Extended-release ciprofloxacin (Cipro XR) for treatment of urinary tract infections

International Journal of Antimicrobial Agents 23S1 (2004) S54–S66

Extended-release ciprofloxacin (Cipro XR) for treatment of urinary tract infections David A. Talan a,∗ , Kurt G. Naber b , Juan Palou c , David Elkharrat d a

Department of Medicine, Divisions of Infectious Diseases and Emergency Medicine, Olive View-UCLA Medical Center, 14445 Olive View Drive, North Annex, Sylmar, CA 91342, USA b Urologic Clinic, Hospital St. Elisabeth, Straubing, Germany c Department of Urology and Pharmacy, Fundacio Puigvert, Universitat Autonoma de Barcelona, Barcelona, Spain d Hopital Lariboisiere, Paris, France

Abstract Symptomatic urinary tract infections (UTIs) constitute a major health problem throughout the Western world. In the USA, UTIs are responsible for 7–8 million outpatient visits each year and for over one-third of all hospital-acquired infections. Empiric antimicrobial therapy for UTIs, which are primarily caused by Escherichia coli, is increasingly being complicated by the emergence of resistance to the most widely used agents. Recent studies indicate that the prevalence of E. coli resistance to trimethoprim/sulphamethoxazole (TMP/SMX), the current first-line therapy for UTIs, exceeds 20% in many North American regions. Importantly, antibiotic resistance often translates into clinical failure. The use of antibiotics with favourable pharmacokinetic/pharmacodynamic profiles and convenient dosing schedules, which effectively increase bacterial eradication and patient compliance, can help to curb the current epidemic of resistance and reduce the rate of clinical failure associated with resistance. Fluoroquinolones have well-established efficacy in the treatment of multiple bacterial infections and, over the years, the rates of resistance to these antibiotics have remained very low. Fluoroquinolones are currently recommended for therapy of uncomplicated UTIs when the local incidence of TMP/SMX resistance is ≥10–20%, as well as for the treatment of complicated UTIs and acute pyelonephritis. Ciprofloxacin, one of the most widely used fluoroquinolones, has a potent bactericidal effect across the full spectrum of uropathogens, as well as a long and excellent efficacy and safety record in the management of UTI and other infections. A recently developed extended (modified)-release formulation of ciprofloxacin (Cipro XR or Cipro XL) provides higher maximum plasma concentrations with lower inter-patient variability than the conventional, immediate-release, twice-daily formulation. Additionally, therapeutic drug levels with extended-release ciprofloxacin are achieved rapidly and maintained over the course of 24 h, allowing once-daily dosing. Clinical trials in patients with cystitis and those with complicated UTIs or acute uncomplicated pyelonephritis indicate that extended-release ciprofloxacin is at least as effective as the immediate-release formulation. These studies have also confirmed good tolerability and safety of extended-release ciprofloxacin, similar to the immediate-release formulation. Therefore, extended-release ciprofloxacin is a convenient, well-tolerated and effective therapy for UTIs that may improve patients’ compliance with treatment and thus decrease the risk of treatment failure and the spread of antibiotic resistance. © 2004 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Ciprofloxacin; Urinary tract infections; Trimethoprim/sulphamethoxazole

1. Introduction Urinary tract infections (UTIs) are among the most prevalent infectious diseases, and their financial burden on society is substantial. In the USA, UTIs are responsible for over 7 million physician visits annually, including >2 million visits for cystitis [1,2]. In addition, UTIs account for more ∗ Corresponding author. Tel.: +1-818-364-3107; fax: +1-818-364-3268. E-mail address: [email protected] (D.A. Talan).

than 100,000 hospital admissions annually, most often for pyelonephritis [1,2], and they also comprise over one-third of all hospital-acquired infections [3]. Approximately 15% of all community-prescribed antibiotics in the USA are dispensed for UTI, at an estimated annual cost of over US$ 1 billion [4]. Furthermore, the direct and indirect costs associated with community-acquired UTIs in the USA alone exceed US$ 1.6 billion [2]. Women are particularly at high risk for the development of UTIs. In the USA, 10.8% of women over 18 years of age experience at least one UTI each year [2,5]. By age of 24

0924-8579/$ – see front matter © 2004 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2003.12.005

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years, about one-third of women will have had one or more UTIs requiring antibiotic treatment, and nearly one-half of women will have a UTI at some point during their lives [2,6] Remarkably, the risk for UTIs among women between 16 and 35 years of age is approximately 40 times that for men [4]. The bacterial aetiology of UTI is well established, with at least 80% of community-acquired, uncomplicated cases being caused by Escherichia coli [1,7–9]. Other important uropathogens include Staphylococcus saprophyticus (almost exclusively in younger women with cystitis), Klebsiella spp., Proteus mirabilis and other Enterobacteriaceae [1,7–9]. Complicated UTIs, including those in catheterised patients, are frequently associated with enterococci and other Gram-positive species [4]. Management of UTIs has been complicated by the emergence of resistance to most commonly used antibiotics. Increasing prevalence of resistance has led to a gradual evolution in the antibiotics used to treat UTIs. Until the 1990s, the ␤-lactam, ampicillin, was the most widely prescribed therapy for UTIs, but the high rates of E. coli resistance to this antibiotic (typically resulting from expression of ␤-lactamase) [10], prompted a switch to trimethoprim/sulphamethoxazole (TMP/SMX), which was subsequently considered the first-line treatment for these infections. However, broad use of TMP/SMX has also resulted in high rates of resistance to this therapy among uropathogens. Surveillance results for Canada and the US indicate that 18–25% of E. coli isolates from outpatients with acute uncomplicated UTI are now resistant to TMP/SMX [6]. The rates are even higher among nosocomial isolates in Europe (33%) and Latin America (45%) [10]. This increase in resistance with wider use of TMP/SMX is highly reminiscent of the previous situation with ampicillin and underscores the need to re-evaluate and optimise first-line therapy of UTI. The fluoroquinolones are well-established broad-spectrum antibiotics with potent bactericidal activity against clinically important pathogens responsible for a variety of infections, including UTIs, gastrointestinal (GI) infections, respiratory tract infections, sexually transmitted diseases, skin infections and chronic osteomyelitis [13,14]. This large class of agents is characterised by a favourable pharmacokinetic profile, with high tissue penetration and rapid bactericidal action. The clinical value of fluoroquinolones in the management of UTIs has been recognised by the guidelines developed by the Infectious Diseases Society of America (IDSA) [1] and the European Association of Urology (EAU) [15], both of which recommend the use of these agents in areas where the local prevalence of TMP/SMX resistance is ≥10–20%. Notably, a recent analysis has revealed that the prevalence of E. coli resistant to TMP/SMX among women with community-acquired UTI is over 10% in each of the nine United States Census Bureau regions [12]. Moreover, the TMP/SMX resistance rates among uropathogenic E. coli isolates from women with community-acquired UTI in

