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Ciprofloxacin Hydrochloride

Ciprofloxacin is a fluoroquinolone anti-infective agent.

Laboratory Test Interferences

Tests for Urinary Glucose

Ciprofloxacin hydrochloride does not interfere with urinary glucose determinations using cupric sulfate solution (e.g., Benedict’s solution, Clinitest®) or with glucose oxidase tests (e.g., Diastix®, Tes-Tape®).

Acute Toxcicity

Limited information is available on the acute toxicity of ciprofloxacin in humans.

The oral LD50 of the drug is greater than 5 g/kg in mice and rats and approximately 2.5 g/kg in rabbits. In mice, rats, rabbits, and dogs, significant toxicity (including tonic/clonic convulsions) was observed with IV ciprofloxacin doses between 125 and 300 mg/kg. If acute overdosage of ciprofloxacin occurs, the stomach should be emptied by inducing emesis or by gastric lavage. If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents.

Supportive and symptomatic treatment should be initiated, and the patient should be observed carefully; adequate hydration must be maintained to minimize the risk of crystalluria. The manufacturer states that if serious toxic reactions occur following overdosage, hemodialysis or peritoneal dialysis may enhance elimination of the drug from the body, especially in patients with impaired renal function. However, some clinicians suggest that the risks associated with hemodialysis or peritoneal dialysis do not justify their possible benefits since only small amounts of the drug are removed by these procedures.

Mechanism of Action

Antibacterial Effects

Ciprofloxacin usually is bactericidal in action. Like other fluoroquinolone anti-infectives, ciprofloxacin inhibits DNA synthesis in susceptible organisms via inhibition of the enzymatic activities of 2 members of the DNA topoisomerase class of enzymes, DNA gyrase and topoisomerase IV. DNA gyrase and topoisomerase IV have distinct essential roles in bacterial DNA replication. DNA gyrase, a type II DNA topoisomerase, was the first identified quinolone target; DNA gyrase is a tetramer composed of 2 GyrA and 2 GyrB subunits.

DNA gyrase introduces negative superhelical twists in DNA, an activity important for initiation of DNA replication. DNA gyrase also facilitates DNA replication by removing positive super helical twists. Topoisomerase IV, another type II DNA topoisomerase, is composed of 2 ParC and 2 ParE subunits. DNA gyrase and topoisomerase IV are structurally related; ParC is homologous to GyrA and ParE is homologous to GyrB.

Topoisomerase IV acts at the terminal states of DNA replication by allowing for separation of interlinked daughter chromosomes so that segregation into daughter cells can occur. Fluoroquinolones inhibit these topoisomerase enzymes by stabilizing either the DNA—DNA gyrase complex or the DNA—topoismerase IV complex; these stabilized complexes block movement of the DNA replication fork and thereby inhibit DNA replication resulting in cell death. Although all fluoroquinolones generally are active against both DNA gyrase and topoisomerase IV, the drugs differ in their relative activities against these enzymes.

For many gram-negative bacteria, DNA gyrase is the primary quinolone target and for many gram-positive bacteria, topoisomerase IV is the primary target; the other enzyme is the secondary target in both cases. However, there are exceptions to this pattern. For certain bacteria (e.g., Streptococcus pneumoniae), the principal target depends on the specific fluoroquinolone. The mechanism by which ciprofloxacin’s inhibition of DNA gyrase or topoisomerase IV results in death in susceptible organisms has not been fully determined. Unlike b-lactam anti-infectives, which are most active against susceptible bacteria when they are in the logarithmic phase of growth, studies using Escherichia coli and

Pseudomonas aeruginosa indicate that ciprofloxacin can be bactericidal during both logarithmic and stationary phases of growth; this effect does not appear to occur with gram-positive bacteria (e.g., Staphylococcus aureus).

In vitro studies indicate that ciprofloxacin concentrations that approximate the minimum inhibitory concentration (MIC) of the drug induce filamentation in susceptible organisms; high concentrations of the drug result in enlarged or elongated cells that may not be extensively filamented.

