"The U.S. Food and Drug Administration today approved Zerbaxa (ceftolozane/tazobactam), a new antibacterial drug product, to treat adults with complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI).
CIPRO XR tablets are formulated to release drug at a slower rate compared to immediate-release tablets. Approximately 35% of the dose is contained within an immediate-release component, while the remaining 65% is contained in a slow-release matrix.
Maximum plasma ciprofloxacin concentrations are attained between 1 and 4 hours after dosing with CIPRO XR. In comparison to the 250 mg and 500 mg ciprofloxacin immediate-release BID treatment, the Cmax of CIPRO XR 500 mg and 1000 mg once daily are higher than the corresponding BID doses, while the AUCs over 24 hours are equivalent.
The following table compares the pharmacokinetic parameters obtained at steady state for these four treatment regimens (500 mg QD CIPRO XR versus 250 mg BID ciprofloxacin immediate-release tablets and 1000 mg QD CIPRO XR versus 500 mg BID ciprofloxacin immediate-release).
Ciprofloxacin Pharmacokinetics (Mean ± SD) Following
CIPRO® and CIPRO XR Administration
|T1/2 (hr)||Tmax (hr)§|
|CIPRO XR 500 mg QD||1.59 ± 0.43||7.97 ± 1.87||6.6 ± 1.4||1.5 (1-2.5)|
|CIPRO 250 mg BID||1.14 ± 0.23||8.25 ± 2.15||4.8 ± 0.6||1 (0.5-2.5)|
|CIPRO XR 1000 mg QD||3.11 ± 1.08||16.83 ± 5.65||6.31 ± 0.72||2 (1-4)|
|CIPRO 500 mg BID||2.06 ± 0.41||17.04 ± 4.79||5.66 ± 0.89||2 (0.5-3.5)|
|§ median (range)|
Results of the pharmacokinetic studies demonstrate that CIPRO XR may be administered with or without food (e.g. high-fat and low-fat meals or under fasted conditions).
The volume of distribution calculated for intravenous ciprofloxacin is approximately 2.1 - 2.7 L/kg. Studies with the oral and intravenous forms of ciprofloxacin have demonstrated penetration of ciprofloxacin into a variety of tissues. The binding of ciprofloxacin to serum proteins is 20% to 40%, which is not likely to be high enough to cause significant protein binding interactions with other drugs. Following administration of a single dose of CIPRO XR, ciprofloxacin concentrations in urine collected up to 4 hours after dosing averaged over 300 mg/L for both the 500 mg and 1000 mg tablets; in urine excreted from 12 to 24 hours after dosing, ciprofloxacin concentration averaged 27 mg/L for the 500 mg tablet, and 58 mg/L for the 1000 mg tablet.
Four metabolites of ciprofloxacin were identified in human urine. The metabolites have antimicrobial activity, but are less active than unchanged ciprofloxacin. The primary metabolites are oxociprofloxacin (M3) and sulfociprofloxacin (M2), each accounting for roughly 3% to 8% of the total dose. Other minor metabolites are desethylene ciprofloxacin (Ml), and formylciprofloxacin (M4). The relative proportion of drug and metabolite in serum corresponds to the composition found in urine. Excretion of these metabolites was essentially complete by 24 hours after dosing. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Coadministration of ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the coadministered drug (see CONTRAINDICATIONS; WARNINGS; PRECAUTIONS: DRUG INTERACTIONS).
The elimination kinetics of ciprofloxacin are similar for the immediate-release and the CIPRO XR tablet. In studies comparing the CIPRO XR and immediate-release ciprofloxacin, approximately 35% of an orally administered dose was excreted in the urine as unchanged drug for both formulations. The urinary excretion of ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of ciprofloxacin, which is approximately 300 mL/minute, exceeds the normal glomerular filtration rate of 120 mL/minute. Thus, active tubular secretion would seem to play a significant role in its elimination. Co-administration of probenecid with immediate-release ciprofloxacin results in about a 50% reduction in the ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation. Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after oral dosing with the immediate-release tablet, only a small amount of the dose administered is recovered from the bile as unchanged drug. An additional 1% to 2% of the dose is recovered from the bile in the form of metabolites. Approximately 20% to 35% of an oral dose of immediate-release ciprofloxacin is recovered from the feces within 5 days after dosing. This may arise from either biliary clearance or transintestinal elimination.
