Ciprofloxacin Dailymed

7 Drug Interactions

Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co-administration 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 co-administered drug.

Table 9: Drugs That are Affected by and Affecting Ciprofloxacin

Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and Ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications ( 4.2 )]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of Ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions ( 5.9 )].
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5.11 ) and Use in

		Specific Populations ( 8.5 )].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when Ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when Ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions ( 6.1 )].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon Ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of Ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when Ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of Ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of Ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant Ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with Ciprofloxacin [see Warnings and Precautions ( 5.16 )].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with Ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity [see Clinical Pharmacology ( 12.3 ) ].
Duloxetine	Avoid Use	If unavoidable, monitor for duloxetine toxicity
	Five-fold increase in duloxetine exposure
Caffeine/Xanthine	Use with caution	Ciprofloxacin inhibits the formation of paraxanthine after caffeine
Derivatives	Reduced clearance resulting in elevated levels and prolongation of serum half-life	administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration ( 2.4 )].	Decrease Ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of Ciprofloxacin and increases Ciprofloxacin serum levels)	Potentiation of Ciprofloxacin toxicity may occur.

Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7 )
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7 )
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7 )
Phenytoin	Monitor phenytoin level ( 7 )
Methotrexate	Monitor for methotrexate toxicity ( 7 )
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7 )
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased Ciprofloxacin absorption. Take 2 hours before or 6 hours after Ciprofloxacin ( 7 )

8 Use In Specific Populations

See full prescribing information for use in pediatric and geriatric patients ( 8.4 , 8.5 )

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Ciprofloxacin should not be used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother. An expert review of published data on experiences with ciprofloxacin use during pregnancy by TERIS–the Teratogen Information System–concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that there is no risk. ²

A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation. ³ In utero exposure to fluoroquinolones during embryogenesis was not associated with increased risk of major malformations. The reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for the control group (background incidence of major malformations is 1–5%). Rates of spontaneous abortions, prematurity and low birth weight did not differ between the groups and there were no clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children.

Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93% first trimester exposures). ⁴ There were 70 ciprofloxacin exposures, all within the first trimester. The malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall were both within background incidence ranges. No specific patterns of congenital abnormalities were found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.

No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women exposed to ciprofloxacin during pregnancy. ^{2, 3} However, these small postmarketing epidemiology studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the safety of ciprofloxacin in pregnant women and their developing fetuses.

Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and 0.3 times the maximum daily human dose based upon body surface area, respectively) and have revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose based upon body surface area) produced gastrointestinal toxicity resulting in maternal weight loss and an increased incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic dose based upon body surface area), no maternal toxicity was produced and no embryo toxicity or teratogenicity was observed.

8.3 Nursing Mothers

Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by the nursing infant is unknown. Because of the potential risk of serious adverse reactions (including articular damage) in infants nursing from mothers taking Ciprofloxacin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Although effective in clinical trials, Ciprofloxacin is not a drug of first choice in the pediatric population due to an increased incidence of adverse reactions compared to controls. Quinolones, including Ciprofloxacin, cause arthropathy in juvenile animals [see Warnings and Precautions ( 5.12 ) and Nonclinical Toxicology ( 13.2)] .

Complicated Urinary Tract Infection and Pyelonephritis

Ciprofloxacin is indicated for the treatment of cUTI and pyelonephritis due to Escherichia coli in pediatric patients 1 to 17 years of age. Although effective in clinical trials, Ciprofloxacin is not a drug of first choice in the pediatric population due to an increased incidence of adverse reactions compared to the controls, including events related to joints and/or surrounding tissues [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.1 )].

Inhalational Anthrax (Post-Exposure)

Ciprofloxacin is indicated in pediatric patients from birth to 17 years of age, for inhalational anthrax (post exposure). The risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate [see Dosage and Administration ( 2.2 ) and Clinical Studies ( 14.2 )].

Plague

Ciprofloxacin is indicated in pediatric patients from birth to 17 years of age, for treatment of plague, including pneumonic and septicemic plague due to Yersinia pestis (Y. pestis) and prophylaxis for plague. Efficacy studies of Ciprofloxacin could not be conducted in humans with pneumonic plague for feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals. The risk-benefit assessment indicates that administration of Ciprofloxacin to pediatric patients is appropriate [see Indications and Usage ( 1.8 ), Dosage and Administration ( 2.2 ) and Clinical Studies ( 14.3 )].

8.5 Geriatric Use

Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as Ciprofloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing Ciprofloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential adverse reaction and advised to discontinue Ciprofloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur . [see Boxed Warning , Warnings and Precautions ( 5.2 ), and Adverse Reactions ( 6.2 )].

