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Abstract

Urinary tract infections are common, especially among women. A number of agents are available for the treatment of urinary tract infections but emerging resistance to commonly used first-line therapies has impacted the selection of empirical therapy. Ciprofloxacin was the first member of the fluoroquinolone class of antibiotics to be widely available and is effective for the management of urinary tract infections. An extended-release formulation has recently become available that allows once-daily dosing, which may improve patient adherence and convenience. Clinical trials have demonstrated that the extended-release formulation is as effective as the standard formulation in the management of acute uncomplicated cystitis, complicated urinary tract infections and acute uncomplicated pyelonephritis. The pharmacokinetics of the extended-release formulation may offer potential advantages in terms of microbial eradication and clinical response; however, this has yet to be demonstrated in clinical trials. In the USA and western Europe, overall rates of quinolone resistance among common uropathogens have remained low; however, reports of increasing resistance from certain geographical areas are of great concern. Risk factors for resistance are currently poorly defined.

Keywords

ciprofloxacin cystitis extended-release ciprofloxacin pyelonephritis urinary tract infection

Urinary tract infection (UTI) is a common clinical entity, especially among women. It is estimated that by the age of 24 years, a third of women will have had a least one episode of UTI, while 50% of women will have a least one UTI in their lifetime, and these infections account for substantial costs [1,2]. In women, most infections are confined to the bladder (cystitis); however, ascending infection of the kidney (pyelonephritis) also occurs. The true incidence of pyelonephritis is poorly defined since many surveys of ambulatory practice do not report pyelonephritis separately from all UTIs. A survey of the largest in patient database in the USA estimated the incidence of pyelonephritis requiring hospitalization to be 11.7 cases/10,000 population among women [2]. It appears that women younger than 50 years of age with pyelonephritis are infrequently hospitalized [3]. UTIs are the most common healthcare-associated infections encountered in hospitalized patients, mainly related to the use of indwelling catheters.

UTIs that occur in otherwise healthy women are termed uncomplicated, while those that occur in pregnant women, diabetics, women who are immunosuppressed, or those with urinary catheters, kidney stones or any underlying functional or anatomical abnormality of the urinary tract are termed complicated infections.

The microbiology of community-acquired UTI has remained quite predictable, with most infections caused by Escherichia coli. What has changed is the prevalence of resistance among uropathogenic E. coli to first-line agents used in the management of UTI, especially trimethoprim–sulfamethoxazole. The prevalence of resistance varies considerably between different geographical regions. While some have questioned the relevance of in vitro resistance to clinical outcomes, it is now clear that resistance is associated with increased clinical and microbiological failure in the treatment of cystitis and pyelonephritis [4 –6]. As treatment decisions, especially for acute uncomplicated cystitis (AUC), are frequently made on an empirical basis, increasing resistance has had an impact on the selection of antimicrobial therapy for the treatment of UTI, although accurate data regarding the prevalence of resistance for a particular geographic region are frequently lacking.

Guidelines for the management of UTI have been developed by the Infectious Diseases Society of America (IDSA) [7] and the European Association of Urology (EAU) [8]. The IDSA guidelines have not been updated since 1999; the EAU guidelines were published in 2001.

Overview of the market

In addition to ciprofloxacin, a variety of fluoroquinolones are currently approved for the treatment of UTIs, including norfloxacin, ofloxacin, levofloxacin, gatifloxacin and lomefloxacin. In addition, an extended-release (ER) formulation of ciprofloxacin is now available. Of these agents, ciprofloxacin, levofloxacin and gatifloxacin are available in both intravenous and oral formulations. Overall, there is no major difference among these agents in terms of efficacy in the treatment of UTI. Norfloxacin, ciprofloxacin and ofloxacin are dosed twice daily while levofloxacin, gatifloxacin, lomefloxacin and the ER formulation of ciprofloxacin are dosed once daily. A number of fluoroquinolones, including ciprofloxacin, have been shown to be effective in 3-day regimens for the treatment of AUC in women; several trials have suggested that single-dose regimens of fluoroquinolones are effective in the treatment of AUC; however, these regimens are not as effective as 3-day regimens [9]. A single dose of gatifloxacin has been shown to be as effective as 3-day regimens of gatifloxacin or ciprofloxacin for AUC, and this agent is the only fluoroquinolone approved by the US FDA as single-dose therapy for the treatment of AUC [10]. While the overall efficacy of various agents may not differ, agents that can be dosed once daily and those that allow the use of shorter courses of therapy offer potential advantages in terms of patient adherence and convenience.

