Ciprofloxacin

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Abstract
Ciprofloxacin is one of a new generation of fluorinated quinolones structurally related to nalidixic acid. The primary mechanism of action of ciprofloxacin is inhibition of bacterial DNA gyrase. It is a broad spectrum antibacterial drug to which most Gram-negative bacteria are highly susceptible in vitro and many Gram-positive bacteria are susceptible or moderately susceptible. Unlike most broad spectrum antibacterial drugs, ciprofloxacin is effective after oral or intravenous administration. Ciprofloxacin has been most extensively studied following oral administration. It attains concentrations in most tissues and body fluids which are at least equivalent to the minimum inhibitory concentration designated as the breakpoint for bacterial susceptibility in vitro. The results of clinical trials with orally and intravenously administered ciprofloxacin have confirmed the potential for its use in a wide range of infections, which was suggested by its in vitro antibacterial and pharmacokinetic profiles. It has proven an effective treatment for many types of systemic infections as well as for both acute and chronic infections of the urinary tract. Ciprofloxacin generally appeared to be at least as effective as alternative orally administered antibacterial drugs in the indications in which they were compared, and in some indications, to parenterally administered antibacterial therapy. However, further studies are needed to fully clarify the comparative efficacy of ciprofloxacin and standard antibacterial therapies. Bacterial resistance to ciprofloxacin develops infrequently, both in vitro and clinically, except in the setting of pseudomonal respiratory tract infections in cystic fibrosis patients. The drug is also well tolerated. Thus, as an orally active, broad spectrum and potent antibacterial drug, ciprofloxacin offers a valuable alternative to broad spectrum parenterally administered antibacterial drugs for use in a wide range of clinical infections, including difficult infections due to multiresistant pathogens. Ciprofloxacin is a fluorinated quinolone, with the most potent in vitro antibacterial activity against most bacterial species of all the newer quinolones marketed to date. The primary mechanism of action of ciprofloxacin and other quinolones involves inhibition of bacterial DNA gyrase. Ciprofloxacin has an MIC90 of ⩽ 1 mg/L (indicating susceptibility) against all species of Enterobacteriaceae, except some species of Providencia. Acinetobacter species, Neisseria gonorrhoeae, Neisseria meningitidis, Branhamella catarrhalis and Haemophilus species (including β-lactamase negative and positive strains) were also highly susceptible to ciprofloxacin. Pseudomonas aeruginosa was susceptible (MIC90 range 0.12–1 mg/L), but ciprofloxacin was less active against other Pseudomonas species (MIC90 range 0.25–16 mg/L). Other Gram-negative organisms susceptible to ciprofloxacin include Campylobacter jejuni, Vibrio species and Legionella species, while Gardnerella vaginalis was only moderately susceptible. In general, against Gram-negative aerobes in vitro, ciprofloxacin has equivalent activity, or was more potent by 1 or 2 dilutions than ofloxacin, and was consistently more potent than other quinolones such as norfloxacin, enoxacin or pefloxacin. Staphylococcus species, such as S. epidermidis, S. saprophyticus and S. aureus (ineluding penicillin-resistant and methicillin-resistant strains) were susceptible to ciprofloxacin (MIC90 range 0.12–1 mg/L). Streptococcus species, including penicillin-resistant strains of S. pneumoniae, were moderately susceptible to ciprofloxacin (MIC90 range 0.5–6.3 mg/L). Among the marketed quinolones only ofloxacin has similar activity to ciprofloxacin in vitro against Gram-positive organisms. Among the non-quinolones reviewed only cefotaxime and mezlocillin show greater activity against non-enterococcal streptococci and only imipenem shows greater activity against S. aureus. Mycobacterium tuberculosis, Mycobacterium fortuitum, Mycobacterium intracellulare and Listeria monocytogenes were susceptible or moderately susceptible to ciprofloxacin, but other Mycobacterium species and Nocardia asteroides tended to be resistant (MIC90 range ⩾ 4 mg/L). Ciprofloxacin has a broad range of reported MIC90 values against Bacteroides species (0.06–32 mg/L); B. oralis and B. ureolyticus tended to be susceptible while B. fragilis tended to be resistant. Peptococcus species were