Although the bactericidal effect of some fluoroquinolones (e.g., norfloxacin) evidently requires competent RNA and protein synthesis in the bacterial cell, and concurrent use of anti-infectives that affect protein synthesis (e.g., chloramphenicol, tetracyclines) or RNA synthesis (e.g., rifampin) inhibit the in vitro bactericidal activity of these drugs, the bactericidal effect of ciprofloxacin is only partially reduced in the presence of these anti-infectives.

This suggests that ciprofloxacin has an additional mechanism of action that is independent of RNA and protein synthesis. For most susceptible organisms, the minimum bactericidal concentration (MBC) of ciprofloxacin is 1-4 times higher than the MIC, although the MBC occasionally may be 8 times higher. Mammalian cells contain type II topoisomerase similar to that contained in bacteria. At concentrations attained during therapy, quinolones do not appear to affect the mammalian enzyme, presumably because it functions differently than bacterial DNA gyrase and does not cause supercoiling of DNA.

Although the clinical importance has not been determined, ciprofloxacin appears to have a postantibiotic inhibitory effect against most susceptible aerobic organisms. The duration of the postantibiotic inhibitory effect and the ciprofloxacin concentration required to produce the effect vary depending on the organism; the duration of this effect also varies according to length of exposure to the drug, increasing with increased exposure.

In vitro studies in Mueller-Hinton broth using S. aureus, Enterobacteriaceae, and Ps. aeruginosa exposed for 1-2 hours to ciprofloxacin concentrations several times higher than the MIC indicate that there is a recovery period of about 1-6 hours before these organisms resume growth after the drug is removed.

Equivocal results have been observed following in vitro exposure of Enterococcus faecalis (formerly Streptococcus faecalis) to the drug, and it is unclear whether the drug exerts a postantibiotic inhibitory effect against this organism. In vitro studies, particularly those involving in vitro susceptibility tests, indicate that the antibacterial activity of ciprofloxacin is decreased in the presence of urine, especially acidic urine. The clinical importance of this in vitro effect has not been determined to date; however, because ciprofloxacin concentrations attained in urine are usually substantially higher than ciprofloxacin MICs for most urinary tract pathogens, the effect probably is not clinically important. The antibacterial activity of ciprofloxacin also is decreased slightly in unbuffered peritoneal dialysis fluid with a pH of 5.5 compared with its activity in dialysis fluid buffered to a pH of 7.4.

Effects on Immune Function

Ciprofloxacin is concentrated within human neutrophils; intracellular concentrations of the drug may be 2-7 times greater than extracellular concentrations. Intracellular ciprofloxacin is microbiologically active, and in vitro studies indicate that the drug can reduce survival of intracellular organisms (e.g., S. aureus, Serratia marcescens, Mycobacterium fortuitum).

Studies in mice indicate that the drug may also reduce in vivo survival of intracellular Salmonella typhimurium. Uptake of ciprofloxacin by human neutrophils is rapid, easily reversible when extracellular concentrations of the drug are reduced, and occurs via diffusion rather than by an active transport mechanism. In vitro studies indicate that preincubation with ciprofloxacin has no direct effect on chemotaxis, phagocytosis, and/or killing by human polymorphonuclear leukocytes (PMNs) or mononuclear leukocytes; however, low concentrations of the drug may enhance phagocytosis and killing of S. aureus by human PMNs.

There is some evidence that low concentrations of ciprofloxacin may unmask previously encapsulated cell envelope components of Klebsiella pneumoniae, making them more accessible to complement and immunoglobulins. Although results have been conflicting, in vitro studies indicate that low concentrations of ciprofloxacin (0.2-12 mcg/mL) increase thymidine uptake by human lymphocytes following stimulation by phytohemagglutinin and other mitogens and that high concentrations of the drug (20 mcg/mL or greater) may decrease thymidine uptake.

There is evidence that ciprofloxacin may block pyrimidine, but not purine, metabolism resulting in a compensatory increased uptake of pyrimidine nucleotide precursors through salvage pathways. In some in vitro studies, ciprofloxacin did not appear to affect human mitogen-stimulated mononuclear cell proliferation at concentrations up to 125 mcg/mL; however, in other studies, in vitro proliferation of these cells was inhibited by ciprofloxacin concentrations of 25-100 mcg/mL.

Studies using human monocytes indicate that high concentrations of ciprofloxacin decrease extracellular interleukin 1, which is essential for antigen- and mitogen-induced T-cell activation, but do not affect cell-associated interleukin 1.162 The clinical importance of these in vitro effects has not been determined.