Clinicians must be aware that the fluoroquinolone moxifloxacin, which has expanded activity against Gram-positive pathogens that are important in respiratory tract infections, achieves much lower levels in the urine than other available fluoroquinolones and should not be used for the treatment of UTI.

It should be noted that several fluoroquinolones, including trovafloxacin, sparfloxacin and grepafloxacin, were removed from the market after approval due to rare but very severe toxicities that were not recognized during preapproval clinical trials.

Other agents available for the treatment of cystitis include trimethoprim–sulfamethoxazole, nitrofurantoin and fosfomycin (a single-dose formulation used only for the treatment of AUC). In addition to the fluoroquinolones, a variety of antimicrobials can be used for the treatment of pyelonephritis, including trimethoprim–sulfamethoxazole, aminoglycosides, third-generation cephalosporins and carbapenems. Despite in vitro activity against many uropathogens and some data from clinical trials suggesting efficacy, first- and second-generation cephalosporins have been associated with clinical failures and their use is not generally recommended [9,11].

Introduction to ciprofloxacin

Ciprofloxacin was the first member of the fluoroquinolone class to become widely available and has been in clinical use for almost two decades. This agent has excellent activity against the pathogens that commonly cause both community-acquired and healthcare-associated UTIs, although emerging resistance to fluoroquinolones among uropathogens is of great concern. The fluoroquinolones inhibit bacterial DNA synthesis through the inhibition of two enzymes, DNA gyrase and topoisomerase IV, and promote the cleavage of DNA in the enzyme–DNA complex. In addition to UTIs, ciprofloxacin has demonstrated efficacy in the treatment of sexually transmitted diseases, gastrointestinal infections, skin and soft-tissue infections, and bone and joint infections [12]. Ciprofloxacin may be utilized for the treatment of some healthcare-associated lower respiratory tract infections, but due to its relatively poor activity compared with other fluoroquinolones against Streptococcus pneumoniae, its use in the treatment of community-acquired infections of the respiratory tract is no longer recommended. This article will focus on data regarding the use of ciprofloxacin in the management of UTIs, with an emphasis on data for the more recently available ER formulation.

Chemistry

All currently available quinolones have a dual ring structure with a nitrogen at position 1 and a carbonyl group at position 4; a carboxyl group is attached to the carbon at the 3 position of the first ring. The chemical structure of ciprofloxacin (1,4-dihydro-1-cyclopropyl-6-fluoro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid) is shown in Figure 1. The chemical formula of ciprofloxacin is C₁₇H₁₈FN₃O₃ and it has a molecular weight of 331.345.

Figure 1.

Ciprofloxacin.

The ER formulation of ciprofloxacin is a bilayer matrix consisting of a salt of ciprofloxacin and the ciprofloxacin base.

Pharmacodynamics, pharmacokinetics & metabolism

Like all fluoroquinolones, the bactericidal activity of ciprofloxacin is concentration dependent. Owing to this concentration-dependent killing, important pharmacodynamic parameters in the evaluation of the fluoroquinolones include the ratio of the area under the 24 h serum concentration–time curve to the minimum inhibitory concentration (MIC) for the pathogen, as well as the ratio of the maximal serum concentration (C_max) to the MIC. In addition, it has been suggested that achieving targeted area under the curve: MIC and C_max:MIC values may help prevent the emergence of bacterial resistance to the fluoroquinolones [13].

Ciprofloxacin is rapidly absorbed after oral administration, achieving peak serum concentrations approximately 1–2 h after dosing. The bioavailability of ciprofloxacin is 70%; newer members of the fluoroquinolone class have higher bioavailability. The serum elimination half-life is approximately 4 h. The area under the curve for the 250 and 500 mg doses are 4.8 and 11.6 μg/h/ml, respectively. Ciprofloxacin is widely distributed throughout the body, achieving high concentrations in the kidney and the urine. Approximately 50% of an orally administered dose is excreted as unchanged drug in the urine. Four metabolites with antimicrobial activity less than that of the parent compound have been recovered from the urine and account for 15% of the drug's elimination; 1–2% is recovered from the bile in the form of metabolites and 20–30% is recovered from the feces. Dose adjustment is required for patients with impaired renal function.

