Ciprofloxacin

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References

Brouwers JR. Drug interactions with quinolone antibacterials. Drug Saf 1992 Jul-Aug;7(4):268-281. (Review)
Abstract: The quinolone antibacterials are prone to many interactions with other drugs. Quinolone absorption is markedly reduced with antacids containing aluminium, magnesium and/or calcium and therapeutic failure may result. Other metallic ion-containing drugs, such as sucralfate, iron salts, and zinc salts, can also reduce absorption. Some of the newer quinolones inhibit the cytochrome P450 system, e.g. enoxacin, pefloxacin and ciprofloxacin. The toxicity of drugs that are metabolised by the cytochrome P450 system is enhanced by concomitant use of some quinolones. Ciprofloxacin, enoxacin and pefloxacin can increase theophylline concentrations to toxic values. The pharmacokinetics of warfarin and cyclosporin are unaffected. Ofloxacin, fleroxacin and temafloxacin have a low inhibitory effect on the cytochrome P450 system and a low interaction potential may result. The affinity of quinolones for the gamma-aminobutyric acid (GABA) receptor may induce CNS adverse effects; these effects are enhanced by some nonsteroidal anti-inflammatory drugs (NSAIDs).

Campbell NR, Hasinoff BB. Iron supplements: A common cause of drug interactions. Brit J Clin Pharmacol 1991 Mar;31(3):251-255. (Review)

Charteris WP, Kelly PM, Morelli L, Collins JK. Antibiotic susceptibility of potentially probiotic Bifidobacterium isolates from the human gastrointestinal tract. Lett Appl Microbiol. 1998 May;26(5):333-337.
Sixteen Bifidobacterium isolates from the human gastrointestinal tract were assayed for susceptibility to 44 antibiotics by soft agar overlay disc diffusion on TPY agar. Five isolates (3/7 B. bifidum and 2/3 B. breve) exhibited atypical antibiotic susceptibility profiles. Poor growth in the agar overlay accounted for susceptibility of B. bifidum but not B. breve isolates. All other isolates were resistant to cefoxitin (30 micrograms), aztreonam (30 micrograms), vancomycin (30 micrograms), amikacin (30 micrograms), gentamicin (10 micrograms), kanamycin (30 micrograms), streptomycin (10 micrograms), fusidic acid (10 micrograms), trimethoprim (5 micrograms), norfloxacin (10 micrograms), nalidixic acid (30 micrograms), metronidazole (5 micrograms), polymyxin B (300 micrograms) and colistin sulphate (10 micrograms), and they were susceptible to the six penicillins studied, cephalothin (30 micrograms), cefuroxime (30 micrograms), cefaclor (30 micrograms), ceftizoxime (30 micrograms), cefotaxime (30 micrograms), bacitracin (10 micrograms), chloramphenicol (30 micrograms), erythromycin (15 micrograms), clindamycin (2 micrograms), rifampicin (5 micrograms) and nitrofurantoin (300 micrograms). In addition, they varied in their susceptibility to cephradine (30 micrograms), cephazolin (30 micrograms), cefoperazone (75 micrograms), ceftriaxone (30 micrograms), ofloxacin (5 micrograms) and furazolidone (15 micrograms). They were resistant, or only marginally moderately susceptible, to ceftazidime (30 micrograms), netilmicin (10 micrograms), sulphamethoxazole (100 micrograms), cotrimoxazole (25 micrograms) and ciprofloxacin (5 micrograms), and susceptible or marginally moderately susceptible to tetracycline (30 micrograms). All B. bifidum isolates were susceptible to cefixime (5 micrograms). Four microorganism-drug combinations were evaluated for beta-lactamase activity but its absence suggested that cell wall impermeability was responsible for cephalosporin resistance among bifidobacteria. The antibiotic susceptibility of B. animalis 25527T was similar to that of the human isolates.