Chemistry and Stability

Chemistry

Ciprofloxacin Ciprofloxacin is a fluoroquinolone anti-infective agent. Like other commercially available fluoroquinolones, ciprofloxacin contains a fluorine at the C-6 position of the quinolone nucleus. Like some other fluoroquinolones (gatifloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, sparfloxacin), ciprofloxacin contains a piperazinyl group at position 7 of the quinolone nucleus. The piperazinyl group in ciprofloxacin results in antipseudomonal activity.

The drug also contains a cyclopropyl group at position 1, which enhances antimicrobial activity. Ciprofloxacin is commercially available for oral administration as conventional tablets containing ciprofloxacin hydrochloride, which is the monohydrochloride monohydrate of the drug. Ciprofloxacin hydrochloride occurs as a faintly yellowish to yellow crystalline powder.

Ciprofloxacin hydrochloride has a solubility of approximately 36 mg/mL in water at 25°C. The pKas of the drug are 6 and 8.8. Ciprofloxacin also is commercially available for oral administration as extended-release tablets containing ciprofloxacin (base) and ciprofloxacin hydrochloride. The extended-release tablets contain approximately 35% of the dose within an immediate-release component; the remaining 65% of the dose is contained in a slow-release matrix.

Ciprofloxacin (base) occurs as a pale yellowing to light yellow crystalline powder. In addition, ciprofloxacin also is commercially available for oral administration as microcapsules for oral suspension. Following mixture with the diluent provided by the manufacturer, ciprofloxacin oral suspensions containing 250 or 500 mg of the drug per 5 mL occur as a strawberry-flavored, white to slightly yellowish suspension and may contain yellow-orange droplets. For IV administration, ciprofloxacin is commercially available as the lactate salt. Ciprofloxacin concentrate for injection and the commercially available injection for IV infusion are prepared with the aid of lactic acid and contain the drug as the lactate salt; potency is expressed in terms of ciprofloxacin.

The concentrate and the commercially available injection for IV infusion occur as clear, colorless to slightly yellow solutions. The concentrate for injection and the commercially available 1.2-g pharmacy bulk package contain the drug in an aqueous solution and have a pH of 3.3-3.9; the commercially available injection for IV infusion contains the drug in 5% dextrose injection and has a pH of 3.5-4.5. The concentrate and commercially available injection for IV infusion also contain hydrochloric acid to adjust pH.

Stability

Ciprofloxacin hydrochloride conventional tablets should be stored in tight containers at a temperature less than 30°C, and protected from intense UV light. Ciprofloxacin extended-release tablets should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.

Ciprofloxacin microcapsules for oral suspension and the diluent provided by the manufacturer should be stored at less than 25°C and protected from freezing. Following mixture with the diluent, ciprofloxacin oral suspension should be stored at less than 30°C and protected from freezing, and is stable for 14 days when stored at room temperature or in a refrigerator.

Aqueous solutions of ciprofloxacin hydrochloride having a pH of 1.5-7.5 are stable for at least 14 days at room temperature. Ciprofloxacin lactate concentrate for injection should be stored at 5-25°C and the commercially available injection for IV infusion should be stored at 5-30°C; the commercially available 1.2-g pharmacy bulk package of the drug should be stored at 5-30°C.

These preparations should be protected from light and freezing, and exposure to temperatures exceeding 40°C should be avoided. When the concentrate for injection or 1.2-g pharmacy bulk package is diluted with sterile water for injection, 5% or 10% dextrose injection, 0.9% sodium chloride injection, 5% dextrose and 0.225 or 0.45% sodium chloride injection, or lactated Ringer’s injection to a final concentration of 0.5-2 mg/mL, the resultant solutions are stable for up to 14 days when stored at room temperature or when refrigerated at 2-8°C.

The commercially available injection for IV infusion containing 2 mg/mL in 5% dextrose is provided in a plastic container fabricated from specially formulated polyvinyl chloride (PVC). Solutions in contact with the plastic can leach out some of the chemical components in very small amounts (e.g., bis(2-ethylhexyl)phthalate [BEHP, DEHP]in up to 5 ppm) within the expiration period of the injection; however, safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.