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various western European countries also exceed 10%, as reviewed by Gupta et al. [16]. Ciprofloxacin became the first widely available fluoroquinolone antibiotic in the second half of the 1980s. This drug has potent bactericidal activity against a broad range of clinically relevant Gram-negative and Gram-positive pathogens, and it has been effectively used to treat a variety of bacterial infections, including UTIs, sexually transmitted infections, gastrointestinal infections, as well as skin and bone infections [13,17]. Importantly, in contrast to the dramatic increases in resistance of uropathogens to ampicillin and TMP/SMX, the resistance to ciprofloxacin has remained low [10–12,18,19]. In a recent surveillance study of urinary E. coli isolates from outpatient women in the USA, collected during the year 2000, the rates of ampicillin and TMP/SMX susceptibility (59.9 and 75.7%, respectively) were far lower than the susceptibility to ciprofloxacin (96.4%) [11]. Similar findings were reported in the analysis of 16,745 E. coli isolates from female outpatients with UTI collected in the Pacific region of the USA in 2001 (ampicillin resistance: 38.0%; TMP/SMX resistance: 20.3%; ciprofloxacin resistance: 2.3%) [12]. The SENTRY Antimicrobial Surveillance Program for the year 2000 also demonstrated that the susceptibility of uropathogenic E. coli isolated from hospitalised patients with UTI is far greater for ciprofloxacin than for either ampicillin or TMP/SMX, across all geographic regions evaluated (North America, Europe, Latin America) [10]. For example, in North America, 95% of E. coli isolates were susceptible to ciprofloxacin, whereas the susceptibility rates for ampicillin and TMP/SMX were only 62 and 77%, respectively [10]. The importance of very high susceptibility rates to ciprofloxacin in the management of UTIs is underscored by several recent reports [16,20–23], which have documented increasing prevalence of clinical failure in areas with high levels of TMP/SMX resistance. These findings further support the IDSA and EAU guidelines’ recommendations for the use of fluoroquinolones in regions where local prevalence of TMP/SMX resistance is ≥10–20% [1,15]. Until recently, oral ciprofloxacin has been available only as conventional, immediate-release tablets that required twice-daily administration. An extended (modified)-release ciprofloxacin (Cipro XR or Cipro XL), which provides both a fast-acting and convenient once-daily alternative to the standard, immediate-release, twice-daily tablets, has now been developed [24]. Taking into account the declining effectiveness of TMP/SMX [10] and the recognition that many patients with UTIs require alternative antimicrobial therapy [1,15], the availability of extended-release ciprofloxacin as an effective, well-tolerated and more convenient alternative to conventional ciprofloxacin, is particularly timely. Extended-release ciprofloxacin therefore provides clinicians with a new treatment option that may enhance patient adherence to treatment and thereby improve clinical success rates. The goal of this review is to describe the impact of increasing prevalence of TMP/SMX resistance on clinical

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outcomes in UTIs and, in this context, discuss the clinical role of extended-release ciprofloxacin, focusing on its pharmacologic and clinical profile versus the conventional, immediate-release, bid ciprofloxacin.

2. The impact of pathogen resistance on clinical outcomes in patients with UTIs 2.1. Pathogens associated with UTIs The prevalence of specific UTI-associated micro-organisms varies geographically, but E. coli is the most common pathogen, typically being isolated from over 80% of outpatients with acute uncomplicated cystitis across the various regions of the world [16]. S. saprophyticus accounts for 5–15% of these infections and is especially prevalent in younger women with cystitis. Causative pathogens in the remaining 5–10% of cases include aerobic Gram-negative rods, such as Klebsiella and Proteus spp. and other enterococci [10,16]. The range of pathogens associated with acute uncomplicated pyelonephritis is similar to that seen in acute uncomplicated cystitis [20,25]. 2.2. Patterns of antibiotic resistance to TMP/SMX Although TMP/SMX has been the cornerstone of UTI therapy over the past 20 years, results from a large number of surveillance studies and clinical trials have demonstrated a significant upward trend in TMP/SMX resistance among major uropathogens, most notably E. coli. For example, in the 5-year period from 1992 to 1996, the percentage of E. coli resistant to TMP/SMX in Seattle, Washington, increased from 9 to 18% in women with acute uncomplicated cystitis [26]. More recent studies have documented a further increase in TMP/SMX resistance in both community acquired and nosocomial E. coli isolates collected from 1997 to 2001 in North America [10–12,18,27,28]. Within the USA, the prevalence of TMP/SMX-resistant E. coli among outpatient females with UTI in 2001 exceeded 10% in all nine Census Bureau regions, and the highest rates were observed in the Pacific and west–south–central regions (20.3 and 21.8%, respectively) [12]. In addition, TMP/SMX resistance has been shown to be even higher (>25%) among uropathogens isolated from outpatients with UTI in Spain (1999–2000) [29], Israel (1997–2000) [23] and the UK (1999–2000) [19]. Additionally, the prevalence of TMP/SMX-resistant E. coli isolates among hospitalised patients with UTI during the year 2000 ranged from 23% in North America to 33% in Europe to 45% in Latin America [10]. Extensive use of TMP/SMX has been demonstrated to be a major driver of TMP/SMX resistance among urinary pathogens. In a study by Wright et al., which retrospectively assessed factors associated with pathogen resistance in 448 emergency department outpatients with UTIs, a multivariate logistic regression analysis identified recent TMP/SMX use