In a retrospective analysis of 23 multiple-dose controlled clinical trials of Ciprofloxacin encompassing over 3500 ciprofloxacin-treated patients, 25% of patients were greater than or equal to 65 years of age and 10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age with normal renal function. However, since some older individuals experience reduced renal function by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal function monitoring may be useful in these patients [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 )].

In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using Ciprofloxacin with concomitant drugs that can result in prolongation of the QT interval (for example, class IA or class III antiarrhythmics) or in patients with risk factors for torsade de pointes (for example, known QT prolongation, uncorrected hypokalemia) [see Warnings and Precautions ( 5.11 )].

8.6 Renal Impairment

Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and partially cleared through the biliary system of the liver and through the intestine. These alternative pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with severe renal dysfunction [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 )].

8.7 Hepatic Impairment

In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The pharmacokinetics of ciprofloxacin in patients with acute hepatic insufficiency, have not been studied.

12.1 Mechanism of Action

Ciprofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology ( 12.4 )].

12.3 Pharmacokinetics

Absorption

The absolute bioavailability of ciprofloxacin when given as an oral tablet is approximately 70% with no substantial loss by first pass metabolism. Ciprofloxacin maximum serum concentrations and area under the curve are shown in the chart for the 250 mg to 1000 mg dose range ( Table 10).

Table 10: Maximum Serum Concentrations and Areas Under the Curve

Dose (mg)	Maximum Serum Concentration (mcg/mL)	Area Under Curve (AUC) (mcg•hr/mL)
250	1.2	4.8
500	2.4	11.6
750	4.3	20.2
1000	5.4	30.8

Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12 hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4 mcg/mL, respectively. The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Serum concentrations increase proportionately with doses up to 1000 mg.

A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg Ciprofloxacin given over 60 minutes every 12 hours. A 750 mg oral dose given every 12 hours has been shown to produce an AUC at steady-state equivalent to that produced by an intravenous infusion of 400 mg given over 60 minutes every 8 hours. A 750 mg oral dose results in a C _max similar to that observed with a 400 mg intravenous dose. A 250 mg oral dose given every 12 hours produces an AUC equivalent to that produced by an infusion of 200 mg Ciprofloxacin given every 12 hours ( Table 11).

Table 11: Steady-state Pharmacokinetic Parameters Following Multiple Oral and IV Doses

1. AUC 0–12h
2. AUC 24h = AUC 0–12h x 2
3. AUC 24h = AUC 0–8h x 3
Parameters	500 mg	400 mg	750 mg	400 mg
	every 12 hours, orally	every 12 hours, intravenous	every 12 hours, orally.	every 8 hours, intravenous
AUC (mcg•hr/mL)	13.7 1	12.7 1	31.6 2	32.9 3
C max (mcg/mL)	2.97	4.56	3.59	4.07

Food

When Ciprofloxacin Tablet is given concomitantly with food, there is a delay in the absorption of the drug, resulting in peak concentrations that occur closer to 2 hours after dosing rather than 1 hour. The overall absorption of Ciprofloxacin Tablet, however, is not substantially affected. The pharmacokinetics of ciprofloxacin given as the suspension are also not affected by food. Avoid concomitant administration of Ciprofloxacin with dairy products (like milk or yogurt) or calcium-fortified juices alone since decreased absorption is possible; however, Ciprofloxacin may be taken with a meal that contains these products.

Distribution

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.

After oral administration, ciprofloxacin is widely distributed throughout the body. Tissue concentrations often exceed serum concentrations in both men and women, particularly in genital tissue including the prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial secretions, mucosa of the sinuses, sputum, skin buler fluid, lymph, peritoneal fluid, bile, and prostatic secretions. Ciprofloxacin has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug diffuses into the cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10% of peak serum concentrations. Low levels of the drug have been detected in the aqueous and vitreous humors of the eye.

Metabolism

Four metabolites have been identified in human urine which together account for approximately 15% of an oral dose. The metabolites have antimicrobial activity, but are less active than unchanged ciprofloxacin. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co-administration 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 co-administered drug [see Contraindications ( 4.2 ), Warnings and Precautions ( 5.9 , 5.15 ), and Drug Interactions ( 7 )].

Excretion

The serum elimination half-life in subjects with normal renal function is approximately 4 hours.

Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged drug. After a 250 mg oral dose, urine concentrations of ciprofloxacin usually exceed 200 mcg/mL during the first two hours and are approximately 30 mcg/mL at 8 to 12 hours after dosing. 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 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, 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 is recovered from the feces within 5 days after dosing. This may arise from either biliary clearance or transintestinal elimination.