Oral administration of the ER formulation results in the immediate release of 35% of the dose; the remaining 65% of the dose is released within 3 h. The area under the curve values of ER ciprofloxacin are equivalent to those achieved with the comparable total dose of the standard compound, while the maximum serum concentrations achieved by the ER formulation are 150–160% higher [14].

In addition, the ER formulation has been demonstrated to have lower absorption variability than the standard dosing formulation, leading to lower variation in the peak serum concentrations of the drug [13]. In vitro pharmacokinetic/pharmacodynamic modeling studies have suggested that the higher maximum serum concentrations achieved with the ER formulation may result in a more rapid and greater bactericidal activity against common uropathogens, leading some authors to suggest that the pharmacokinetic advantages of the ER formulation could potentially translate into improved bacteriological activity and clinical outcomes [15].

The distribution, metabolism and elimination of the ER preparation are similar to those of the standard formulation. It is important that patients be instructed that the ER formulation cannot be split, crushed or chewed. A summary of the pharmacokinetics of the two formulations is shown in Box 1.

Clinical efficacy

Ciprofloxacin at a dose of 250 mg twice daily for 3 days has been established to be a highly effective therapy for AUC. This 3-day regimen is comparable to 7-day regimens of ciprofloxacin and 3-day regimens of ofloxacin, as well as 3-and 7-day regimens of trimethoprim–sulfamethoxazole and 7-day regimens of nitrofurantoin [16,17]. Although studies of single-dose regimens of ciprofloxacin have suggested efficacy [18], there is concern that these regimens are not as effective as 3-day regimens and many experts discourage their use [9]. Due to the higher cost of the fluoroquinolones (although the availability of generic formulations of ciprofloxacin should lessen this cost differential) and concerns that the use of broad-spectrum antibiotic therapy for this common infection may lead to increasing resistance, many experts continue to recommend trimethoprim–sulfamethoxazole as first-line therapy for AUC, with fluoroquinolones reserved for those patients with risk factors for a trimethoprim–sulfamethoxazole-resistant pathogen or sulfa allergy [4,7,9]. The IDSA guidelines recommend that trimethoprim–sulfamethoxazole be avoided in geographical areas where the prevalence of resistance among E. coli to this agent exceeds 10–20%; however, most clinicians do not have access to meaningful local resistance data. Fosfomycin single-dose therapy is an alternative, although this agent is expensive and there are questions regarding its efficacy compared with other first-line agents for the treatment of AUC [9]. Nitrofurantoin remains highly effective and very little resistance to this agent is reported; however, a 7-day course of therapy must be used.

Box 1.

Main pharmacokinetic characteristics of ciprofloxacin.

Standard formulation

Rapid absorption with peak concentrations approximately 1–2 h after dosing

Bioavailability 70%

Half-life approximately 4 h; area under the curve for 250 and 500 mg doses 4.8 and 11.6 (μg/hr/ml, respectively

A total of 50% of dose excreted unchanged in the urine; 15% of elimination in the form of metabolites excreted in the urine, 1–2% recovered from bile and 20–30% from feces

May increase serum levels of theophylline, reduce clearance of caffeine, enhance the anticoagulant effect of warfarin and increase plasma levels of methotrexate

Cannot be administered with products containing multivalent cations

Extended-release formulation

A total of 35% of dose released immediately after oral administration; 65% of dose released within 3 h; lower absorption variability than the standard formulation

Maximum serum concentrations 150–160% higher than standard formulation; equivalent area under the curve values

Distribution, metabolism, elimination and potential drug interactions similar to the standard formulation

The ER formulation of ciprofloxacin (500 mg once daily for 3 days) has been shown to be comparable to 3-day regimens of the standard formulation for the treatment of AUC [19,20]. The ER formulation was associated with a reduced incidence of nausea and diarrhea in one clinical trial [20] and it has been suggested that the pharmacokinetic advantages of the drug could improve clinical outcomes; however, this is yet to be demonstrated in clinical trials. Once-daily dosing offers convenience and may improve patient adherence but these advantages must be weighed against the increased cost of the ER formulation.