(odds ratio: 5.1; 95% confidence intervals (CI): 2.2–11.5) and current antimicrobial use (odds ratio: 4.5; 95% CI: 2.0–10.2) as the two strongest predictors of TMP/SMX resistance [30]. These findings were confirmed more recently by Steinke et al., who demonstrated that prior TMP use was the most powerful factor associated with TMP/SMX resistance (adjusted odds ratio: 3.81; 95% CI: 2.93–4.96) [31]. Collectively, these findings are consistent with the hypothesis that the high use of TMP/SMX is a major cause of antibiotic resistance among pathogens responsible for UTIs. 2.3. Resistance to fluoroquinolones In contrast to TMP/SMX, the resistance to which has markedly increased over the past 10 years, ciprofloxacin has continued to exhibit potent bactericidal activity against the pathogens most often associated with UTIs [10,27,28,32,33]. Surveillance studies in hospital and community settings have shown that only a small percentage of E. coli isolates from patients with UTIs shows resistance to this fluoroquinolone, and that resistance rates have not risen substantially over the last several years. In a study conducted in the UK, using samples collected from outpatients and hospitalised patients with UTIs in 1999 and 2000, over 97% of E. coli isolates were susceptible to ciprofloxacin [19]. Karlowsky et al. have assessed the prevalence of ciprofloxacin resistance in over 250,000 E. coli isolates from female outpatients with UTIs in the US in the period between 1995 and 2001, demonstrating only a modest increase in resistance over this 7-year period (from 0.7 to 2.5%, respectively) [12]. Additionally, the comparison of resistance rates to ciprofloxacin and TMP/SMX in over 350,000 E. coli isolates collected from female outpatients with UTIs in the US between 1998 and 2001 shows substantially lower prevalence of resistance to ciprofloxacin (2.3% versus 17.5% for TMP/SMX) [18]. Moreover, in a 1999–2000 European survey, over 93% of 1927 uropathogenic E. coli isolates from outpatients with UTI were susceptible to ciprofloxacin (MIC ≤ 1 mg/l), with little variability across individual countries [34]. Similar findings were also reported in a separate study of 2478 uropathogenic E. coli isolates from female outpatients with UTI in European countries and Canada (ciprofloxacin resistance: 2.3%), although in Spain, where the incidence of TMP/SMX resistance is very high (25.7%), the incidence of ciprofloxacin resistance was higher (14.7%) [29]. This maintenance of high activity of ciprofloxacin against E. coli and other uropathogens, including strains resistant to TMP/SMX, suggests that ciprofloxacin is likely to remain clinically and bacteriologically effective therapy in patients with UTIs. 2.4. Impact of pathogen resistance on clinical outcomes Several studies have clearly demonstrated that resistance to TMP/SMX can result in bacteriologic and clinical failure in patients with UTIs. In one study of women with

D.A. Talan et al. / International Journal of Antimicrobial Agents 23S1 (2004) S54–S66 Table 1 Clinical and bacteriologic success of trimethoprim/sulphamethoxazole (TMP/SMX) at 5–9 days in women with urinary tract infections treated with this therapy according to the pathogens’ susceptibility to TMP/SMX (adapted with permission from Raz et al. [23]) Parameter

TMP/SMX-susceptible pathogens (%)

TMP/SMX-resistant pathogens (%)

P-value

Clinical cure Bacteriologic cure

88 82

54 42

<0.001 <0.001

acute uncomplicated UTIs, bacteriologic success rates with TMP/SMX (960 mg bid for 7 days) among patients infected with TMP/SMX-resistant pathogens was substantially lower than in the overall TMP/SMX cohort (50 and 86.2%, respectively), and clinical failure was significantly correlated with TMP resistance (P ≤ 0.05) [21]. Similar results were obtained in a study of 866 women with UTIs and positive urine cultures (81% infected with E. coli) who were randomised to 3 days of treatment with ciprofloxacin (100 mg bid), ofloxacin (200 mg bid), or TMP/SMX (960 mg bid) [22]. In this study, clinical and bacteriologic success rates with TMP/SMX were considerably lower among patients who had TMP/SMX-resistant uropathogens (60 and 50%, respectively) than in the overall population of patients receiving TMP/SMX (95 and 92.5%, respectively) [22]. Most recently, the strong correlation between TMP/SMX resistance and clinical failure in women with uncomplicated UTIs was corroborated by the results of a study conducted in Israel (Table 1), a region with high prevalence of TMP/SMX resistance (29%) [23]. A study by Talan et al., which compared the efficacy of ciprofloxacin (500 mg bid for 7 days) versus TMP/ SMX (960 mg bid for 14 days) in 255 women with acute pyelonephritis, confirms the association between TMP/ SMX resistance and clinical failure in patients with acute pyelonephritis and demonstrates excellent efficacy of ciprofloxacin in patients with TMP/SMX-resistant uropathogens [20]. In agreement with previously described studies in women with uncomplicated UTIs, clinical and bacteriologic success rates at the test-of-cure visit (4–11 days) among patients treated with TMP/SMX were substantially lower if the pathogens were resistant to this treatment (35 and 50%, respectively, versus 92 and 96%, respectively, in patients with TMP/SMX-susceptible isolates). Furthermore, in patients with TMP/SMX-resistant isolates, ciprofloxacin achieved very high rates of clinical cure and bacteriologic eradication (95 and 100%, respectively) [20]. Taken together with the results from studies in uncomplicated UTIs (see earlier), these findings underscore the need for alternative first-line therapies, such as fluoroquinolones, in areas with high prevalence of TMP/SMX resistance. This need is recognised in the most recent guidelines for treatment of UTIs developed by the IDSA [1] and the EAU [15], whose recommendations are summarised in Section 3.