Preparations

Ciprofloxacin Oral For suspension 250 mg/5 mL Cipro®, (with povidone) Bayer 500 mg/5 mL Cipro®, (with povidone) Bayer  Ciprofloxacin and Ciprofloxacin Hydrochloride Oral Tablets, extended- 500 mg total ciprofloxacin Cipro® XR, release, film- (with ciprofloxacin 212. mg Bayer coated [of anhydrous ciprofloxacin] and ciprofloxacin hydrochloride 287. mg [of anhydrous  ciprofloxacin]) Ciprofloxacin Hydrochloride Oral Tablets, film- 100 mg (of ciprofloxacin) Cipro® Cystitis Pack, coated Bayer 250 mg (of ciprofloxacin) Cipro®, Bayer 500 mg (of ciprofloxacin) Cipro®, Bayer 750 mg (of ciprofloxacin) Cipro®, Bayer Ciprofloxacin Lactate Parenteral For injection 10 mg (of ciprofloxacin) per Cipro® I.V., concentrate, for mL (200 or 400 mg) Bayer IV infusion 10 mg (of ciprofloxacin) per Cipro® I.V., mL (1. g) pharmacy bulk Bayer package Ciprofloxacin Lactate in Dextrose Parenteral Injection, for IV 2 mg (of ciprofloxacin) per Cipro® I.V. in 5% Dextrose infusion mL (200 or 400 mg) in 5% Injection, (in flexible dextrose container) Bayer

Ciprofloxacin Hydrochloride: Pharmacokinetics

In studies in the Pharmacokinetics section, ciprofloxacin was administered orally as conventional tablets containing the monohydrochloride monohydrate salt (i.e., ciprofloxacin hydrochloride), as extended-release tablets containing ciprofloxacin (base) and ciprofloxacin hydrochloride, or as an oral suspension containing the base; the drug was administered parenterally as the lactate salt.

Dosages and concentrations of the drug are expressed in terms of ciprofloxacin. Body fluid and tissue concentrations of ciprofloxacin were measured with either a high-pressure liquid chromatographic (HPLC) assay,or a microbiologic assay. HPLC assays are more specific for ciprofloxacin than microbiologic assays since the latter method measures the antibacterial activity of the parent drug as well as its microbiologically active metabolites.

Controlled studies using HPLC and microbiologic assays indicate that there is good correlation between both methods for serum ciprofloxacin concentrations and pharmacokinetic parameters determined using these serum concentrations. However, mean ciprofloxacin concentrations in urine or bile generally are 30-40% higher when a microbiologic assay is used than when an HPLC assay is used.

The pharmacokinetics of ciprofloxacin after oral administration (as the hydrochloride) are best described by a 2-compartment model assuming zero-order absorption, and pharmacokinetics after IV administration (as the lactate) are best described by an open, 3-compartment model. The manufacturer states that a 500-mg dose of ciprofloxacin administered as ciprofloxacin oral suspension containing 250 mg/5 mL is bioequivalent to a 500-mg conventional tablet and that 10 mL of the ciprofloxacin oral suspension containing 250 mg/5 mL is bioequivalent to 5 mL of the oral suspension containing 500 mg/5 mL.

Ciprofloxacin conventional tablets are not bioequivalent to ciprofloxacin extended-release tablets.

Absorption

Oral Administration

Ciprofloxacin hydrochloride is rapidly and well absorbed from the GI tract following oral administration, and undergoes minimal first-pass metabolism. Presence of food in the GI tract decreases the rate but not the extent of absorption of ciprofloxacin administered as conventional tablets; food does not affect pharmacokinetics of ciprofloxacin administered as the oral suspension.

Concomitant administration with dairy products (milk, yogurt) alone may substantially reduce GI absorption of ciprofloxacin; however, absorption is not affected substantially by dietary calcium that is part of a meal. Magnesium-, aluminum-, and/or calcium-containing antacids or products containing calcium, iron, or zinc decrease the oral bioavailability of ciprofloxacin hydrochloride. (See Drug Interactions: Antacids.)

The oral bioavailability of ciprofloxacin administered as conventional tablets is 50-85% in healthy, fasting adults, and peak serum concentrations of the drug generally are attained within 0.5-2.3 hours. Peak serum concentrations and area under the serum concentration-time curve (AUC) increase in proportion to the dose over the oral dosage range of 250-1000 mg and are unaffected by gender.