Pharmacokinetic studies of the immediate-release oral tablet (single dose) and intravenous (single and multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects ( > 65 years) as compared to young adults. Cmax is increased 16% to 40%, and mean AUC is increased approximately 30%, which can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant. (See PRECAUTIONS, Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. No dose adjustment is required for patients with uncomplicated urinary tract infections receiving 500 mg CIPRO XR For complicated urinary tract infection and acute uncomplicated pyelonephritis, where 1000 mg is the appropriate dose, the dosage of CIPRO XR should be reduced to CIPRO XR 500 mg q24h in patients with creatinine clearance below 30 mL/min. (See DOSAGE AND ADMINISTRATION.)
In studies in patients with stable chronic cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency, however, have not been fully elucidated. (See DOSAGE AND ADMINISTRATION.)
Concomitant administration with tizanidine is contraindicated. (See CONTRAINDICATIONS). Previous studies with immediate-release ciprofloxacin have shown that concomitant administration of ciprofloxacin with theophylline decreases the clearance of theophylline resulting in elevated serum theophylline levels and increased risk of a patient developing CNS or other adverse reactions. Ciprofloxacin also decreases
caffeine clearance and inhibits the formation of paraxanthine after caffeine administration. Absorption of ciprofloxacin is significantly reduced by concomitant administration of multivalent cation-containing products such as magnesium/aluminum antacids, sucralfate, VIDEX® (didanosine) chewable/buffered tablets or pediatric powder, or products containing calcium, iron, or zinc. (See WARNINGS, PRECAUTIONS: DRUG INTERACTIONS and PATIENT INFORMATION, and DOSAGE AND ADMINISTRATION.)
When CIPRO XR given as a single 1000 mg dose was administered two hours before, or four hours after a magnesium/aluminum-containing antacid (900 mg aluminum hydroxide and 600 mg magnesium hydroxide as a single oral dose) to 18 healthy volunteers, there was a 4% and 19% reduction, respectively, in the mean Cmax of ciprofloxacin. The reduction in the mean AUC was 24% and 26%, respectively. CIPRO XR should be administered at least 2 hours before or 6 hours after antacids containing magnesium or aluminum, as well as sucralfate, VIDEX® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, metal cations such as iron, and multivitamin preparations with zinc. Although CIPRO XR may be taken with meals that include milk, concomitant administration with dairy products or with calcium-fortified juices alone should be avoided, since decreased absorption is possible. (See PRECAUTIONS, PATIENT INFORMATION and DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION.)
Omeprazole: When CIPRO XR was administered as a single 1000 mg dose concomitantly with omeprazole (40 mg once daily for three days) to 18 healthy volunteers, the mean AUC and Cmax of ciprofloxacin were reduced by 20% and 23%, respectively. The clinical significance of this interaction has not been determined. (See PRECAUTIONS: DRUG INTERACTIONS.)
Mechanism of Action
The bactericidal action of ciprofloxacin results from inhibition of topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination.
The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of other antimicrobial agents such as beta-lactams, macrolides, tetracyclines, or aminoglycosides; therefore, microorganisms resistant to these classes of drugs may be susceptible to ciprofloxacin. There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials. Resistance to ciprofloxacin in vitro develops slowly (multiple-step mutation). Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between < 10-9 to 1x10-6.
Activity in vitro and in vivo
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive microorganisms Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has littie effect when tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS section of the package insert for CIPRO XR (ciprofloxacin extended-release tablets).
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible)
Aerobic gram-negative microorganisms
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against most ( ≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of CIPRO XR in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Aerobic gram-negative microorganisms
| Citrobacter koseri
| Morganella morganii
- Dilution Techniques
Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ciprofloxacin. The MIC values should be interpreted according to the criteria outlined in Table 1.
- Diffusion Techniques
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-µg ciprofloxacin disk should be interpreted according to the criteria outlined in Table 1. Interpretation involves correlation of the diameter obtained in the disk text with the MIC for ciprofloxacin.
Table 1: Susceptibility Interpretive Criteria for Ciprofloxacin
| Zone Diameter
|Enterobacteriacae||≤ 1||2||≥ 4||≥ 21||16-20||≤ 15|
|Enterococcus faecalis||≤ 1||2||≥ 4||≥ 21||16-20||≤ 15|
|Pseudomonas aeruginosa||≤ 1||2||≥ 4||≥ 21||16-20||≤ 15|
|Staphylococcus saprophyticus||≤ 1||2||≥ 4||≥ 21||16-20||≤ 15|
|S=Susceptible, I=Intermediate, and R=Resistant.|
A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
- Quality Control
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. For dilution technique, standard ciprofloxacin powder should provide the MIC values according to criteria outlined in Table 2. For the diffusion technique, the 5-gciprofloxacin disk shoul d provide the zone diameters outlined in Table 2.