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3. Guidelines for the treatment of UTIs 3.1. IDSA guidelines The IDSA guidelines’ recommendations were based on the analyses of clinical trials of antimicrobial therapies in women with uncomplicated acute symptomatic bacterial cystitis or acute pyelonephritis, taking into account the local prevalence and clinical impact of TMP/SMX resistance [1]. According to the IDSA guidelines, use of a 3-day TMP/SMX regimen for treatment of acute uncomplicated cystitis may be considered in geographic areas where the rate of TMP/SMX-resistant E. coli is <20%, although the use of alternate first-line therapies, most notably fluoroquinolones, is recommended in regions in which the incidence of TMP/SMX resistance is ≥10–20% [1]. In outpatients with acute pyelonephritis, the IDSA guidelines recommend the use of a 7–14-day oral fluoroquinolone regimen, whereas TMP/SMX use should be reserved for those patients in whom the pathogenic isolates are known to be susceptible to this therapy [1]. This recommendation was subsequently supported by the results of the study by Talan et al., which showed that the use of TMP/SMX in patients with TMP/SMX-resistant pathogens dramatically increases the rate of clinical and bacteriologic failure, and that ciprofloxacin is highly active against TMP/SMX-resistant pathogens [20]. Parenteral fluoroquinolones (or aminoglycosides or extended-spectrum cephalosporins) are recommended for hospitalised patients with acute pyelonephritis, whereas no specific recommendations are made for treatment of recurrent, complicated or nosocomial urinary infections [1]. 3.2. EAU guidelines The EAU guidelines recommendations (Table 2) [15] are similar to those developed by the IDSA expert panel. For empiric treatment of acute uncomplicated cystitis, the EAU guidelines recommend the use of a 3-day regimen of TMP/SMX in regions where the incidence of TMP/SMX resistance is less than 10%, and a 3-day course of fluoroquinolone therapy in areas in which the prevalence of TMP/SMX resistance is ≥10–20% [15]. In patients with mild cases of acute, uncomplicated pyelonephritis, the EAU guidelines recommend 7 days of treatment with oral fluoroquinolones. For more severe cases of acute pyelonephritis, the EAU guidelines recommend hospitalisation and initial treatment with parenteral fluoroquinolones, with conversion to oral fluoroquinolones guided by symptom improvement [15]. The EAU guidelines also address treatment of complicated and nosocomial UTI, recommending the use of a fluoroquinolone, a ␤-lactam, or an aminoglycoside for empiric therapy [15]. In addition, a variety of therapies, including ciprofloxacin, are recommended for prevention of recurrent UTI [15].

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Table 2 Recommendations for treatment of acute cystitis, acute pyelonephritis, and complicated urinary tract infections by the European Association of Urology Working Group (reproduced with permission from Naber et al. [15]) Diagnosis

Most frequent pathogen

Initial empiric antimicrobial therapy

Duration of treatment

Acute uncomplicated cystitis

E. coli, Klebsiella, Proteus, Staphylococcus

Trimethoprim/sulphamethoxazole

3 days

Fluoroquinolone Alternatives: Fosfomycin trometamol Pivmecillinam Nitrofurantoin

3 days 1 day 7 days 7 days

Fluoroquinolone

7–10 days

Acute uncomplicated pyelonephritis

E. coli, Proteus, Klebsiella, other Enterobacteria, Staphylococcus

Cephalosporin Gr. 2/3a Alternatives: Aminopenicillin/BLI Aminoglycoside UTI with complicating factors

E. coli, Enterococcus

Nosocomial UTI Acute complicated pyelonephritis

Staphylococcus, Klebsiella, Proteus Enterobacter, other Enterobacteria, Pseudomonas (Candida)

In summary, both the IDSA and EAU guidelines recognise the increasing prevalence of TMP/SMX resistance and its clinical ramifications, most notably the decreasing utility of TMP/SMX for empiric therapy of UTIs and, therefore, the increasing need for alternate first-line therapies (i.e. fluoroquinolones). Taking into account the low levels of uropathogen resistance to ciprofloxacin (and other fluoroquinolones) and the high bacteriologic potency of this class of agents, the wider use of fluoroquinolones can be expected to translate into more favourable clinical and bacteriologic outcomes.