Ciprofloxacin is also an option for the treatment of complicated cystitis in women. It should be emphasized that the drug should not be used in pregnancy. The ER formulation was demonstrated to be as effective as the standard formulation in a study of men and women with complicated UTI [21].

Very few randomized, controlled trials have specifically addressed antimicrobial therapy for acute pyelonephritis (APN). Although a number of fluoroquinolones are approved for the treatment of APN, most registration trials include a smaller number of patients with APN along with larger numbers of men and women with complicated UTI. Although 14 days of therapy has traditionally been recommended for APN, Talan and colleagues demonstrated that a 7-day course of ciprofloxacin was associated with higher clinical and bacteriological cure rates compared with a 14-day course of trimethoprim–sulfamethoxazole [6]. The higher failure rates of trimethoprim–sulfamethoxazole were due mainly to the high prevalence of resistance to this agent among the causative uropathogens. Many experts recommend fluoroquinolones as the first-line empiric therapy for the outpatient management of APN [9,22]; the ER formulation of ciprofloxacin (1000 mg once daily) has been shown to be as effective as the standard formulation for the management of this infection [21]. A variety of parenteral agents can be used for the management of hospitalized patients with APN. At the author's institution, the use of third-generation cephalosporins or aminoglycosides is encouraged rather than fluoroquinolones due to concerns regarding the selection of resistance in the hospital setting. Broad-spectrum β-lactams, fluoroquinolones and carbapenems should be reserved for patients in whom there is a special concern regarding the possibility of a multi-drug-resistant pathogen. Once the patient responds clinically, oral therapy can be chosen on the basis of susceptibility results from a urine culture. A summary of key published studies comparing ER ciprofloxacin with standard ciprofloxacin for the treatment of UTI is shown in Table 1.

Table 1.

Summary of key published studies comparing ER ciprofloxacin with standard ciprofloxacin for the treatment of UTI.

N	Treatment	Summary of efficacy results	Ref.
891	Ciprofloxacin ER 500 mg once daily vs ciprofloxacin 250 mg twice daily for 3-day therapy of AUC	Clinical cure 95.5% in the ciprofloxacin ER group vs 92.7% in the ciprofloxacin group (95% CI: −1.6–7.1); bacteriological cure 94.5 vs 93.7% (95% CI: −3.5–5.1)	[19]
1035	Ciprofloxacin ER 1000 mg once daily vs ciprofloxacin 500 mg twice daily for 7–14 days for the therapy of complicated UTI and uncomplicated APN	Clinical cure in 97% in the ciprofloxacin ER group vs 94% in the ciprofloxacin group (95% CI: −1.2–6.9); bacteriological cure 89 vs 85% (95% CI: −2.4–10.3)	[21]
1037	Ciprofloxacin ER 500 mg once daily vs ciprofloxacin 250 mg twice daily for 3-day therapy of AUC	Clinical cure 85.7% in the ciprofloxacin ER group vs 86.1% in the ciprofloxacin group (95% CI: −6.4–5.6); bacteriological cure 93.4 vs 89.6% (95% CI: −0.99–8.6)	[20]

APN: Acute pyelonephritis; AUC: Acute uncomplicated cystitis; CI: Confidence interval; ER: Extended release; UTI: Urinary tract infection.

Safety & tolerability

The most frequent adverse events reported with fluoroquinolone use include gastrointestinal symptoms (e.g., anorexia, nausea, vomiting and, less commonly, diarrhea), symptoms referable to the CNS (e.g., mild headache, dizziness and insomnia) and skin reactions including phototoxicity. The relative frequencies of these adverse events are 3–17, 0.9–11 and 0.4–2.8%, respectively [12]. The incidence of phototoxicity with ciprofloxacin, ofloxacin and levofloxacin is similar and lower than the incidence with lomefloxacin. In treatment studies of UTI, ciprofloxacin has generally shown similar safety and tolerability to comparator agents; in a study comparing 7 days of ciprofloxacin with 14 days of trimethoprim–sulfamethoxazole for the treatment of APN, lower rates of gastrointestinal and CNS events were observed in the ciprofloxacin group [6]. Studies of the ER formulation have demonstrated safety and tolerability that is comparable to the standard formulation [19 –21]. In one study, the ER formulation was associated with a reduced incidence of nausea and diarrhea [20].