Specific Populations

Elderly

Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (older than 65 years) as compared to young adults. Although the C _max is increased 16% to 40%, the increase in mean AUC is approximately 30%, and 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 Use in Specific Populations ( 8.5 )].

Renal Impairment

In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage adjustments may be required [see Use in Specific Populations ( 8.6 ) and Dosage and Administration ( 2.3 )].

Hepatic Impairment

In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency, have not been fully studied.

Pediatrics

Following a single oral dose of 10 mg/kg Ciprofloxacin suspension to 16 children ranging in age from 4 months to 7 years, the mean C _max was 2.4 mcg/mL (range: 1.5 mcg/mL to 3.4 mcg/mL) and the mean AUC was 9.2 mcg*hr/mL (range: 5.8 mcg*hr/mL to 14.9 mcg*h/mL). There was no apparent age-dependence, and no notable increase in C _max or AUC upon multiple dosing (10 mg/kg three times a day). In children with severe sepsis who were given Ciprofloxacin IV (10 mg/kg as a 1-hour intravenous infusion), the mean C _max was 6.1 mcg/mL (range: 4.6 mcg/mL to 8.3 mcg/mL) in 10 children less than 1 year of age; and 7.2 mcg/mL (range: 4.7 mcg/mL to 11.8 mcg/mL) in 10 children between 1 year and 5 years of age. The AUC values were 17.4 mcg*hr/mL (range: 11.8 mcg*hr/mL to 32 mcg*hr/mL) and 16.5 mcg*hr/mL (range: 11 mcg*hr/mL to 23.8 mcg*hr/mL) in the respective age groups. These values are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric patients with various infections, the predicted mean half-life in children is approximately 4 hours –5 hours, and the bioavailability of the oral suspension is approximately 60%.

Drug-Drug Interactions

Antacids

Concurrent administration of antacids containing magnesium hydroxide or aluminum hydroxide may reduce the bioavailability of ciprofloxacin by as much as 90% [see Dosage and Administration ( 2.4 ) and Drug Interactions ( 7 )].

Histamine H2-receptor antagonists

Histamine H ₂-receptor antagonists appear to have no significant effect on the bioavailability of ciprofloxacin.

Metronidazole

The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly.

Tizanidine

In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly increased (C _max 7-fold, AUC 10-fold) when the drug was given concomitantly with Ciprofloxacin (500 mg twice a day for 3 days). Concomitant administration of tizanidine and Ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications ( 4.2)].

Ropinirole

In a study conducted in 12 patients with Parkinson's disease who were administered 6 mg ropinirole once daily with 500 mg Ciprofloxacin twice-daily, the mean C _max and mean AUC of ropinirole were increased by 60% and 84%, respectively. Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with Ciprofloxacin [see Warnings and Precautions ( 5.9 )].

Clozapine

Following concomitant administration of 250 mg Ciprofloxacin with 304 mg clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with Ciprofloxacin are advised.

Sildenafil

Following concomitant administration of a single oral dose of 50 mg sildenafil with 500 mg Ciprofloxacin to healthy subjects, the mean C _max and mean AUC of sildenafil were both increased approximately two-fold. Use sildenafil with caution when co-administered with Ciprofloxacin due to the expected two-fold increase in the exposure of sildenafil upon co-administration of Ciprofloxacin.

Duloxetine

In clinical studies it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in a 5-fold increase in mean AUC and a 2.5-fold increase in mean C _max of duloxetine.

Lidocaine

In a study conducted in 9 healthy volunteers, concomitant use of 1.5 mg/kg IV lidocaine with Ciprofloxacin 500 mg twice daily resulted in an increase of lidocaine C _max and AUC by 12% and 26%, respectively. Although lidocaine treatment was well tolerated at this elevated exposure, a possible interaction with Ciprofloxacin and an increase in adverse reactions related to lidocaine may occur upon concomitant administration.

Metoclopramide

Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in a shorter time to reach maximum plasma concentrations. No significant effect was observed on the bioavailability of ciprofloxacin.

Omeprazole

When Ciprofloxacin 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 C _max of ciprofloxacin were reduced by 20% and 23%, respectively. The clinical significance of this interaction has not been determined.

12.4 Microbiology

Mechanism of Action

The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination.

Mechanism of Resistance

The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to ciprofloxacin. Resistance to fluoroquinolones occurs primarily by either mutations in the DNA gyrases, decreased outer membrane permeability, or drug efflux. In vitro resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between < 10 ^-9 to 1x10 ^-6 .