4. Improving clinical and bacteriologic success in management of UTI: additional considerations Although pathogen resistance is clearly an important consideration in the management of UTIs, other parameters, such as compliance with therapy, can also significantly influence treatment outcomes. Poor patient adherence to treatment, resulting from side effects and/or inconvenient regimens, often leads to sub-therapeutic antibiotic concentrations at sites of infection, which can result in prolonged pathogen persistence, clinical failure and/or selection of resistant organisms. The development of a short, convenient, once-daily regimen of a proven antibiotic has thus long remained an important challenge in the management of UTIs. Recent development and approval of extended-release ciprofloxacin represents an important milestone in the treatment of UTI, as the short course of therapy with this once-daily formulation is likely to increase patient adherence to therapy and, thereby, improve patient outcomes. Additionally, the short duration of therapy with extended-release

3–5 days after defervescence or control/elimination of complicating factor

ciprofloxacin effectively reduces the risk for development of resistance and can result in lower overall cost [24,35,36].

5. Extended-release ciprofloxacin 5.1. Rationale and criteria for development The overall aim of clinical development of extendedrelease ciprofloxacin was to enhance the pharmacokinetic and pharmacodynamic profile achieved with conventional, immediate-release, twice-daily ciprofloxacin, in order to allow more convenient, once-daily dosing, while providing clinical and bacteriologic efficacy at least equivalent to that observed with the conventional, twice-daily regimen. One of the major criteria in the development of extended-release ciprofloxacin was to obtain single-dose systemic exposure, as reflected by the area under the time versus plasma concentration curve (AUC), equivalent to that observed with twice-daily administration of the conventional formulation. Such a formulation would provide an AUC/MIC ratio equivalent to that of immediate-release ciprofloxacin and thereby retain high activity against pathogens associated with UTIs. A second developmental criterion was the achievement of a maximum plasma concentration (Cmax ) higher than that observed with a corresponding regimen of conventional, twice-daily ciprofloxacin. Attainment of both equivalent AUC and higher Cmax values was critical, because the bactericidal activity of ciprofloxacin is concentration-dependent, and the AUC/MIC and Cmax /MIC ratios are the key determinants in this respect [37,38]. Additionally, achievement of targeted AUC/MIC and Cmax /MIC values may help prevent the development of resistance [39]. In order to preserve

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the good tolerability and safety profile established for the conventional, immediate-release ciprofloxacin bid, it was essential that the Cmax with extended-release ciprofloxacin does not exceed the safety threshold established with the 750 mg bid regimen of immediate-release ciprofloxacin. At the same time, it was important to reduce temporal and inter-patient variability in pharmacokinetic parameters versus the conventional, immediate-release ciprofloxacin bid to maintain therapeutic drug concentrations over time and across individual patients. Because previous studies with conventional ciprofloxacin have demonstrated that the attainment of therapeutic drug concentrations requires absorption in the upper gastrointestinal tract (absorption window), as opposed to the distal GI tract (e.g. jejunum, ileum, colon) [40], a major goal in development of extended-release ciprofloxacin was that the drug should primarily be absorbed in the “absorption window”. 5.1.1. Absorption The extended-release ciprofloxacin tablet is composed of a bilayer matrix containing two different salts of ciprofloxacin. It is important to stress that extended-release ciprofloxacin does not provide two pulses of immediate drug release (i.e. it is not a “staggered-dose” delivery system). Instead, oral administration of the tablet results in the immediate release of 35% of the total dose, providing a rapid onset of action, and the remaining 65% of the dose is released within 3 h, allowing complete drug absorption in the upper GI tract. A population kinetic analysis demonstrated reduced absorption variability with extended-release ciprofloxacin (coefficient of variation: 29.5% versus 78.8% with immediate-release ciprofloxacin) [41], indicating that this dosage form has an improved pharmaceutical quality, which may enhance its therapeutic profile. It is important to emphasise that extended-release ciprofloxacin tablets should never be crushed prior to ingestion, because this action may significantly alter drug absorption and, therefore, can dramatically impact the pharmacokinetic and clinical/bacteriologic profile of this formulation. 5.2. Pharmacokinetic and pharmacodynamic parameters The pharmacokinetic properties of extended-release ciprofloxacin (Table 3) indicate that the developmental goals discussed earlier were achieved [42–45]. In particu-

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lar, AUC values with extended-release ciprofloxacin (500 and 1000 mg qd) are equivalent to those achieved with conventional, immediate-release ciprofloxacin (250 and 500 mg bid), whereas the Cmax values with extended-release ciprofloxacin (500 and 1000 mg qd) are 150–160% higher than those obtained with standard immediate-release ciprofloxacin (250 and 500 mg bid) [43,44]. Additionally, reduced absorption variability with extended-release ciprofloxacin translates into lower variation in peak plasma levels of the drug [41]. Lower pharmacokinetic variability contributes to the fact that the Cmax value achieved after treatment with 1000 mg qd extended-release ciprofloxacin does not exceed the peak plasma concentrations attained with 750 mg bid immediate-release ciprofloxacin, which have been established to represent a safety ceiling for the use of oral ciprofloxacin. In contrast, maximal plasma concentrations achieved after simultaneous administration of two 500 mg tablets of the immediate-release formulation exceed this safety threshold. Therefore, the pharmacokinetic profile of extended-release ciprofloxacin (500 and 1000 mg qd) is superior to that of conventional, immediate-release ciprofloxacin (250 and 500 mg bid). The pharmacokinetics of extended-release ciprofloxacin 500 and 1000 mg qd is dose-linear, with AUC and Cmax values being approximately twice as high with the 1000 mg qd dose (Table 3) [42–44]. Importantly, extended-release ciprofloxacin does not exhibit sustained drug release, and there is no accumulation of the drug with repeated dosing [43,44]. Pharmacokinetic parameters of extended-release ciprofloxacin are not significantly affected by ingestion of food [45], indicating that this therapy can be administered either with or without food. The primary route of ciprofloxacin elimination (for both the extended-release and immediate-release formulations) is renal, with approximately one-third of the total dose excreted in the urine as unmodified ciprofloxacin [42]. Steady-state urinary drug concentrations after administration of extended-release ciprofloxacin 500 and 1000 mg qd far exceed the MIC90 values for common urinary pathogens over the entire 24 h dosing interval (Fig. 1) [43,44]. Additionally, drug concentrations in the urine after therapy with extended-release ciprofloxacin 500 mg qd are substantially higher than those achieved with conventional, immediate-release ciprofloxacin 250 mg bid during the first 12 h, both on days 1 and 5 (Fig. 2) [42–44,46,47].