Coadministration of fluoroquinolones with products containing multivalent cations markedly reduces the bioavailability of the antibiotic. These products include magnesium- and aluminum-containing antacids, sucralfate, and supplements containing calcium, iron or zinc. Ciprofloxacin can increase serum levels of theophylline and reduce the clearance of caffeine. In addition, ciprofloxacin may enhance the anticoagulant effect of warfarin and increase plasma levels of methotrexate. Hypoglycemia has been reported in patients taking ciprofloxacin in combination with oral sulfonylureas, and high doses of fluoroquinolones in combination with nonsteroidal anti-inflammatory agents have been reported to precipitate seizures [12].

The safety of fluoroquinolones in pregnant women has not been clearly established and they are classed as pregnancy category C in the USA [12]. These agents are excreted in breast milk and are not recommended for use in women who are breastfeeding.

Owing to concerns regarding the potential for cartilage toxicity in children based on data from animal models, routine pediatric use has not been advised; however, for certain indications the potential benefits of therapy may outweigh the potential risks [12].

Resistance

As discussed above, the increasing prevalence of resistance among the most common uropathogen, E. coli, has had a major impact on the selection of antimicrobials for the treatment of UTI. A recent study of 1142 E. coli urinary tract isolates from men and women in various geographical regions in the USA and Canada determined the prevalence of resistance to antimicrobials commonly used in the management of UTI [23]. The results are summarized in Table 2. One limitation of this study that is common to many previously published studies on the prevalence of resistance is that isolates were obtained by passive surveillance and could represent symptomatic infections or asymptomatic bacteriuria. Since culture of the urine in women with AUC is not recommended, these studies may overestimate the true prevalence of resistance in this population. The ECO-SENS study is a prospective study of the prevalence of resistance among uropathogens in women with acute cystitis in 16 European countries and Canada; the results are also summarized in Table 2 [24]. It should be noted that, although the overall prevalence of resistance to ciprofloxacin in this study was low, resistance rates as high as 14.7% have been reported from Spain [25] and as high as 36% from Greece [26].

Table 2.

Resistance among uropathogenic Escherichia coli to selected antimicrobials.

Study	Prevalence of resistance (%)				Ref.
	Trimethoprim–sulfamethoxazole	Nitrofurantoin	Ciprofloxacin	Fosfomycin
NAUTICA (outpatient isolates from men and women; passive surveillance; disparate geographical areas of USA and Canada)	21.3	1.1	5.5	Not tested	[23]
ECO-SENS (prospective surveillance study of women aged 18–65 years with uncomplicated UTI in 16 European countries and Canada)	14.1	1.2	2.3	0.7	[24]

NAUTICA: North American Urinary Tract Infection Surveillance Study; UTI: Urinary tract infection.

Executive summary

Introduction

Ciprofloxacin is a member of the fluoroquinolone class of antimicrobials.

It has excellent activity against commonly isolated uropathogens and it inhibits bacterial DNA synthesis through the inhibition of DNA gyrase and topoisomerase IV.

In addition to the treatment of urinary tract infections (UTIs), ciprofloxacin has demonstrated efficacy in the treatment of sexually transmitted diseases, gastrointestinal infections, skin and soft-tissue infections, and bone and joint infections.

Although increasing resistance to ciprofloxacin among uropathogenic Escherichia coli has been reported from certain geographical areas, the overall prevalence of resistance in North America and Europe remains low.

In addition to the standard formulation of ciprofloxacin, an extended-release formulation that can be dosed once daily has recently become available.

Pharmacokinetic properties

Standard formulation

Rapid absorption with peak concentrations approximately 1–2 h after dosing; bioavailability is 70%.

Its half-life is approximately 4 h; area under the curve for 250 and 500 mg doses are 4.8 and 11.6 μg/h/ml, respectively.

A total of 50% of the dose is excreted unchanged in the urine; 15% of elimination is in the form of metabolites excreted in the urine; 1–2% is recovered from bile and 20–30% from feces.