Following oral administration of a single 250-, 500-, 750-, or 1000-mg dose of ciprofloxacin as conventional tablets or oral suspension in healthy, fasting adults, peak serum concentrations average 0.76-1.5, 1.6-2.9, 2.5-4.3, or 3.4-5.4 mcg/mL, respectively; serum concentrations 12 hours after the dose average 0.1, 0.2, 0.4, or 0.6 mcg/mL, respectively. In adults, oral administration of 500 mg of ciprofloxacin as conventional tablets every 12 hours results in mean peak or trough serum concentrations at steady-state of 2.97 or 0.2 mcg/mL, respectively.

Following oral administration of ciprofloxacin extended-release tablets, peak plasma concentrations are attained within 1-4 hours. Extended-release tablets contain approximately 35% of the dose within an immediate-release component; the remaining 65% of the dose is contained in a slow-release matrix.

Oral administration of ciprofloxacin 500 mg daily as extended-release tablets or 250 mg twice daily as conventional tablets results in steady-state mean peak plasma concentrations of 1.59 or 1.14 mcg/mL, respectively; however, the area under the concentration-time curve (AUC) is similar with both regimens. Peak serum concentrations of ciprofloxacin and AUCs of the drug are slightly higher in geriatric patients than in younger adults; this may occur because of increased bioavailability, reduced volume of distribution, and/or reduced renal clearance in these patients.

Single-dose oral studies using ciprofloxacin conventional tablets and single- and multiple-dose IV studies indicate that, compared with younger adults, peak plasma concentrations are 16-40% higher, mean AUC is approximately 30% higher, and elimination half-life is prolonged approximately 20% in individuals older than 65 years of age. The manufacturer states that these differences can be at least partially attributed to decreased renal clearance in this age group and are not clinically important. In one study, GI absorption of ciprofloxacin was slower and the elimination half-life of the drug was shorter in cystic fibrosis patients 18 years of age or older than in healthy adults.

Several other studies, however, indicate that the pharmacokinetics of ciprofloxacin are not appreciably altered in cystic fibrosis patients 18 years of age or older compared with healthy adults. Although peak serum concentrations of ciprofloxacin and the AUC increased slightly after repeated oral doses in a few studies in fasting, healthy adults, most multiple-dose studies in fasting, healthy adults with normal renal function indicate that neither peak nor trough serum concentrations of ciprofloxacin increase after repeated oral doses and that the drug does not accumulate.

IV Administration

Following IV infusion over 60 minutes of a single 200- or 400-mg dose of ciprofloxacin in healthy adults, peak serum concentrations average 2.1 and 4.6 mcg/mL, respectively, immediately following the infusion; serum concentrations 6 hours after the start of infusion (i.e., 5 hours after completion) average 0.3 and 0.7 mcg/mL and those 12 hours after the start of infusion average 0.1 and 0.2 mcg/mL, respectively. In adults receiving 400 mg of ciprofloxacin IV every 12 hours, mean peak or trough serum concentrations at steady-state are 4.56 or 0.2 mcg/mL, respectively.

In a limited number of pediatric patients 6-16 years of age who received 2 ciprofloxacin doses of 10 mg/kg given by IV infusion over 30 minutes 12 hours apart, mean peak plasma concentrations were 8.3 mcg/mL and trough concentrations ranged from 0.09-0. mcg/mL. After the second IV infusion, these pediatric patients were switched to oral ciprofloxacin given in a dosage of 15 mg/kg every 12 hours and achieved a mean peak concentration of 3.6 mcg/mL after the initial oral dose.

Following IV injection over 15 minutes of a single 100-mg dose of ciprofloxacin in healthy adults, serum concentrations of the drug average 2.8 mcg/mL immediately following the injection and 0.32, 0.14, and 0.07 mcg/mL at 1, 6, and 12 hours, respectively, after the dose. In healthy adults who receive a single 200-mg dose of ciprofloxacin by IV injection over 10 minutes, serum concentrations of the drug immediately following the injection average 6.3-6. mcg/mL and serum concentrations 1 and 12 hours later average 0.87 and 0.1 mcg/mL, respectively.