Table 3 Pharmacokinetic properties of once-daily extended-release ciprofloxacin and twice-daily immediate-release ciprofloxacin [42] Cmax (mg/l)

AUC0–24 h (mg·h/l)

T1/2 (h)

Tmax (h)

Extended-release ciprofloxacin 500 mg qd Immediate-release ciprofloxacin 250 mg bid

1.59 ± 0.43 1.14 ± 0.23

7.97 ± 1.87 8.25 ± 2.15

6.6 ± 1.4 4.8 ± 0.6

1.5 (1.0–2.5) 1.0 (0.5–2.5)

Extended-release ciprofloxacin 1000 mg qd Immediate-release ciprofloxacin 500 mg bid

3.11 ± 1.08 2.06 ± 0.41

16.83 ± 5.65 17.04 ± 4.79

6.31 ± 0.72 5.66 ± 0.89

2.0 (1–4) 2.0 (0.5–3.5)

Values are expressed as mean ± standard deviation (S.D.); Tmax is expressed as median and range. Cmax : maximum plasma concentration; AUC0–24 h : area under concentration versus time curve during 24 h after dosing; T1/2 : elimination time constant; Tmax : time to Cmax .

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Fig. 1. Urinary drug concentrations at steady-state following administration of extended-release ciprofloxacin 500 and 1000 mg qd [43,44] are far greater than the minimal inhibitory concentration (MIC90 ) values for common urinary pathogens, which are taken from Sahm et al. [46] and Woodcock et al. [47].

Furthermore, pharmacokinetic modelling studies indicate that prostatic drug concentrations following treatment with 1000 mg qd extended-release ciprofloxacin are much greater than the MIC90 values for pathogens most frequently associated with prostatitis, suggesting that this preparation may also be effective in the management of prostatic infections [41]. Superior initial Cmax values with extended-release ciprofloxacin qd (500 and 1000 mg) may result in more

rapid and/or greater bactericidal effect (versus the conventional, immediate-release ciprofloxacin qd (250 and 500 mg)) against common uropathogens. Recent in vitro and in silico pharmacokinetic/pharmacodynamic modelling studies, which showed that the 500 mg qd extended-release ciprofloxacin provides more rapid killing of E. coli (MIC90 : 0.03 mg/l) than the standard, immediate-release ciprofloxacin 250 mg bid (Fig. 3), are consistent with this hypothesis, and suggest that rapid achievement of

Fig. 2. Urinary drug concentrations following treatment with extended-release ciprofloxacin 500 mg qd are much higher than those achieved after treatment with immediate-release ciprofloxacin 250 mg bid during the first 12 h. The concentrations attained with both formulations are far greater than the minimal inhibitory concentration (MIC90 ) values for most common urinary pathogens over the entire 24 h (12 h for the 250 mg bid) dosing interval, both at days 1 and 5 [44]. The MIC90 values for ciprofloxacin are taken from Sahm et al. [46] and Woodcock et al. [47].

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Fig. 3. In vitro and in silico pharmacokinetic/pharmacodynamic (PK/PD) modelling studies indicate that extended-release ciprofloxacin 500 mg qd provides more rapid killing of E. coli (MIC90 : 0.03 mg/l) than the conventional, immediate-release ciprofloxacin 250 mg bid [48]. Circles: experimental PK/PD data; solid lines: curve fits obtained from PK/PD data by computer modelling.

higher peak plasma concentrations with extended-release ciprofloxacin may translate into clinical benefits [48]. Additionally, higher maximum plasma concentrations achieved with extended-release ciprofloxacin 1000 mg qd (versus the conventional, immediate-release ciprofloxacin 500 mg bid) correlate with a greater bactericidal effect over the 24 h period [48]. Taken together, these findings suggest that the pharmacokinetic advantages of extended-release ciprofloxacin may be associated with improved bacteriologic activity in patients with UTI.

5.3. Clinical experience The clinical efficacy of extended-release ciprofloxacin has been documented in studies involving patients with uncomplicated UTIs (500 mg qd) [24,49], as well as in a trial of patients with complicated UTIs or acute pyelonephritis (1000 mg qd) [50]. Results of these studies indicate that extended-release ciprofloxacin is at least as effective as conventional, immediate-release ciprofloxacin (250 and 500 mg bid, respectively) in the treatment of these infections.

Fig. 4. Clinical and bacteriologic efficacy of extended-release ciprofloxacin 500 mg qd and conventional, immediate-release ciprofloxacin 250 mg bid in women with uncomplicated urinary tract infections [24].

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Fig. 5. Eradication of various bacterial pathogens with extended-release ciprofloxacin 500 mg qd and conventional, immediate-release ciprofloxacin 250 mg bid in women with uncomplicated urinary tract infections [24].