moderately susceptible to ciprofloxacin, but Peptostreptococcus species and Clostridium species were resistant. Chlamydia trachomatis proved moderately susceptible (MIC range 0.5–2 mg/L). The antibacterial activity of ciprofloxacin is influenced little, if at all, by inoculum size, growth medium or the presence of serum. However, both bacteriostatic and bactericidal activities (which are achieved at similar concentrations for ciprofloxacin) are reduced by magnesium ions and acidity, which may account for the drug’s reduced activity in urine. Mutants having reduced susceptibility to ciprofloxacin emerge at a relatively low incidence in vitro. Moreover, strains which become less susceptible to ciprofloxacin rarely become resistant (i.e. MIC values generally remain < 4 mg/L). Cross-resistance with nalidixic acid or other quinolones occurs, but it is rare with non-quinolone antibacterial drugs. The mechanisms of resistance to quinolones are unclear. Plasmid-mediated resistance does not occur, but chromosomal mutation influencing DNA gyrase and/or the cell membrane may confer resistance. Ciprofloxacin has little, if any, effect on chemotaxis of — and may increase phagocytosis and killing by — polymorphonuclear leucocytes. At concentrations up to 125 mg/L it has no effect on human mitogen-stimulated mononuclear cell proliferation. In the gastrointestinal tract ciprofloxacin markedly reduces or eradicates Enterobacteriaceae, with a less dramatic effect against staphylococci and enterococci and little effect on the anaerobic microflora. There is little evidence of overgrowth or superinfection. Preclinical toxicology studies, including ophthalmological examination, in various animal species reveal no significant evidence of toxicity. In young rats and dogs ciprofloxacin does cause articular damage, but the clinical implications, if any, are unknown. After oral administration of single doses (50 to l000mg) of ciprofloxacin, peak serum concentrations of 0.28 to 5.92 mg/L were reached within 0.5 to 2 hours. Mean peak concentrations increased in proportion to the dose within the normal therapeutic range. Multiple dose administration for up to 8 days in healthy volunteers, either orally (500mg bid) or intravenously (200mg bid), did not produce significant drug accumulation. Food had no significant effect on the pharmacokinetics of ciprofloxacin, except to delay absorption, but simultaneous administration of antacids containing magnesium hydroxide and/or aluminium hydroxide with ciprofloxacin reduced the bioavailability of the latter. Following intravenous administration, the plasma concentration profile of ciprofloxacin is best characterised by a 3-compartment open model. The absolute bioavailability of oral ciprofloxacin averages between 69 and 85%. The apparent volume of distribution of ciprofloxacin was calculated to be approximately 2 to 3 L/kg. The volume of the central compartment was between 0.16 and 0.63 L/kg, which approximately represents the total volume of extracellular water. The tissue concentrations achieved are at least as high as the serum concentrations for most tissues. Ciprofloxacin was approximately 16 to 40% bound to plasma proteins. After administration of a single oral dose (259mg) of 14C-labelled ciprofloxacin to healthy volunteers, approximately 94% of the dose was recovered in urine and faeces over 5 days, with most radioactivity being recovered in the urine (55.4%). This study demonstrates that unchanged ciprofloxacin is the major moiety in both urine (45%) and faeces (25%). After a single intravenous dose (107mg) of 14C-labelled ciprofloxacin to healthy volunteers, approximately 89% of the dose was recovered in urine and faeces over 5 days with about 75% of radioactivity being recovered in the urine. As with oral dosage, unchanged ciprofloxacin is also the major moiety in urine (62%) and faeces (15%). Small amounts of 4 metabolites are present in urine and faeces, all with some antibacterial activity, but less than that of ciprofloxacin. Total serum clearance of ciprofloxacin in healthy volunteers ranged from 23 to 43 L/h/1.73m2. Renal clearance accounts for approximately 60 to 70% of total serum clearance, and was approximately 3 times higher than creatinine clearance. Active tubular secretion of ciprofloxacin is confirmed by the observation that coadministration of probenecid decreases the ciprofloxacin renal clearance. The elimination half-life of ciprofloxacin after single and multiple doses ranged from 3.4 to 6.9 hours following oral