Table 2: Quality Control for Susceptibility Testing
|Strains|| MIC range
| Zone Diameter
|Enterococcus faecalis ATCC29212||0.25-2||-|
|Escherichia coli ATCC 25922||0.004-0.015||30-40|
|Pseudomonas aeruginosa ATCC 27853||0.25-1.0||25-33|
|Staphylococcus aureus ATCC29212||0.12-0.5||-|
|Staphylococcus aureus ATCC25923||-||22-30|
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in beagles, removal of weight bearing from the joint reduced the lesions but did not totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically acidic. In rhesus monkeys, crystalluria without nephropathy has been noted after single oral doses as low as 5 mg/kg. After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of quinolones.
Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals.
Uncomplicated Urinary Tract Infections (acute cystitis)
CIPRO XR was evaluated for the treatment of uncomplicated urinary tract infections (acute cystitis) in a randomized, double-blind, controlled clinical trial conducted in the US. This study compared CIPRO XR (500 mg once daily for three days) with ciprofloxacin immediate-release tablets (CIPRO® 250 mg BID for three days). Of the 905 patients enrolled, 452 were randomly assigned to the CIPRO XR treatment group and 453 were randomly assigned to the control group. The primary efficacy variable was bacteriologic eradication of the baseline organism(s) with no new infection or superinfection at test-of-cure (Day 4-11 Post-therapy).
The bacteriologic eradication and clinical success rates were similar between CIPRO XR and the control group. The eradication and clinical success rates and their corresponding 95% confidence intervals for the differences between rates (CIPRO XR minus control group) are given in the following table:
| CIPRO XR 500 mg
QD x 3 Days
| CIPRO 250 mg
BID x 3 Days
|Per Protocol Patients†||199||223|
|Bacteriologic Eradication at TOC (n/N)*||188/199 (94.5%)||209/223 (93.7%)|
||CI [-3.5%, 5.1%]|
|Bacteriologic Eradication (by organism) at TOC (n/N)**|
|E. coli||156/160 (97.5%)||176/181 (97.2%)|
|E. faecalis||10/11 (90.9%)||17/21 (81%)|
|P. mirabilis||11/12 (91.7%)||7/7 (100%)|
|S. saprophyticus||6/7 (85.7%)||9/9 (100%)|
|Clinical Response at TOC (n/N)***||189/199 (95%)||204/223 (91.5%)|
CI [-1.1%, 8.1%]
|* n/N = patients with baseline
organism(s) eradicated and no new infections or superinfections/ total
number of patients
** n/N = patients with specified baseline organism eradicated/patients with specified baseline organism
*** n/N = patients with clinical success /total number of patients
†The presence of a pathogen at a level of ≥ 105 CFU/mL was required for microbiological evaluability criteria, except for S. saprophyticus ( ≥ 104 CFU/mL).
Complicated Urinary Tract Infections and Acute Uncomplicated Pyelonephritis
CIPRO XR was evaluated for the treatment of complicated urinary tract infections (cUTI) and acute uncomplicated pyelonephritis (AUP) in a randomized, double-blind, controlled clinical trial conducted in the US and Canada. The study enrolled 1,042 patients (521 patients per treatment arm) and compared CIPRO XR (1000 mg once daily for 7 to 14 days) with immediate-release ciprofloxacin (500 mg BID for 7 to 14 days). The primary efficacy endpoint for this trial was bacteriologic eradication of the baseline organism(s) with no new infection or superinfection at 5 to 11 days post-therapy (test-of-cure or TOC) for the Per Protocol and Modified Intent-To-Treat (MITT) populations.
The Per Protocol population was defined as patients with a diagnosis of cUTI or AUP, a causative organism(s) at baseline present at ≥ 105 CFU/mL, no inclusion criteria violation, a valid test-of-cure urine culture within the TOC window, an organism susceptible to study drug, no premature discontinuation or loss to follow-up, and compliance with the dosage regimen (among other criteria). More patients in the CIPRO XR arm than in the control arm were excluded from the Per Protocol population and this should be considered in the interpretation of the study results. Reasons for exclusion with the greatest discrepancy between the two arms were no valid test-of-cure urine culture, an organism resistant to the study drug, and premature discontinuation due to adverse events.