5.3.1. Uncomplicated UTI The clinical and bacteriologic efficacy of 3-day therapy with either extended-release ciprofloxacin 500 mg qd or immediate-release ciprofloxacin 250 mg bid was addressed in a randomised, double-blind study of 891 women with uncomplicated UTIs [24]. Clinical and bacteriologic success rates were evaluated at a test-of-cure visit and longer-term follow-up (4–11 and 25–50 days after completion of therapy, respectively). As shown in Fig. 4, clinical and bacteriologic success rates were consistently higher with extended-release ciprofloxacin 500 mg qd, although the differences did not reach statistical significance [24]. Extended-release ciprofloxacin was highly active against all pathogenic species, and eradication rates with immediate-release ciprofloxacin were comparable (Fig. 5). Importantly, the rates of clinical failure and new infection at long-term follow-up were lower with extended-release ciprofloxacin (5.0 and 1.7%, respectively, versus 7.4 and 4.9%, respec-

tively, with immediate-release ciprofloxacin), confirming the clinical and bacteriologic efficacy of extended-release ciprofloxacin 500 mg qd [24]. These results support the use of extended-release ciprofloxacin as at least an equally effective alternative to conventional, immediate-release ciprofloxacin in women with uncomplicated UTIs. The clinical efficacy of short-course (3-day) therapy with extended-release ciprofloxacin 500 mg qd was also corroborated by a large, prospective study in adult women with uncomplicated UTI [49]. This community-based study enrolled 7360 female outpatients with uncomplicated UTI presenting to over 1900 primary care physicians’ offices in the US, thereby allowing evaluation of the efficacy of extended-release ciprofloxacin 500 mg qd in standard clinical practice. Clinical cure at the end-of-study visit (2–7 days post-therapy) was achieved in 91.3% of outpatients, without significant differences in outcomes in various subgroups defined by age, race, or educational status [49].

Fig. 6. Clinical and bacteriologic efficacy of extended-release ciprofloxacin 1000 mg qd and conventional, immediate-release ciprofloxacin 500 mg bid in men and women with complicated urinary tract infections or acute pyelonephritis [50].

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Fig. 7. Bacterial eradication at a test-of-cure visit (5–11 days) with extended-release ciprofloxacin 1000 mg qd and conventional, immediate-release ciprofloxacin 500 mg bid in men and women with complicated urinary tract infections or acute pyelonephritis [50]. Slightly lower bacteriologic success rate with extended-release ciprofloxacin 1000 mg qd in patients with acute pyelonephritis can be attributed to development of new infections in three patients; the original pathogen was completely eradicated in two of these three patients [50].

5.3.2. Complicated UTI and acute uncomplicated pyelonephritis Clinical and bacteriologic efficacy of 7–14-day therapy with extended-release ciprofloxacin 1000 mg qd versus conventional, immediate-release ciprofloxacin 500 mg bid in patients presenting with complicated UTI or acute pyelonephritis was evaluated in a large (N = 435 men and women) multi-centre, double-blind, randomised study [50]. Clinical cure and bacteriologic eradication rates were higher in patients receiving extended-release ciprofloxacin at both the test-of-cure visit (5–11 days) and late follow-up (28–42 days) (Fig. 6), although the differences were not statistically significant. Extended-release ciprofloxacin 1000 mg qd exhibited high potency across the full spectrum of bacterial pathogens, and conventional, immediate-release ciprofloxacin 500 mg bid showed similar efficacy [50]. Treatment with extended-release ciprofloxacin 1000 mg qd was associated with high rates of bacteriologic eradication at a test-of-cure visit in patients with complicated UTI, as well as in those presenting with acute pyelonephritis (Fig. 7), whereas immediate-release ciprofloxacin was slightly less effective in patients with complicated UTI (Fig. 7) [50]. At late follow-up (28–42 days), extended-release ciprofloxacin 1000 mg qd was associated with reduced rates of clinical failure, new infection and persistent infection (Fig. 8) [50]. Collectively, these findings demonstrate that, in patients with complicated UTI or acute pyelonephritis, extended-release ciprofloxacin 1000 mg qd provides clinical and bacteriologic efficacy comparable to that observed with immediate-release ciprofloxacin 500 mg bid, with a dosing schedule that may facilitate greater patient adherence to therapy. Therefore, extended-release ciprofloxacin 1000 mg qd represents a useful and more convenient treatment

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Fig. 8. Clinical failure, new infection, and bacterial persistence at late follow-up (28–42 days) after treatment with extended-release ciprofloxacin 1000 mg qd and conventional, immediate-release ciprofloxacin 500 mg bid in men and women with complicated urinary tract infections or acute pyelonephritis [50].

alternative to conventional ciprofloxacin in the management of these infections. 5.4. Safety and tolerability Conventional ciprofloxacin has established an excellent record for tolerability and safety in patients with a wide spectrum of bacterial infections [13,51]. Results from a comparison of immediate-release ciprofloxacin versus TMP/SMX in women with acute pyelonephritis indicate lower rates of digestive or central nervous system adverse events with ciprofloxacin [20]. Clinical studies of extended-release ciprofloxacin described earlier indicate that its safety and tolerability are comparable to those of the conventional formulation. In women with uncomplicated UTIs, treatment-emergent adverse events, regardless of cause, were reported in 27.3% of patients who received extended-release ciprofloxacin 500 mg qd and in 23.5% of those treated with the immediaterelease 250 mg bid formulation [24]. The respective rates for treatment-related adverse events were 10.4 and 9.2% (Table 4) [24]. Most adverse events were mild or moderate in severity, and there were no serious treatment-related adverse events in either group. Only two women in each group discontinued treatment prematurely due to adverse events [24]. Good tolerability of extended-release ciprofloxacin (500 mg qd) was also confirmed in a large study that included over 7000 women with uncomplicated UTI [49]. Treatment was discontinued due to adverse events (primarily gastrointestinal disturbances and rash/urticaria) in <1% of patients, and the incidence of treatment-emergent

