Drug interactions between ampicillin and anisindione
Interactions between your drugs
Applies to: ampicillin and anisindione
MONITOR: Penicillins may occasionally potentiate the risk of bleeding in patients treated with oral anticoagulants. The exact mechanism of interaction is unknown but may involve penicillin inhibition of platelet aggregation. In one study, defective platelet aggregation occurred with predictability in patients receiving penicillin G 24 million units/day, ampicillin 300 mg/kg/day, and methicillin 300 mg/kg/day. Other penicillins such as nafcillin, piperacillin, and ticarcillin have also been found to affect platelet function, and benzylpenicillin and carbenicillin have been reported to increase bleeding times and cause bleeding in the absence of an anticoagulant. There have been case reports describing increases in prothrombin time and INR as well as spontaneous bruising and bleeding in anticoagulated patients following initiation or completion of penicillin therapy. Although most cases have involved large, intravenous doses of some penicillins (e.g., carbenicillin, penicillin G, ticarcillin), the interaction has also been reported with regular, oral doses of amoxicillin and amoxicillin-clavulanate. In fact, a case-control study found amoxicillin-clavulanate to be one of only two medications to significantly increase the risk of overanticoagulation in previously stable outpatients treated with phenprocoumon or acenocoumarol. In that study, 300 outpatients at a Netherlands anticoagulant clinic who presented with an INR value greater than or equal to 6.0 (median value 6.8) were compared with 302 randomly selected matched controls with INR values within the target range (median value 3.2), and changes in the use of 87 potentially interacting drugs or drug classes in the four weeks prior to the index day were identified and analyzed. A course of amoxicillin-clavulanate increased the risk of overanticoagulation even after adjustment for potential confounding factors, particularly in patients treated with acenocoumarol. A follow-up study focusing on antibiotic use in outpatients treated with phenprocoumon or acenocoumarol at a different Netherlands anticoagulant clinic also identified amoxicillin use as a risk factor for overanticoagulation, with the relative risk most strongly increased four days or more after start of the antibiotic.
MANAGEMENT: Caution is recommended if a penicillin is prescribed during oral anticoagulant therapy, especially in the elderly and patients with uremia or hepatic impairment. The INR should be checked frequently and anticoagulant dosage adjusted accordingly, particularly following initiation or discontinuation of penicillin therapy in patients who are stabilized on their anticoagulant regimen. Patients should be advised to promptly report any signs of bleeding to their doctor, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.
- Ku LL, Ward CO, Durgin SJ "A clinical study of drug interaction and anticoagulant therapy." Drug Intell Clin Pharm 4 (1970): 300-6
- Alexander DP, Russo ME, Fohrman DE, Rothstein G "Nafcillin-induced platelet dysfunction and bleeding." Antimicrob Agents Chemother 23 (1983): 59-62
- Andrassy K, Ritz E, Weisschedel E "Bleeding after carbenicillin administration." N Engl J Med 292 (1975): 109
- Davydov L, Yermolnik M, Cuni LJ "Warfarin and amoxicillin/clavulanate drug interaction." Ann Pharmacother 37 (2003): 367-370
- Brown CH 3d, Natelson EA, Bradshaw MW, Alfrey CP Jr, Williams TW Jr "Study of the effects of ticarcillin on blood coagulation and platelet function." Antimicrob Agents Chemother 7 (1975): 652-7
- Visser LE, Penning-Van Bees FJ, Harrie Kasbergen AA, et al. "Overanticoagulation associated with combined use of antibacterial drugs and acenocoumarol or phenprocoumon anticoagulants." Thromb Haemost 88 (2002): 705-10
- Penning-van Beest F, Erkens J, Petersen KU, Koelz HR, Herings R "Main comedications associated with major bleeding during anticoagulant therapy with coumarins." Eur J Clin Pharmacol 61 (2005): 439-44
- Brown CH 3d, Bradshaw MJ, Natelson EA, Alfrey CP Jr, Williams TW Jr "Defective platelet function following the administration of penicillin compounds." Blood 47 (1976): 949-56
- Rice PJ, Perry RJ, Afzal Z, Stockley IH "Antibacterial prescribing and warfarin: a review." Br Dent J 194 (2003): 411-5
- Penning-van Beest FJ, van Meegen E, Rosendaal FR, Stricker BH "Drug interactions as a cause of overanticoagulation on phenprocoumon or acenocoumarol predominantly concern antibacterial drugs." Clin Pharmacol Ther 69 (2001): 451-7
- Andrassy K, Ritz E, Hasper B, Scherz M, Walter E, Storch H "Penicillin-induced coagulation disorder." Lancet 2 (1976): 1039-41
- Bandrowsky T, Vorono AA, Borris TJ, Marcantoni HW "Amoxicillin-related postextraction bleeding in an anticoagulated patient with tranexamic acid rinses." Oral Surg Oral Med Oral Pathol 82 (1996): 610-2
- Larsen TR, Gelaye A, Durando C "Acute warfarin toxicity: an unanticipated consequence of amoxicillin/clavulanate administration." Am J Case Rep 15 (2014): 45-8
- Kelly M, Moran J, Byrne S "Formation of rectus sheath hematoma with antibiotic use and warfarin therapy: a case report." Am J Geriatr Pharmacother 3 (2005): 266-9
- Gentry LO, Jemsek JG, Natelson EA "Effects of sodium piperacillin on platelet function in normal volunteers." Antimicrob Agents Chemother 19 (1981): 532-3
- Brown CH 3d, Natelson EA, Bradshaw W, Williams TW Jr, Alfrey CP Jr "The hemostatic defect produced by carbenicillin." N Engl J Med 291 (1974): 265-70
- Wood GD "Antibiotic prescribing and warfarin enhancement." Br Dent J 175 (1993): 241
Drug and food interactions
Applies to: ampicillin
ADJUST DOSING INTERVAL: Certain penicillins may exhibit reduced gastrointestinal absorption in the presence of food. The therapeutic effect of the antimicrobial may be reduced.