Distribution

Ciprofloxacin is widely distributed into body tissues and fluids following oral or IV administration. Highest concentrations of the drug generally are attained in bile, lungs, kidney, liver, gallbladder, uterus, seminal fluid, prostatic tissue and fluid, tonsils, endometrium, fallopian tubes, and ovaries.

Concentrations of the drug achieved in most of these tissues and fluids substantially exceed those in serum. The drug also is distributed into bone, aqueous humor, sputum, saliva, nasal secretions, skin, muscle, adipose tissue, cartilage, and pleural, peritoneal, ascitic, blister, lymphatic, and renal cyst fluid. Ciprofloxacin is concentrated within neutrophils, achieving concentrations in these cells that may be 2-7 times greater than extracellular concentrations. In healthy adults, the apparent volume of distribution of ciprofloxacin is 2-3.5 L/kg and the apparent volume of distribution at steady state is 1.7-2.7 L/kg.

The apparent volume of distribution of ciprofloxacin in geriatric patients 64-91 years of age averages 3.5-3.6 L/kg. Only low concentrations of ciprofloxacin are distributed into CSF; peak CSF concentrations may be 6-10% of peak serum concentrations. In adults with meningitis who received 200-mg doses of ciprofloxacin every 12 hours by IV infusion over 30 minutes, the ratio of CSF/serum concentrations in samples obtained 1-2 hours after a dose was 0.11-0.46 during the first 2-4 days of therapy when meninges were inflamed and 0.04-0.3 during days 10-14 when meninges were uninflamed.

Following oral or IV administration of the drug, biliary ciprofloxacin concentrations are several fold higher than simultaneous serum concentrations of the drug. In adults undergoing cholecystectomy who received a single 750-mg oral dose of ciprofloxacin, peak concentrations of the drug and active metabolites ranged from 68-225 mcg/mL in gallbladder bile, 16-17 mcg/mL in common duct bile, 3.6-32.4 mcg/g in liver, 0.8-14.1 mcg/g in gallbladder, and 1.5-7.8 mcg/mL in serum. Following oral administration, ciprofloxacin concentrations in prostatic tissue and fluid generally exceed concurrent serum concentrations of the drug. In a study in men undergoing transurethral resection for prostatic hyperplasia or cancer who received 500 mg of the drug orally every 12 hours, ciprofloxacin concentrations in prostatic tissue obtained 75-120 minutes after a dose averaged 3 mg/kg and the ratio of prostate/serum concentrations ranged from 1-7.

Ciprofloxacin is 16-43% bound to serum proteins in vitro. Ciprofloxacin crosses the placenta and is distributed into amniotic fluid in humans. The drug is also distributed into milk. In lactating women who received 750 mg of ciprofloxacin every 12 hours for 3 doses, concentrations of the drug in milk obtained 2-4 hours after a dose averaged 2.26-3. mcg/mL; milk concentrations were higher than concomitant serum concentrations for up to 12 hours after a dose.

Elimination

The serum elimination half-life of ciprofloxacin in adults with normal renal function is 3-7 hours.Following IV administration in healthy adults, the distribution half-life of ciprofloxacin averages 0.18-0.37 hours and the elimination half-life averages 3-4. hours.

The elimination half-life of the drug is slightly longer in geriatric adults than in younger adults, and ranges from 3.3-6.8 hours in adults 60-91 years of age with renal function normal for their age. In patients with impaired renal function, serum concentrations of ciprofloxacin are higher and the half-life prolonged. In adults with creatinine clearances of 30 mL/minute or less, half-life of the drug ranges from 4.4-12. hours. Further study is needed to determine whether half-life of ciprofloxacin is affected by hepatic impairment, although slight prolongation has been reported. Ciprofloxacin is eliminated by renal and nonrenal mechanisms. The drug is partially metabolized in the liver by modification of the piperazinyl group to at least 4 metabolites.

These metabolites, which have been identified as desethyleneciprofloxacin (M1), sulfociprofloxacin (M2), oxociprofloxacin (M3), and N-formylciprofloxacin (M4), have microbiologic activity that is less than that of the parent drug but may be similar to or greater than that of some other quinolones (e.g., M3 and M4 are comparable to norfloxacin for certain organisms).