Cross Resistance

There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials.

Ciprofloxacin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage ( 1 )].

Gram-positive bacteria

Bacillus anthracis

Enterococcus faecalis

Staphylococcus aureus (methicillin-susceptible isolates only)

Staphylococcus epidermidis (methicillin-susceptible isolates only)

Staphylococcus saprophyticus

Streptococcus pneumoniae

Streptococcus pyogenes

Gram-negative bacteria

Campylobacter jejuni

Citrobacter koseri

Citrobacter freundii

Enterobacter cloacae

Escherichia coli

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella pneumoniae

Moraxella catarrhalis

Morganella morganii

Neisseria gonorrhoeae

Proteus mirabilis

Proteus vulgaris

Providencia rettgeri

Providencia stuartii

Pseudomonas aeruginosa

Salmonella typhi

Serratia marcescens

Shigella boydii

Shigella dysenteriae

Shigella flexneri

Shigella sonnei

Yersinia pestis

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ciprofloxacin (≤1 mcg/mL). However, the efficacy of ciprofloxacin in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria

Staphylococcus haemolyticus (methicillin-susceptible isolates only)

Staphylococcus hominis (methicillin-susceptible isolates only)

Gram-negative bacteria

Acinetobacter lwoffi

Aeromonas hydrophila

Edwardsiella tarda

Enterobacter aerogenes

Klebsiella oxytoca

Legionella pneumophila

Pasteurella multocida

Salmonella enteritidis

Vibrio cholerae

Vibrio parahaemolyticus

Vibrio vulnificus

Yersinia enterocolitica

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth and/or agar). ^5,6,7 The MIC values should be interpreted according to criteria provided in Table 12.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method. ^6,7,8 This procedure uses paper disks impregnated with 5 mcg ciprofloxacin to test the susceptibility of bacteria to ciprofloxacin. The disc diffusion interpretive criteria are provided in Table 12.

Table 12: Susceptibility Test Interpretive Criteria for Ciprofloxacin

1. The current absence of data on resistant isolates precludes defining any results other than “Susceptible.” If isolates yield MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.
2. MIC is determined by the agar dilution method
	MIC (mcg/mL)			Zone Diameter (mm)
Bacteria	S	I	R	S	I	R
Enterobacteriaceae	≤1	2	≥4	≥21	16–20	≤15
Enterococcus faecalis	≤1	2	≥4	≥21	16–20	≤15
Staphylococcus aureus	≤1	2	≥4	≥21	16–20	≤15
Staphylococcus epidermidis	≤1	2	≥4	≥21	16–20	≤15
Staphylococcus saprophyticus	≤1	2	≥4	≥21	16–20	≤15
Pseudomonas aeruginosa	≤1	2	≥4	≥21	16–20	≤15
Haemophilus influenzae 1	≤1	-	-	≥21	-	-
Haemophilus parainfluenzae 1	≤1	-	-	≥21	-	-
Salmonella typhi	≤0.06	0.12–0.5	≥1	≥31	21–30	≤20
Streptococcus pneumoniae	≤1	2	≥4	≥21	16–20	≤15
Streptococcus pyogenes	≤1	2	≥4	≥21	16–20	≤15
Neisseria gonorrhoeae 2	≤0.06	0.12–0.5	≥1	≥41	28–40	≤27
Bacillus anthracis 1	≤0.25	-	-	-	-	-
Yersinia pestis 1	≤0.25	-	-	-	-	-
S=Susceptible, I=Intermediate, and R=Resistant.

A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the site of infection necessary to inhibit growth of the pathogen. 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 that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. ^5,6,7,8 Standard ciprofloxacin powder should provide the following range of MIC values noted in Table 13. For the diffusion technique using the ciprofloxacin 5 mcg disk the criteria in Table 13 should be achieved.

Table 13: Acceptable Quality Control Ranges for Ciprofloxacin

1MIC is determined by the agar dilution method
Bacteria	MIC range (mcg/mL)	Zone Diameter (mm)
Enterococcus faecalis ATCC 29212	0.25–2	-
Escherichia coli ATCC 25922	0.004–0.015	30–40
Haemophilus influenzae ATCC 49247	0.004–0.03	34–42
Pseudomonas aeruginosa ATCC 27853	0.25–1	25–33
Staphylococcus aureus ATCC 29213	0.12–0.5	-
Staphylococcus aureus ATCC 25923	-	22–30
Neisseria gonorrhoeae ATCC 49226 1	0.001–0.008	48–58
Campylobacter jejuni ATCC 33560	0.06–0.25 and 0.03–0.12	-