administration (50 to 1000mg) and from 3 to 4.4 hours following intravenous administration (50 to 200mg). The pharmacokinetics of ciprofloxacin are altered in patients with renal dysfunction. After single doses, peak serum concentration, area under the serum concentration-time curve (AUC) and elimination half-life are substantially increased depending on the degree of renal impairment. Thus, dosage adjustment may be required in such subjects. Ciprofloxacin is poorly removed from the body by haemodialysis. The pharmacokinetics of ciprofloxacin are generally not affected to a clinically significant extent by age or the presence of cystic fibrosis. However, serum concentrations tend to be higher in elderly subjects, possibly due to diminished renal function or changes in volume of distribution. With its broad spectrum of antibacterial activity and widespread distribution to most tissues and body fluids, ciprofloxacin should have potential therapeutic application in many types of infection. Cumulated European and US clinical trial data revealed that ciprofloxacin (in most cases administered orally in a daily dosage of 500 to 1500mg divided into two 12-hourly doses, for 7 to 14 days) was clinically effective in greater than 88% of patients with infections of the urinary tract, respiratory tract, skin and skin structure, bones or joints, gastrointestinal tract, blood and gynaecological organs. In Japanese patients (most of whom received 200mg of oral ciprofloxacin 3 times daily) cumulated clinical trial data revealed clinical efficacy rates of greater than 80% in most infection types and of approximately 75% in lower respiratory tract infections, and ear, nose and throat infections. High rates of clinical efficacy were achieved in infections due to most Gram-positive and Gram-negative pathogens, including multiresistant but ciprofloxacinsusceptible nosocomial pathogens. However, only 43.2% of patients in Japan with infections of various sites due to P. aeruginosa responded versus approximately 75% of non-Japanese patients, a difference which may be a consequence of the lower dosages used in Japan as compared with the rest of the world. Bacterial eradication rates for most species of pathogens reported in data cumulated worldwide are generally 75% or greater, with the majority being 85% or greater. P. aeruginosa is again an exception in the Japanese data, being eradicated from only 22.7% of infections. As with many broad spectrum antibacterial drugs, superinfection due to Candida species or bacterial pathogens occurs with ciprofloxacin, in some cases requiring additional antimicrobial therapy. Development of resistance or reduced susceptibility to ciprofloxacin generally occurs infrequently. However, transitory, or in a few cases persistent, resistance to P. aeruginosa is commonly encountered among cystic fibrosis patients. In addition, among debilitated patients or in those suffering chronic and/or complicated infections, emergence of reisistance to P. aeruginosa or other bacteria occurs occasionally and has resulted in clinical treatment failures. Cross-resistance has been reported rarely in Pseudomonas species between ciprofloxacin and aminoglycosides, ureidopenicillins and cephalosporins, and cross-resistance has also been reported between ciprofloxacin and aminoglycosides in S. aureus. Several small randomised studies have compared the clinical efficacy of ciprofloxacin and alternative antibacterial drugs in the treatment of urinary tract infections (UTI). While none of these trials provided statistical analyses of the results, oral ciprofloxacin appeared to be similar in clinical and bacteriological efficacy to orally administered cotrimoxazole (trimethoprim/sulphamethoxazole) [complicated and uncomplicated infections], trimethoprim (uncomplicated infections), norfloxacin (complicated infections) and cinoxacin (uncomplicated infections). Intravenous ciprofloxacin appeared to be similar in clinical and bacteriological efficacy to intravenous mezlocillin (complicated infections). In addition, in a large Japanese study, oral ciprofloxacin 200mg 3 times daily was reported to be statistically superior to oral norfloxacin 200mg 4 times daily in both clinical efficacy and bacterial eradication rates in the treatment of complicated UTI. Of note, in the above studies the incidence of side effects was lower with ciprofloxacin than with co-trimoxazole. Results of several comparative and non-comparative studies indicated that single oral doses of ciprofloxacin 100 to 2000mg (usually 100 to 500mg) produced 100% bacteriological cure rates in gonococcal urethritis. Comparative rates for single doses of ampicillin 2 to 3.5g plus probenecid 1g were 90 to 92%. Ciprofloxacin was consistently effective against penicillinase-producing strains of N. gonorrhoeae, and was often effective in curing oropharyngeal or rectal infections. In contrast, ciprofloxacin lacks a reliable degree of clinical efficacy in non-gonococcal urethritis due to Chlamydia trachomatis or Ureaplasma urealyticum. Ciprofloxacin appears to be similar to or, in the studies which analysed the results statistically, was not significantly different in clinical efficacy from doxycycline, cephalexin, amoxycillin, bacampicillin or co-trimoxazole in various lower respiratory tract infections. Randomised comparative studies showed oral ciprofloxacin to be statistically (p < 0.001) superior to cefaclor in clinical efficacy in the treatment of infectious exacerbations of chronic bronchitis and other chronic lung diseases, and statistically (p < 0.05) superior to ampicillin in clinical efficacy in outpatients with acute bronchitis. Several randomised comparative studies documented the efficacy of oral ciprofloxacin in young adult patients with cystic fibrosis who were suffering from lower respiratory tract infections due, in most instances, to colonising P. aeruginosa. Statistical analyses in 2 separate studies demonstrated that ciprofloxacin 500 or 750mg twice daily was generally no different in clinical efficacy to the combination of intravenous azlocillin plus an aminoglycoside, although in one of these two studies oral ciprofloxacin produced a superior improvement in 2 parameters of lung function (p < 0.05). Two crossover studies showed no statistically significant difference in clinical efficacy between twice daily oral administration of ciprofloxacin (500 or 750mg) and ofloxacin (400mg). Because of the potential for the development of resistant P. aeruginosa, ciprofloxacin is not recommended for long term prophylaxis or multiple sequential courses of treatment in recurrent lung infections in cystic fibrosis patients. Three double-blind randomised studies revealed oral ciprofloxacin 750mg twice daily to be not statistically different in clinical efficacy from intravenous cefotaxime 2g 3 times daily in skin and soft tissue infections. A fourth study, involving mild to moderate infections, reported significantly (p < 0.05) more failures among the cefotaxime-treated patients (21% vs 3%). Several case studies reported the successful treatment with ciprofloxacin of systemic Salmonella infections in immunocompromised patients. Encouraging preliminary results were also noted in other immunocompromised patients with fever or documented infection. Prophylaxis of remission induction therapy with oral ciprofloxacin 500mg twice daily resulted in a significantly (p < 0.05) lower infection rate (18%) than prophylaxis with the combination of co-trimoxazole 160/800mg plus colistin 200mg orally 3 times daily (50%). However, results of both prophylaxis and treatment in immunocompromised patients suggest that streptococci and staphylococci may not be adequately inhibited by ciprofloxacin alone. Treatment with ciprofloxacin eliminates nasopharyngeal carriage of Neisseria meningitidis and gastrointestinal carriage of Salmonella species and nosocomial Klebsiella species. Significant adverse effects associated with ciprofloxacin therapy are uncommon. The overall worldwide incidence of side effects in patients treated with the drug was reported to be from 5 to 10%, and therapy had to be discontinued in less than 2% of patients. Gastrointestinal symptoms, mainly nausea, vomiting, abdominal pain, diarrhoea, and anorexia, were reported most frequently (in up to 10% of patients receiving higher oral dosages), followed by central nervous system events such as anxiety, nervousness, insommia, euphoria, tremor and, very rarely, seizures and hallucinations (1 to 4%), and hypersensitivity reactions of a dermatological nature (1%). Other untoward effects that have been reported rarely (incidence less than 1%) include eye disorders and chest pain. Mild, transient alterations in laboratory values were sometimes observed [eosinophilia, elevated serum creatinine, blood urea nitrogen, AST (SGOT) and ALT (SGPT)], although their clinical significance is unknown. Isolated cases of haematuria, interstitial nephritis and arthropathy have also been reported....

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