Ciprofloxacin and its metabolites are excreted in urine and feces. Unchanged ciprofloxacin is excreted in urine by both glomerular filtration and tubular secretion. Following oral administration of a single 250-, 500-, or 750-mg dose in adults with normal renal function, 15-50% of the dose is excreted in urine as unchanged drug and 10-15% as metabolites within 24 hours; 20-40% of the dose is excreted in feces as unchanged drug and metabolites within 5 days. Most, but not all, of unchanged ciprofloxacin in feces appears to result from biliary excretion.

Renal clearance of ciprofloxacin averages 300-479 mL/minute in adults with normal renal function. Urinary concentrations of ciprofloxacin generally exceed 200 mcg/mL during the first 2 hours and average about 30 mcg/mL 8-12 hours after a single 250-mg oral dose of the drug. Following oral administration of a single 500-mg dose in adults with normal renal function, urinary concentrations of ciprofloxacin and active metabolites average 350, 162, and 105 mcg/mL in urine collected over 1-3, 3-6, and 6-12 hours, respectively, after the dose.

Concentrations of unchanged drug and active metabolites in feces range from 185-2220 mcg/g after 7 days of therapy with the drug in a dosage of 500 mg every 12 hours. Small amounts of ciprofloxacin are removed by hemodialysis.

The amount of the drug removed during hemodialysis depends on several factors (e.g., type of coil used, dialysis flow rate). In patients with end-stage renal disease undergoing hemodialysis, the serum half-life of ciprofloxacin averaged 3.2 hours during hemodialysis and 5.8 hours between dialysis sessions. A 4-hour period of hemodialysis generally removes into the dialysate 2-30% of a single 250- or 500-mg oral dose of the drug. Only small amounts of ciprofloxacin appear to be removed by peritoneal dialysis.

Ciprofloxacin Hydrochloride: Resistance

Resistance to ciprofloxacin can be produced in vitro in some organisms, including some strains of Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis (formerly Streptococcus faecalis), by serial passage in the presence of increasing concentrations of the drug. Ciprofloxacin resistance resulting from spontaneous mutation occurs rarely in vitro (i.e., with a frequency of 10-9 to 10-7).

Resistant strains of Ps. aeruginosa have emerged occasionally during therapy with the drug. Ciprofloxacin-resistant strains of S. aureus (including oxacillin-resistant strains; previously known as methicillin-resistant strains or MRSA) and S. epidermidis also have emerged during therapy with the drug. Strains of S. aureus, especially oxacillin-resistant S. aureus resistant to ciprofloxacin and other fluoroquinolones have been reported with increasing frequency, and such strains can emerge at relatively rapid rates (e.g., increasing within an institution from 0% of isolates prior to introduction of the drug to 80% 1 year later for oxacillin-resistant S. aureus).

Rapid emergence of resistance to fluoroquinolones in Campylobacter also has been reported and appears to be associated with widespread use or prolonged therapy with the drugs. Over a 10- to 12-year period in Finland, fluoroquinolone-resistant strains of C. jejuni and C. coli increased from 0-4% to 9-11%. A similar increase was observed over a 7-year period in Campylobacter isolates obtained from poultry and humans in the Netherlands; this increase in resistance was attributed to use of enrofloxacin in the poultry industry. In the US, fluoroquinolone-resistant isolates of Campylobacter have been obtained from raw turkey or chicken products in the retail market. Ciprofloxacin-resistant strains of initially susceptible Mycobacterium fortuitum have developed in a few patients who received ciprofloxacin alone or in conjunction with amikacin.

Resistance in Neisseria gonorrhoeae

Strains of Neisseria gonorrhoeae with decreased susceptibility to ciprofloxacin and other fluoroquinolones have been reported within the last several years. Until 1992, virtually all strains of N. gonorrhoeae tested were susceptible to ciprofloxacin in vitro; however, in vitro susceptibility of the organism to fluoroquinolones is changing. Strains of N. gonorrhoeae with decreased susceptibility to fluoroquinolones are endemic in many Asian countries and have been reported sporadically in other parts of the world, including North America, Australia, Africa, and Great Britain. In the US, strains with decreased susceptibility to fluoroquinolones have been isolated from patients in Hawaii, Ohio, Oregon, California, and Washington.