Gugler R, Allgayer H. Effects of antacids on the clinical pharmacokinetics of drugs. An update. Clin Pharmacokinet 1990 Mar;18(3):210-219.
Abstract: Since a previous review by Hurwitz was published in 1977 a large number of reports on drug interactions with antacids have appeared, few of which are of clinical relevance. Tetracyclines form insoluble complex molecules by metal ion chelation with various antacids; tetracycline absorption may be decreased by more than 90% by this interaction. Of the new class of quinolone antibiotics, the absorption of ciprofloxacin and ofloxacin is reduced by 50 to 90% in the presence of aluminium- and magnesium hydroxide-containing antacids. In contrast to early work showing inhibition of the absorption of beta-adrenergic blocking drugs by antacids, subsequent studies did not confirm a reduction in the bioavailability of either atenolol or propranolol during antacid treatment; indeed, they showed an increase in the plasma concentrations of metoprolol when the drug was coadministered with an antacid. The bioavailability of captopril was significantly reduced in the presence of an antacid, and lower plasma concentrations of this angiotensin-converting enzyme inhibitor were accompanied by a reduction of its effect on the systolic blood pressure of the patients. The absorption of the cardiac glycosides digoxin and digitoxin is not inhibited by antacids to a significant degree, although earlier studies had shown a positive effect when the dissolution of the glycoside preparations was relatively poor. Antacids reduce the bioavailability of the H2-receptor antagonists cimetidine and ranitidine only when high antacid doses are used and when the drugs are administered simultaneously. The bioavailability of famotidine was not significantly altered by a potent antacid preparation, although a trend towards reduced absorption was observed. Iron absorption is significantly decreased in the presence of sodium bicarbonate and calcium carbonate, but is nearly complete when coadministered with aluminium-magnesium hydroxide. Nonsteroidal anti-inflammatory drugs such as naproxen, tenoxicam, ketoprofen, ibuprofen and piroxicam are not affected in their absorption by antacid treatment. Theophylline bioavailability is unchanged when the drug is given together with antacids, although its rate of absorption may be altered, leading to a reduction or an increase in the time of the occurrence of peak plasma drug concentrations.

Hadimeri H, Almroth G, Cederbrant K, Enestrom S, Hultman P, Lindell A.  Allergic nephropathy associated with norfloxacin and ciprofloxacin therapy. Report of two cases and review of the literature. Scand J Urol Nephrol. 1997 Oct;31(5):481-485. (Review)
Abstract: Allergic nephropathy associated with quinolone antibiotics has been reported in an increasing number of cases. The mechanism might be a hypersensitivity reaction. Norfloxacin has been incriminated previously as a cause once only, with acute interstitial nephritis (AIN) as the histopathological finding. Ciprofloxacin-associated nephropathy has been reported in 28 cases, with AIN as the main histopathological finding. This report describes a second case of AIN associated with norfloxacin treatment and another ciprofloxacin-associated renal interstitial drug adverse reaction. Clinicians should be aware of quinolone-associated AIN, which is a rare but potentially dangerous renal complication.

Hoffken G, Borner K, Glatzel PD, Koeppe P, Lode H. Reduced enteral absorption of ciprofloxacin in the presence of antacids. Eur J Clin Microbiol. 1985 Jun;4(3):345. (Letter)

Kara M, Hasinoff BB, McKay DW, Campbell NR. Clinical and chemical interactions between iron preparations and ciprofloxacin. Br J Clin Pharmacol 1991 Mar;31(3):257-261
Abstract: 1. The effect of ferrous sulphate (300 mg), ferrous gluconate (600 mg), and a combination tablet of iron (10 mg), magnesium (100 mg), zinc (15 mg), calcium (162 mg), copper (2 mg), and manganese (5 mg) (Centrum Forte) co-administration on ciprofloxacin bioavailability was tested in eight healthy subjects. 2. Peak serum ciprofloxacin concentrations and area under the curve (AUC) were significantly reduced when ciprofloxacin was administered with 300 mg ferrous sulphate (3.0 vs 2.0 mg l-1, P less than 0.05 and 12.3 vs 6.7 mg l-1 h, P less than 0.01, respectively). Reductions in peak ciprofloxacin concentrations and AUC also occurred when ciprofloxacin was ingested with 600 mg ferrous gluconate (1.3 mg l-1, P less than 0.01 and 4.1 mg l-1 h, P less than 0.01, respectively) and a Centrum Forte tablet (1.4 mg l-1, P less than 0.01 and 5.4 mg l-1 h, P less than 0.01, respectively). 3. When ferrous ion was mixed with ciprofloxacin, rapid spectral changes occurred (t1/2 = 1.9 min). Additional studies were consistent with oxidation of the ferrous form of iron to its ferric form, which is followed by rapid formation of a Fe(3+)-ciprofloxacin complex. Ciprofloxacin seems to bind to ferric ion in a ratio of 3:1 by interacting with the 4-keto and 3-carboxyl groups on ciprofloxacin. 4. The formation of a ferric ion-ciprofloxacin complex is probably the cause of the reduction in ciprofloxacin bioavailability in the presence of iron.