Extended-release formulation

A total of 35% of the dose is released immediately after oral administration; 65% of the dose is released within 3 h; it has lower absorption variability than the standard formulation.

Maximum serum concentrations are 1 50–160% higher than the standard formulation, with equivalent area under the curve values.

Distribution, metabolism and elimination are similar to the oral formulation.

Clinical efficacy

A 3-day course of ciprofloxacin has been shown to be as effective as 3-day regimens of trimethoprim-sulfamethoxazole and ofloxacin, and 7-day regimens of ciprofloxacin, nitrofurantoin and trimethoprim-sulfamethoxazole for the treatment of acute uncomplicated cystitis.

A 7-day treatment course of ciprofloxacin was found to have higher clinical and bacteriological cure rates than a 14-day course of trimethoprim-sulfamethoxazole in women with acute uncomplicated pyelonephritis; most trimethoprim-sulfamethoxazole failures in this study could be attributed to the higher prevalence of trimethoprim-sulfamethoxazole resistance among the causative uropathogens.

The extended-release formulation of ciprofloxacin has shown similar clinical and microbiological efficacy when compared with the standard formulation in the treatment of acute uncomplicated cystitis, complicated UTIs and pyelonephritis.

Safety & tolerability

The safety and tolerability of ciprofloxacin are similar to other members of the fluoroquinolone class as well as other agents used in the management of UTIs.

The most frequently reported adverse events are gastrointestinal symptoms (3–17%), CNS symptoms (0.9–11%) and allergic and skin reactions (0.4–2.8%).

Lower rates of gastrointestinal and CNS events were observed in patients treated with 7 days of ciprofloxacin as compared with those treated for 14 days with trimethoprim-sulfamethoxazole for acute uncomplicated pyelonephritis.

Studies of the extended-release formulation have demonstrated similar safety and tolerability; in one study, the extended-release formulation was associated with a reduced incidence of nausea and diarrhea.

Drug interactions

Ciprofloxacin may increase serum levels of theophylline, reduce the clearance of caffeine, enhance the anticoagulant effect of warfarin and increase plasma levels of methotrexate.

Dosage & administration

Oral ciprofloxacin is dosed at 250 mg twice daily for 3 days for the treatment of acute uncomplicated cystitis and 250 mg for 7–10 days for complicated UTI; 500 mg twice daily for 7–14 days is recommended for the treatment of acute uncomplicated pyelonephritis.

200–400 mg every 12 h of the parenteral formulation is recommended for the management of pyelonephritis.

The extended-release formulation is given at a dose of 500 mg once daily for 3 days for the treatment of acute uncomplicated cystitis and 1000 mg once daily for the management of complicated UTI and acute uncomplicated pyelonephritis.

Coadministration with products containing multivalent cations, including magnesium- and aluminum-containing antacids, sucralfate, and supplements containing calcium, iron or zinc, markedly reduce the bioavailability of ciprofloxacin and should be avoided.

Risk factors for UTI with a ciprofloxacin-resistant pathogen are currently poorly defined. Recent fluoroquinolone use, recurrent UTI, complicated UTI and older age have been suggested [27,28]; however, further research regarding the epidemiology of fluoroquinolone-resistant uropathogens is clearly necessary.

Regulatory affairs

Ciprofloxacin is approved for the treatment of a variety of bacterial infections, including UTI, and is widely available throughout the world. The USA patent has recently expired and a generic formulation has become available. The ER formulation is approved at present only for the treatment of AUC, complicated UTIs and uncomplicated APN. It is available in the USA as well as many countries in western Europe.

