therapy in patients with recurrent urinary tract infections is not yet well established, although this appears a worthwhile area for further study. Antibacterial Activity: Cinoxacin is closely related structurally to nalidixic and oxolinic acids, and its in vitro antibacterial spectrum qualitatively resembles that of these related compounds. Most Gram-negative urinary pathogens are susceptible to cinoxacin, including Escherichia coli, Proteus species (indole positive and negative), Klebsiella, Enterobacter, Serratia and Citrobacter, with the exception of Pseudomonas, most strains of which are insensitive to cinoxacin. Generally, most sensitive pathogens are inhibited in vitro at a cinoxacin concentration of 8 to 16 µg/ml or less. Many strains of E. coli, which are particularly susceptible, are inhibited at concentrations as low as 0.5 to 2 µg/ml. Anaerobic and Gram-positive bacteria are generally not sensitive to cinoxacin. Increasing the inoculum size of Gram-negative pathogens results in higher minimum inhibitory concentrations of cinoxacin, although the inoculum effect with cinoxacin may be less than that seen with nalidixic acid, especially in the presence of serum. The activity of cinoxacin is reduced only slightly in the presence of serum, compared with the more marked effects of serum on the activity of nalidixic acid. Increasing pH from 5 to 8 results in a 4- to 8-fold reduction in in vitro activity of cinoxacin, but in view of the high urinary concentration of cinoxacin which occurs in both acidic and alkaline urine it is unlikely that urinary pH is of major clinical importance in determining the response to cinoxacin therapy. In vitro studies involving transfer of bacterial cultures through increasing concentrations of cinoxacin have resulted in progressive increases in minimum inhibitory concentrations for the bacteria involved, as also occurred with nalidixic acid. However, the high urinary concentrations usually achieved with cinoxacin (see below) may tend to prevent the emergence of resistance in clinical use. Pharmacokinetic Studies: A mean peak plasma concentration of about 15 µg/ml occurs 1 to 3 hours after a 500mg dose of cinoxacin. When cinoxacin is given with food peak plasma concentrations are reduced by about 30%, but the total extent of absorption is not altered. Cinoxacin reaches potentially useful concentrations in prostate (30 to 60% of corresponding serum concentrates), renal (variable, but usually greater than serum concentrations) and bladder tissue (45 to 81% of serum concentrations). Cinoxacin is about 63% bound to protein in human serum. Its volume of distribution in healthy subjects or in patients with renal dysfunction is about 0.25 L/kg. Cinoxacin is excreted in the urine, with 60% of a dose appearing in the urine in unchanged form and 30 to 40% as inactive metabolites. Cinoxacin mean peak urinary concentrations of up to 700 µg/ml or higher may occur during administration of usual doses. The mean elimination half-life of cinoxacin in subjects with normal renal function is about 1 to 1.5 hours. As might be expected, elimination of cinoxacin is prolonged in patients with renal dysfunction, with an elimination half-life of 12 hours in patients with end-stage renal failure. However, even in moderate to severe renal failure, peak urinary concentrations of cinoxacin exceed the minimum inhibitory concentration for most susceptible Gram-negative pathogens. Therapeutic Trials: Cinoxacin has been studied in acute, uncomplicated as well as in complicated urinary tract infections. In open trials in simple or acute infections the bacteriological cure rate with cinoxacin (usually 7 to 14 days of treatment) was reported to be 80 to 100%. However, in many such studies the duration of follow-up was short. In those studies with longer follow-up periods the response rate was 72 to 98% after 4 to 6 weeks. A few comparative studies in patients with simple or acute urinary tract infections, usually conducted on a single-blind basis, showed cinoxacin 500mg twice daily to be at least as effective as nalidixic acid lg 4 times daily, with a trend for a higher bacteriological cure rate with cinoxacin in all such studies. Similarly, the same dose of cinoxacin tended to produce a higher bacteriological response (94 to 100%) than co-trimoxazole (trimethoprim-sulfamethoxazole 320/1600mg daily). In open trials in complicated urinary tract infections the bacteriological response rate with cinoxacin (usually 800 or 1000mg daily for 7 to 10 days) after a short follow-up period varied from 42 to 96%, but in most studies was about 50 to 65%. In a small number of comparative studies in this type of infection cinoxacin was at least as effective as usual doses of nalidixic acid, co-trimoxazole, nitrofurantoin or amoxycillin. Long term prophylactic administration of cinoxacin to prevent recurrent urinary tract infection has also been studied. Although results in an open study were encouraging, results of placebo controlled studies were somewhat divergent. However, such studies have demonstrated a low order of faecal and vaginal bacterial resistance during and after therapy with cinoxacin, and further controlled studies to clarify the role of cinoxacin when used in this way would seem justified. Side Effects: Cinoxacin is generally well tolerated, with an overall incidence of side effects of about 4%. In comparative studies the incidence of adverse effects with cinoxacin was usually lower than that with nalidixic acid. The most frequent adverse reaction to cinoxacin is gastrointestinal disturbance, occurring in about 3% of patients. Central nervous system reactions such as headache, dizziness or nervousness occur with an incidence of 1% or less. Hypersensitivity reactions involving the skin occur in about 1 to 3% of patients. Cinoxacin significantly decreases faecal and vaginal Enterobacteriaceae, and with longer term therapy there appears to be a relatively low incidence of induction of resistance in faecal E. coli, although this latter finding requires confirmation. Dosage and Administration: The usual adult dose of cinoxacin for treating urinary tract infection is 1g daily in 2 or 4 divided doses. In the presence of renal function impairment dosage reductions are recommended. The drug is not recommended for use in anuric patients, or in prepubertal children or during pregnancy.

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