Ledergerber B, Bettex JD, Joos B, Flepp M, Luthy R. Effect of standard breakfast on drug absorption and multiple-dose pharmacokinetics of ciprofloxacin. Antimicrob Agents Chemother 1985 Mar;27(3):350-352.
Abstract: Ciprofloxacin was administered to 10 volunteers, who received seven oral doses of 250 mg each at 12-h intervals. Volunteers alternately fasted (F) or received a standard breakfast (B) before the morning dose. Pharmacokinetic parameters were derived from high-pressure liquid chromatography data from samples taken after the first and seventh doses and were analyzed in addition for differences caused by food intake. A significant (P less than 0.05) influence of the standard breakfast on the time to the peak was observed. Peak levels (+/- standard deviation) after the first and seventh doses averaged F (fasting): 1.35 +/- 0.17, B (breakfast): 1.02 +/- 0.28 micrograms/ml, and F: 1.41 +/- 0.32, B: 1.17 +/- 0.5 micrograms/ml, respectively. Mean trough concentrations after the first and seventh doses were F: 0.10 +/- 0.03, B: 0.14 +/- 0.03 micrograms/ml, and F: 0.16 +/- 0.05, B: 0.14 +/- 0.04 microgram/ml, respectively. As with the peak, trough concentrations were not affected significantly by food intake or by accumulation over the study period. Breakfast equally did not affect the terminal half-lives, which averaged F: 3.97 +/- 0.67, B: 4.35 +/- 0.88 h after the first dose and F: 4.64 +/- 0.91, B: 3.72 +/- 0.84 h after the seventh dose. Twelve-hour urinary recovery measured by high-pressure liquid chromatography averaged F: 31, B: 30% for the first dose and, in spite of a possible carry-over from the sixth dose, decreased to F: 25, B: 28% after the seventh dosing interval. When measured by bioassay, an increase of urinary recovery between the first dose (F: 38, B: 38%) and the seventh dose (F: 45, B: 45%) was observed. These differences suggest induction of drug metabolism with repeated doses. Ciprofloxacin was well tolerated by the volunteers.

Lehto P, Kivisto KT, Neuvonen PJ. The effect of ferrous sulphate on the absorption of norfloxacin, ciprofloxacin and ofloxacin. Br J Clin Pharmacol 1994 Jan;37(1):82-85.
Abstract: The effect of ferrous sulphate on the absorption of norfloxacin, ciprofloxacin and ofloxacin was studied in three separate, two-period crossover trials, each involving eight healthy volunteers. After an overnight fast, a single dose of norfloxacin (400 mg), ciprofloxacin (500 mg) or ofloxacin (400 mg) was administered with and without ferrous sulphate (corresponding to 100 mg elemental iron). The absorption of all the fluoroquinolones studied was significantly reduced when they were co-administered with ferrous sulphate. The reduction in the area under the plasma drug concentration-time curve from 0 to 24 h was most marked in the case of norfloxacin, while ofloxacin was least affected by ferrous sulphate. The AUC of norfloxacin was reduced by 73% (P < 0.001) and its peak plasma concentration by 75% (P < 0.01) by concomitant ingestion of ferrous sulphate. The AUC and peak plasma concentration of ciprofloxacin were reduced by 57% (P < 0.001) and 54% (P < 0.01), respectively, by ferrous sulphate. Concomitant ingestion of ferrous sulphate reduced the AUC and peak plasma concentration of ofloxacin by 25% (P < 0.01) and 36% (P < 0.01), respectively. Similar results were obtained with respect to the urinary recoveries of each fluoroquinolone. We recommend that norfloxacin and ciprofloxacin should not be taken together with ferrous sulphate. It would also be advisable not to take ofloxacin with ferrous sulphate, especially if the organism causing infection is only moderately susceptible.