Conclusion & future perspective

A variety of fluoroquinolones are effective for the treatment of UTI. Ciprofloxacin was the first member of the fluoroquinolone class to be widely available and has been in use for almost two decades. A new ER formulation is now available and has been shown to be as effective as the standard formulation for the management of AUC, complicated UTI and uncomplicated APN. There are several favorable pharmacokinetic characteristics of the ER formulation but it is unclear at the present time if these will translate into improved clinical outcomes. The once-daily dosing of the ER formulation offers greater patient convenience and may improve adherence, but several other fluoroquinolones can also be used with once-daily dosing in the management of UTI. Generic formulations of ciprofloxacin are available and may be favorable due to decreased costs. In North America and Europe, overall rates of resistance to fluoroquinolones among uropathogens have remained low; however, reports of higher rates of resistance from certain geographical areas are alarming. Trimethoprim–sulfamethoxazole remains the first choice for the management of AUC in many women, with fluoroquinolones reserved for patients with sulfa allergy, risk factors for a trimethoprim–sulfamethoxazole-resistant pathogen, or those from geographical areas where the prevalence of trimethoprim–sulfamethoxazole-resistant E. coli is known to be high. Nitrofurantoin is an effective and inexpensive alternative in this setting, but cannot offer the convenience of short-course (3-day) therapy. Fluoroquinolones have clearly emerged as the first choice for the empiric therapy of pyelonephritis in outpatients, but a number of other alternatives are available for the parenteral therapy of patients hospitalized with pyelonephritis.

Future studies should further address the pharmacokinetics and pharmacodynamics of quinolone dosing regimens and their impact on bacteriological and clinical response, and the frequency of selection of resistant mutants. Resistance to quinolones should be closely monitored and studies to more clearly define risk factors for resistance are clearly needed. These data can help inform treatment decisions that can help ensure that this very valuable class of agents will remain useful for a long time to come.

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Shore

: Efficacy and safety of a novel once-daily extended-release ciprofloxacin tablet formulation for treatment of uncomplicated urinary tract infection in women. Antimicrob. Agents Chemother. 49(10), 4137–4143 (2005).

26.

Trial demonstrating the safety and efficacy of the extended-release formulation of ciprofloxacin in the treatment of uncomplicated UTI in women

27.

Talan

Klimberg

Nicolle

Song

Kowalsky

Church

: Once daily, extended release ciprofloxacin for complicated urinary tract infections and acute uncomplicated pyelonephritis. J. Urol. 171(2 Pt 1), 734–739 (2004).

28.

Clinical trial demonstrating the safety and efficacy of the extended-release formulation of ciprofloxacin in the treatment of complicated UTI and uncomplicated pyelonephritis

29.

Brown

: Antimicrobial selection in the treatment of pyelonephritis. Curr. Infect. Dis. Rep. 6(6), 457–461 (2004).

30.

Zhanel

Hisanaga

Liang

: Antibiotic resistance in outpatient urinary isolates: final results from the North American Urinary Tract Infection Collaborative Alliance (NAUTICA). Int. J. Antimicrob. Agents 26(5), 380–388 (2005).

31.

Although passive surveillance studies likely overestimate the true prevalence of resistance, this study provides data regarding the prevalence of resistance among uropathogens to commonly used antimicrobials and is notable for higher rates of fluoroquinolone resistance than those reported from previous studies

32.

Kahlmeter

: Prevalence and antimicrobial susceptibility of pathogens in uncomplicated cystitis in Europe. The ECO.SENS study. Int. J. Antimicrob. Agents 22(Suppl. 2), 49–52 (2003).

33.

Kahlmeter

: An international survey of the antimicrobial susceptibility of pathogens from uncomplicated urinary tract infections: the ECO.SENS Project. J. Antimicrob. Chemother. 51(1), 69–76 (2003).

34.

Large prospective study addressing the prevalence of resistance among uropathogens isolated from women with acute cystitis in 16 European countries and Canada

35.

Chaniotaki

Giakouppi

Tzouvelekis

: Quinolone resistance among Escherichia coli strains from community-acquired urinary tract infections in Greece. Clin. Microbiol. Infect. 10(1), 75–78 (2004).

36.

Arslan

Azap

Ergonul

Timurkaynak

: Risk factors for ciprofloxacin resistance among Escherichia coli strains isolated from community-acquired urinary tract infections in Turkey. J. Antimicrob. Chemother. 56(5), 914–918 (2005).

37.

Killgore

March

Guglielmo

: Risk factors for community-acquired ciprofloxacin-resistant Escherichia coli urinary tract infection. Ann. Pharmacother. 38(7–8), 1148–1152 (2004).

Ciprofloxacin for the Management of Urinary Tract Infection

Abstract

Keywords

Overview of the market

Introduction to ciprofloxacin

Chemistry

Pharmacodynamics, pharmacokinetics & metabolism

Clinical efficacy

Safety & tolerability

Resistance

Regulatory affairs

Conclusion & future perspective

References