In some cases, these isolates appeared to have been introduced into the US by travelers returning from the Philippines; however, in Ohio, these strains appeared to have been transmitted locally and were not linked to travel outside the US.

The recent increase in ciprofloxacin-resistant N. gonorrhoeae in Hawaii also appears to be the result of endemic spread. The prevalence of quinolone-resistant N. gonorrhoeae (QRNG) in the US is being monitored by the CDC Gonococcal Isolate Surveillance Project (GISP). According to GISP data, about 6% of urethral isolates collected from samples of men at sexually transmitted diseases (STD) clinics in Cleveland, Ohio from January 1992 to June 1993 had decreased susceptibility to ciprofloxacin; expanded screening of all isolates from men at one clinic in Ohio during November and December 1993 revealed that about 14% of isolates had decreased susceptibility.

There is some evidence that strains of N. gonorrhoeae with reduced susceptibility to ciprofloxacin that were identified in Hawaii were different phenotypically than the strains identified in Ohio. The clinical importance of reduced susceptibility to fluoroquinolones has not been fully determined, and it is unclear whether uncomplicated gonococcal infections caused by these strains respond to currently recommended single-dose fluoroquinolone regimens.

Treatment failures have been reported with the currently recommended single-dose regimens; the likelihood of treatment failure seems greatest when the gonococcal strain has a ciprofloxacin MIC of 1 mcg/mL or greater. During 1996, less than 0.05% of clinical isolates collected by GISP in the US had ciprofloxacin MICs of 1 mcg/mL or greater.

If Hawaii is excluded, 0.2% of isolates collected by GISP in the US in 1999 were resistant to fluoroquinolones. GISP data collected during 2000 indicate that 0.4% of clinical isolates were resistant to ciprofloxacin (MICs 1 mcg/mL or greater); although QRNG made up 0.2% of samples collected from 25 cities within the continental US and Alaska, 14.% of isolates from the Honolulu GISP sample were QRNG. The CDC states that, as long as QRNG comprise less than 1% of all N. gonorrhoeae strains isolated at each of the cities included in the GISP sample, fluoroquinolone regimens recommended for treatment of gonorrhea can be used with confidence.

However, importation of QRNG will probably continue and the prevalence of these strains in the US could increase to the point that fluoroquinolones no longer reliably eradicate gonococcal infections. Strains ofN. gonorrhoeae with decreased susceptibility to ciprofloxacin also have decreased susceptibility to other fluoroquinolones (e.g., lomefloxacin, norfloxacin, ofloxacin), but may be susceptible to ceftriaxone, cefixime, and spectinomycin. A few strains with decreased susceptibility to ciprofloxacin also were resistant to tetracycline.

Resistance in Bacillus anthracis

Strains of Bacillus anthracis with natural resistance to ciprofloxacin have not been reported to date. There are published reports of B. anthracis strains that have been engineered to have tetracycline and penicillin resistance as well as resistance to other anti-infectives (e.g., macrolides, chloramphenicol, rifampin). In addition, reduced susceptibility to ofloxacin (4-fold increase in MICs from baseline) has been produced in vitro following sequential subculture of the Sterne strain of B. anthracis in subinhibitory concentrations of the fluoroquinolone.

Mechanisms of Fluoroquinolone Resistance

The mechanism(s) of resistance to fluoroquinolones, including ciprofloxacin, has not been fully elucidated but appears to involve mutations in the target DNA type II topoisomerase enzymes and mutations that result in alterations in membrane permeability and/or efflux pumps.

Cross-resistance

Cross-resistance can occur among the fluoroquinolones. Cross-resistance generally does not occur between ciprofloxacin and other anti-infectives, including aminoglycosides, b-lactam antibiotics, sulfonamides (including co-trimoxazole), macrolides, and tetracyclines. However, rare strains of Enterobacteriaceae and Ps. aeruginosa resistant to ciprofloxacin have also been resistant to aminoglycosides, b-lactam antibiotics, chloramphenicol, trimethoprim, and/or tetracyclines. Resistance in these organisms appears to be related to decreased permeability of the organism to the drug, principally because of alterations in outer-membrane porin proteins; however, other mechanisms that affect permeability may also be involved.