Lim D, McKay M. Food-drug interactions. Drug Information Bull UCLA Department of Pharmaceutical Services. 1995;15(2). (Review).

Lomaestro BM, Bailie GR. Effect of multiple staggered doses of calcium on the bioavailability of ciprofloxacin. Ann Pharmacother 1993 Nov;27(11):1325-1328.
Abstract: OBJECTIVE: To determine the effect on the relative bioavailability (Fr) of a staggered single dose of ciprofloxacin given two hours after a morning dose of calcium carbonate given three times daily over the three previous days. DESIGN: Thirteen male volunteers participated in this randomized, nonblinded, crossover investigation; 12 subjects were included in the final analysis. SETTING: Data collection and ciprofloxacin administration occurred at Albany Medical Center, a tertiary-care teaching institution. Calcium carbonate administration was on an outpatient basis. RESULTS: For 12 volunteers, the mean +/- SD Fr of ciprofloxacin staggered with calcium was 0.87 +/- 0.23 (noncompartmental model) and 0.98 +/- 0.27 (compartmental model). Other statistically significant findings were a decrease in the time to maximum concentration of ciprofloxacin staggered with calcium in serum compared with ciprofloxacin alone (from 1.76 +/- 0.54 to 1.23 +/- 0.52 h in the noncompartmental model; p < 0.05), and a decrease in the same parameter (from 1.92 +/- 0.96 to 0.77 +/- 0.53 in the compartmental model; p < 0.005). Maximum concentration of ciprofloxacin staggered with calcium was decreased in the noncompartmental model compared with ciprofloxacin alone (from 2.11 +/- 0.72 to 1.60 +/- 0.33, respectively; p < 0.05). The elimination half-life and area under the concentration-time curve of ciprofloxacin were not significantly altered. CONCLUSIONS: Repeated doses of calcium carbonate, administered two hours before ciprofloxacin, did not significantly alter the Fr of this fluoroquinolone.

Mizuki Y, Fujiwara I, Yamaguchi T. Pharmacokinetic interactions related to the chemical structures of fluoroquinolones. J Antimicrob Chemother 1996 May;37 Suppl A:41-55.
Abstract: Fluoroquinolone derivatives interact with methylxanthines (theophylline, caffeine) and metallic ion-containing drugs to different degrees. The rat appears to be a suitable model for predicting such interactions in man. It has been possible to determine the relationship between the chemical structure of the fluoroquinolone and the magnitude of the interaction. Fluoroquinolones with a bulky substituent at the position 8, such as sparfloxacin, lomefloxacin and fieroxacin, are less prone to interact with theophylline than those without an 8-substituent, such as enoxacin. This substituent determines the planarity of the whole fluoroquinolone molecule and the interaction tends to be more significant for planar fluoroquinolones. Furthermore, a 4'-nitrogen atom in the 7-piperazinyl group is essential for the interaction to occur. The nitrogen atom is possibly the site that binds cytochrome P-450, which catalyses theophylline metabolism. The reduction in bioavailability of fluoroquinolones by concurrent administration of aluminium hydroxide is more striking for derivatives with fewer substituents on the essential structure and on the piperazinyl group, such as norfloxacin, ciprofloxacin and enoxacin. Substitution at the 5-position diminishes the interaction, which suggests that the 5-substituent may affect the formation and/or stability of unabsorbable chelate complex which is the probable cause of the interaction. These findings are potentially useful in designing fluoroquinolones less prone to drug interactions.