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Table 4 Adverse events in patients with uncomplicated UTI, complicated UTI, or acute pyelonephritis treated with extended-release ciprofloxacin or conventional ciprofloxacin [24,50] Uncomplicated UTI

Nausea Vaginal moniliasis Headache Diarrhoea Dizziness Vaginitis

Complicated UTI or acute pyelonephritis

Extended-release ciprofloxacin 500 mg qd (n = 444)

Immediate-release ciprofloxacin 250 mg bid (n = 447)

Extended-release ciprofloxacin (n = 517)

Immediate-release ciprofloxacin 500 mg bid (n = 518)

12 4 7 – – 4

4 10 3 – – 7

15 9 7 12 9 –

15 7 8 7 3 –

(3) (<1) (2)

(<1)

(<1) (2) (<1)

(2)

(3) (2) (1) (2) (2)

(3) (1) (2) (1) (<1)

Values given in parentheses are percentages.

and drug-related adverse events was low. The majority of adverse events were mild or moderate and the frequency of most individual events was <1% [49]. These results are consistent with the findings from the comparative study discussed earlier and confirm the good tolerability and safety of extended-release ciprofloxacin 500 mg qd. Safety and tolerability results with extended-release ciprofloxacin 1000 mg qd in the study of patients with complicated UTIs or acute pyelonephritis were comparable to those obtained with conventional, immediate-release ciprofloxacin 500 mg bid (Table 4) [50]. Premature discontinuation of therapy due to adverse events occurred in 5% of patients receiving extended-release ciprofloxacin 1000 mg qd and in 4% of those treated with conventional ciprofloxacin 500 mg bid. The most frequently reported adverse event in this trial was nausea (3% in both groups) and the overall incidence of adverse events was low [50]. 5.5. Drug interactions Extended-release ciprofloxacin shares an identical profile of drug interactions with conventional, immediate-release ciprofloxacin bid. Co-administration of extended-release ciprofloxacin with omeprazole, didanosine, sulphacrate and antacids or other products containing di- or trivalent cations (e.g. calcium, magnesium, aluminium, iron, or zinc) reduces absorption of ciprofloxacin [42]. Probenecid modifies renal excretion of ciprofloxacin and may therefore increase its levels in serum [42]. Ciprofloxacin decreases the elimination of caffeine and theophylline, and also prevents the generation of paraxanthine after administration of caffeine [42]. In addition, ciprofloxacin may affect the metabolism of phenytoin, and it may also interact with cyclosporines and glyburide [42], and enhance the action of warfarin. Patients treated concurrently with ciprofloxacin and warfarin should be monitored for coagulation status, because ciprofloxacin may increase the antithrombotic activity of warfarin [42]. 5.6. Dosing considerations in special populations No dose adjustment of extended-release ciprofloxacin (500 and 1000 mg qd) is required in the elderly and patients

with stable chronic cirrhosis [42]. In patients with renal impairment (creatinine clearance <30 ml/min), clearance of ciprofloxacin is slightly reduced, and dose adjustment is required for 1000 mg qd extended-release ciprofloxacin (to 500 mg qd extended-release ciprofloxacin), but not for 500 mg qd extended-release ciprofloxacin [42].

6. Conclusions UTI is a common medical condition that affects millions of women in the USA each year and is associated with significant cost. The previously accepted first-line antimicrobial for uncomplicated UTIs, TMP/SMX, has been used to treat these infections for over 20 years, but increasing resistance among common uropathogens has significantly compromised its clinical and bacteriologic efficacy. The rates of resistance to TMP/SMX among E. coli isolates is over 20% in some areas of the USA and approaches or exceeds 30% in Latin America, Europe and the Middle East. High rates of TMP/SMX resistance in different regions of the world and their clinical implications are recognised as an important therapeutic issue by the most recent guidelines developed by the IDSA and EAU, both of which recommend the use of a fluoroquinolone for treatment of uncomplicated UTIs in regions where resistance to TMP/SMX is over 10%. Ciprofloxacin is a highly potent fluoroquinolone, with excellent bactericidal activity against the Gram-negative pathogens commonly associated with UTIs and welldocumented clinical efficacy in a wide range of infections, including UTI. For these reasons, ciprofloxacin has emerged as an important alternative to TMP/SMX in the management of UTI. Compared with conventional, immediate-release ciprofloxacin bid, recently developed extended-release ciprofloxacin qd achieves equivalent AUC with a single daily dose, and provides urinary drug levels that far exceed the MIC90 values for the most prevalent urinary pathogens over the entire 24 h period, thereby permitting convenient, once-daily dosing. In addition, higher peak plasma concentrations with extended-release ciprofloxacin (versus conventional, immediate-release ciprofloxacin) translate into an enhanced Cmax /AUC ratio and a more rapid onset

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of bactericidal action. The results of pharmacokinetic and modelling studies further indicate that extended-release ciprofloxacin may have bactericidal activity superior to that of conventional, immediate-release ciprofloxacin bid. Comparative clinical trials of extended-release ciprofloxacin in patients with uncomplicated UTI and in those with complicated UTIs or acute pyelonephritis have demonstrated clinical and bacteriologic efficacy that is at least equivalent to that of conventional ciprofloxacin, with a similar tolerability and safety profile. These results, along with the convenient once-daily dosing regimen, indicate that the use of extended-release ciprofloxacin may facilitate greater patient compliance with therapy, which can effectively translate into higher rates of clinical and bacteriologic success, while also reducing the spread of TMP/SMX resistance.

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