An analysis of all patients with a causative organism(s) isolated at baseline and who received study medication, defined as the MITT population, included 342 patients in the CIPRO XR arm and 324 patients in the control arm. Patients with missing responses were counted as failures in this analysis. In the MITT analysis of cUTI patients, bacteriologic eradication was 160/271 (59%) versus 156/248 (62.9%) in CIPRO XR and control arm, respectively [97.5% CI* (-13.5%, 5.7%)]. Clinical cure was 184/271 (67.9%) for CIPRO XR and 182/248 (73.4%) for control arm, respectively [97.5% CI* (-14.4%, 3.5%)]. Bacterial eradication in the MITT analysis of patients with AUP at TOC was 47/71 (66.2%) and 58/76 (76.3%) for CIPRO XR and control arm, respectively [97.5% CI* (-26.8%, 6.5%)]. Clinical cure at TOC was 50/71 (70.4%) for CIPRO XR and 58/76 (76.3%) for the control arm [97.5% CI* (-22.0%, 10.4%)].
In the Per Protocol population, the differences between CIPRO XR and the control arm in bacteriologic eradication rates at the TOC visit were not consistent between AUP and cUTI patients. The bacteriologic eradication rate for cUTI patients was higher in the CIPRO XR arm than in the control arm. For AUP patients, the bacteriologic eradication rate was lower in the CIPRO XR arm than in the control arm. This inconsistency was not observed between the two treatment groups for clinical cure rates. Clinical cure rates were 96.1% (198/206) and 92.1% (211/229) for CIPRO XR and the control arm, respectively.
The bacterial eradication and clinical cure rates by infection type for CIPRO XR and the control arm at the TOC visit and their corresponding 97.5% confidence intervals for the differences between rates (CIPRO XR minus control arm) are given below for the Per Protocol population analysis:
| CIPRO XR
500 mg BID
|Per Protocol Patients^||206||229|
|Bacteriologic Eradication at TOC (n/N)*||148/166 (89.2%)||144/177 (81.4%)|
|CI [-0.7%, 16.3%]|
|Bacteriologic Eradication (by organism) at TOC (n/N)**|
|E. coli||91/94 (96.8%)||90/92 (97.8%)|
|K. pneumoniae||20/21 (95.2%)||19/23 (82.6%)|
|E. faecalis||17/17 (100%)||14/21 (66.7%)|
|P. mirabilis||11/12 (91.6%)||10/10 (100%)|
|P. aemginosa||3/3 (100%)||3/3 (100%)|
|Clinical Cure at TOC (n/N)***||159/166 (95.8%)||161/177 (91.0%)|
|CI [-1.1%, 10.8%]|
|Bacteriologic Eradication at TOC (n/N)*||35/40 (87.5%)||51/52 (98.1%)|
|CI [-34.8%, 6.2%]|
|Bacteriologic Eradication of E. coli at TOC (n/N)**||35/36 (97.2%)||41/41 (100%)|
|Clinical Cure at TOC (n/N)***||39/40 (97.5%)||50/52 (96.2%)|
|CI [-15.3%, 21.1%]|
|A Patients excluded from the Per Protocol population
were primarily those with no causative organism(s) at baseline or no organism
present at > 105 CFU/mL at baseline, inclusion criteria violation, no
valid test-of-cure urine culture within the TOC window, an organism resistant
to study drug, premature discontinuation due to an adverse event, lost to
follow-up, or non-compliance with dosage regimen (among other criteria).
* n/N = patients with baseline organism(s) eradicated and no new infections or superinfections/total number of patients
** n/N = patients with specified baseline organism eradicated/patients with specified baseline organism
***n/N = patients with clinical success /total number of patients
Of the 166 cUTI patients treated with CIPRO XR, 148 (89%) had the causative organising) eradicated, 8 (5%) had persistence, 5 (3%) patients developed superinfections and 5 (3%) developed new infections. Of the 177 cUTI patients treated in the control arm, 144 (81%) had the causative organism(s) eradicated, 16 (9%) patients had persistence, 3 (2%) developed superinfections and 14 (8%) developed new infections. Of the 40 patients with AUP treated with CIPRO XR, 35 (87.5%) had the causative organism(s) eradicated, 2 (5%) patients had persistence and 3 (7.5%) developed new infections. Of the 5 CIPRO XR AUP patients without eradication at TOC, 4 were considered clinical cures and did not receive alternative antibiotic therapy. Of the 52 patients with AUP treated in the control arm, 51 (98%) had the causative organism(s) eradicated. One patient (2%) had persistence.
* confidence interval of the difference in rates (CIPRO XR minus control).
1. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically: Approved Standard - Eighth Edition. CLSI Document M7-A8, Vol. 29, No. 2, CLSI, Wayne, PA, January, 2009.
2. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk Susceptibility Tests: Approved Standard - Tenth Edition. CLSI Document M2-A10, Vol. 29, No. 1, CLSI, Wayne, PA, January, 2009.
Last reviewed on RxList: 7/21/2011
This monograph has been modified to include the generic and brand name in many instances.
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