Pazzucconi F, Barbi S, Baldassarre D, Colombo N, Dorigotti F, Sirtori CR. Iron-ovotransferrin preparation does not interfere with ciprofloxacin absorption.  Clin Pharmacol Ther 1996 Apr;59(4):418-422.
Abstract: Iron supplements can interfere with the bioavailability of a number of drugs, including thyroxine, tetracycline derivatives, penicillamine, methyldopa, levodopa, carbidopa, ciprofloxacin, and the newer fluoroquinolones. A new iron formulation was tested in which iron ions are bound to ovotransferrin, a protein that shares more than an 80% similarity with the sequence of human transferrin and apparently is less likely than the commonly used iron salts to reduce drug absorption. Ciprofloxacin was taken as a model drug, of wide use and restricted range of therapeutic levels, and its absorption was evaluated after the administration of the iron-ovotransferrin complex versus an iron-gluconate formulation in healthy volunteers. At variance with the iron gluconate formulation, which led to a reduction of about 50% of peak serum ciprofloxacin levels (Cmax; 1.0 +/- 0.2 versus 2.4 +/- 0.3 micrograms/ml; p < 0.01) and of the area under the serum concentration-time curve from time 0 to infinity [AUC(0 - infinity); 10.1 +/- 1.1 versus 18.3 +/- 1.0 mg.L-1.hr; p < 0.01], the iron-ovotransferrin complex caused only modest, non significant changes in absorption with a minimal reduction of the AUC[0 - infinity) (17.3 +/- 1.0 versus 18.3 +/- 1.0 mg.L-1.hr; difference not significant) and a nonsignificant decrease in the Cmax (2.2 +/- 0.3 versus 2.4 +/- 0.3 microgram/ml; difference not significant). Iron was also well absorbed from the formulation in the presence of a fatty meal. The very common drug interactions with oral iron preparations can be effectively prevented by the use of the iron-ovotransferrin complex interacting to a minimal extent with a sensitive drug with a reduced margin of efficacy, such as ciprofloxacin.

Polk RE. Drug-drug interactions with ciprofloxacin and other fluoroquinolones. Am J Med 1989 Nov 30;87(5A):76S-81S.
Abstract: Early investigational trials with new quinolone antibiotics revealed two important drug-drug interactions: decreased fluoroquinolone absorption when co-administered with magnesium-aluminum antacids and inhibition of theophylline metabolism. Subsequent studies have investigated the mechanisms of these interactions. With respect to the effect of antacids, the absorption of all quinolones appears to be significantly reduced by antacids containing magnesium and/or aluminum, and concomitant administration must be avoided. Other cations, such as calcium, iron, and probably zinc, appear to interact in a similar manner. Chelation between the quinolone and cation is the most likely mechanism. With respect to the effect on theophylline metabolism, quinolones inhibit specific cytochrome P-450 isozymes responsible for metabolism of methylxanthines, although there are major differences between the quinolones. Enoxacin is the most potent inhibitor, followed by ciprofloxacin, pefloxacin, norfloxacin, and ofloxacin. Caffeine metabolism is also inhibited, although the clinical significance is uncertain. Case reports describe renal failure associated with concomitant administration of cyclosporine and ciprofloxacin, although controlled trials have not demonstrated an interaction. Enoxacin has little effect on warfarin metabolism, suggesting that other quinolones may not affect warfarin disposition. Case reports of central nervous system toxicity from administration of nonsteroidal anti-inflammatory agents and quinolones need confirmation. Patients should be monitored closely when potential interacting agents are used; it is probable that not all interactions have been identified.

Polk RE, Healy DP, Sahai J, Drwal L, Racht E. Effect of ferrous sulfate and multivitamins with zinc on absorption of ciprofloxacin in normal volunteers. Antimicrob Agents Chemother 1989 Nov;33(11):1841-1844.
Abstract: Cations such as magnesium and aluminum significantly impair the absorption of ciprofloxacin. Twelve healthy adult male volunteers participated in this four-way crossover study to investigate the effects of ferrous sulfate and multivitamins with zinc on the absorption of ciprofloxacin. Doses of ciprofloxacin (500 mg) were given 7 days apart and after an overnight fast. Dose 1 was administered alone (regimen A). The subjects then received either a ferrous sulfate tablet (325 mg three times a day; regimen B) or a once-daily multivitamin with zinc (regimen C) for 7 days; dose 2 of ciprofloxacin was then given with the last dose of regimen B or C. Subjects were crossed over to the alternate regimen for 7 days, and dose 3 of ciprofloxacin was again administered with the last dose of regimen B or C. After a 7-day washout, dose 4 of ciprofloxacin was given (regimen D). Ciprofloxacin concentrations were determined by high-pressure liquid chromatography. The areas under the concentration-time curve (AUCs) of ciprofloxacin for regimens A and D were not significantly different (14.5 +/- 2.3 versus 15.7 +/- 2.8 micrograms.h/ml, mean +/- standard deviation). The AUCs for regimen B (5.4 +/- 1.7 micrograms.h/ml) and regimen C (11.3 +/- 2.4 micrograms.h/ml) were significantly different from the AUCs for regimens A and D. Peak concentrations of ciprofloxacin with regimen B were below the MIC for 90% of strains of many organisms normally considered susceptible. Ferrous sulfate and multivitamins with zinc significantly impaired the absorption of ciprofloxacin. The effect of ferrous sulfate is likely to be clinically significant; the responsible component of multivitamins with zinc requires additional study.

Raja N, Miller WE, McMillan R, Mason JR.  Ciprofloxacin-associated acute renal failure in patients undergoing high-dose chemotherapy and autologous stem cell rescue. Bone Marrow Transplant. 1998 Jun;21(12):1283-1284.
Abstract: The broad spectrum of activity of ciprofloxacin makes it an ideal drug for the prophylaxis of bacterial infections in patients undergoing high-dose chemotherapy (HDC) with autologous stem cell rescue. We present two cases of ciprofloxacin-associated acute renal failure (ARF) in patients undergoing HDC. Maintaining a high index of suspicion for this complication will allow a prompt diagnosis, with discontinuation of the drug usually resulting in a reversal of renal failure. Renal biopsy usually reveals changes compatible with interstitial nephritis, but is not always possible in these patients due to severe thrombocytopenia following HDC. A brief course of steroid therapy may be beneficial although the role of glucocorticoids is difficult to ascertain in the absence of data regarding its efficiency in this clinical setting.

Sanchez Navarro A, Martinez Cabarga M, Dominguez-Gil Hurle A. Comparative study of the influence of Ca2+ on absorption parameters of ciprofloxacin and ofloxacin. J Antimicrob Chemother 1994 Jul;34(1):119-125.
Abstract: A comparative study was undertaken to investigate the influence of calcium on the absorption of ofloxacin and ciprofloxacin. The presence of CaCO3 did not significantly lower the partition coefficients of either fluoroquinolone although values for ofloxacin were significantly higher than those for ciprofloxacin (P = 0.0085). In intestinal sacs, the presence of 5000 mg/L CaCO3 significantly reduced both the absorption constant and the fraction of absorbed dose of 2000 mg/L ciprofloxacin but not 2000 mg/L ofloxacin. When the same concentration of CaCO3 was introduced into the isolated intestinal segments of rats, the absorption of both 200 mg/L ofloxacin and 400 mg/L ciprofloxacin was reduced significantly from 49% and 35% respectively to approximately 30% in each case. Co-administration of 500 mg/L CaCO3 to healthy volunteers significantly reduced the urinary excretion of 250 mg/L ciprofloxacin but not 200 mg/L ofloxacin although neither the fraction of absorbed dose nor the half-lives were markedly affected. Calcium therefore shares the same propensity as other cations in impairing the absorption of ciprofloxacin but not ofloxacin.

Threlkeld DS, ed. Systemic Anti-Infectives, Fluoroquinolones. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Feb 1994, 340n-340o.

Teixeira MH, Vilas-Boas LF, Gil VM, Teixeira F. Complexes of ciprofloxacin with metal ions contained in antacid drugs. J Chemother 1995 Apr;7(2):126-132.
Abstract: Simultaneous administration of antacids containing magnesium or aluminium and ciprofloxacin or other quinolones decreases the gastrointestinal absorption of those antibacterial agents. Current speculation about the mechanism of this interaction has focused on drug-cation chelation. The present study was designed to detect the protonation in solutions and the formation of the complex species at the pH levels typical of the gastrointestinal tract. It involves the study of ciprofloxacin in aqueous solutions containing Al3+ and (or) Mg2+ by combining the results of potentiometric and spectroscopic (1H nuclear magnetic resonance) techniques. Calculations were only performed for data in the range 4.5 < pH < 5.5 (pH levels typical of gastrointestinal tract) and the results of both methods are made self-consistent, assuming an equilibrium model including complex species MHL, MLOH (where H2L denotes ciprofloxacin and M is Al3+ or Mg2+); their formation constants are given.

Note: For more extensive citations relating to antibiotics and probiotics see the Footnotes subsection for the "Antibiotics" topic in this Interactions section.