MANAGEMENT: The interacting penicillin should be administered one hour before or two hours after meals. Penicillin V and amoxicillin are not affected by food and may be given without regard to meals.
- McCarthy CG, Finland M "Absorption and excretion of four penicillins." N Engl J Med 263 (1960): 315-26
- Cronk GA, Wheatley WB, Fellers GF, Albright H "The relationship of food intake to the absorption of potassium alpha-phenoxyethyl penicillin and potassium phenoxymethyl penicillin from the gastrointestinal tract." Am J Med Sci 240 (1960): 219-25
- Neuvonen PJ, Elonen E, Pentikainen PJ "Comparative effect of food on absorption of ampicillin and pivampicillin." J Int Med Res 5 (1977): 71-6
- Neu HC "Antimicrobial activity and human pharmacology of amoxicillin." J Infect Dis 129 (1974): s123-31
- Welling PG, Huang H, Koch PA, Madsen PO "Bioavailability of ampicillin and amoxicillin in fasted and nonfasted subjects." J Pharm Sci 66 (1977): 549-52
- Klein JO, Sabath LD, Finland M "Laboratory studies on oxacillin. I: in vitro activity against staphylococci and some other bacterial pathogens. II: absorption and urinary excretion in normal young." Am J Med Sci 245 (1963): 399-411
Applies to: anisindione
MONITOR: Vitamin K may antagonize the hypoprothrombinemic effect of oral anticoagulants. Vitamin K is a cofactor in the synthesis of blood clotting factors that are inhibited by oral anticoagulants, thus intake of vitamin K through supplements or diet can reverse the action of oral anticoagulants. Resistance to oral anticoagulants has been associated with consumption of foods or enteral feedings high in vitamin K content. Likewise, a reduction of vitamin K intake following stabilization of anticoagulant therapy may result in elevation of the INR and bleeding complications. Foods rich in vitamin K include beef liver, broccoli, Brussels sprouts, cabbage, collard greens, endive, kale, lettuce, mustard greens, parsley, soy beans, spinach, Swiss chard, turnip greens, watercress, and other green leafy vegetables. Moderate to high levels of vitamin K are also found in other foods such as asparagus, avocados, dill pickles, green peas, green tea, canola oil, margarine, mayonnaise, olive oil, and soybean oil. Snack foods containing the fat substitute, olestra, are fortified with 80 mcg of vitamin K per each one ounce serving so as to offset any depletion of vitamin K that may occur due to olestra interference with its absorption. Whether these foods can alter the effect of oral anticoagulants has not been extensively studied. One small study found that moderate consumption (1.5 servings/day) does not significantly affect the INR after one week in patients receiving long-term anticoagulation.
Consumption of large amounts of mango fruit has been associated with enhanced effects of warfarin. The exact mechanism of interaction is unknown but may be related to the vitamin A content, which may inhibit metabolism of warfarin. In one report, thirteen patients with an average INR increase of 38% reportedly had consumed one to six mangos daily 2 to 30 days prior to their appointment. The average INR decreased by 17.7% after discontinuation of mango ingestion for 2 weeks. Rechallenge in two patients appeared to confirm the interaction.
Limited data also suggest a potential interaction between warfarin and cranberry juice resulting in changes in the INR and/or bleeding complications. The mechanism is unknown but may involve alterations in warfarin metabolism induced by flavonoids contained in cranberry juice. At least a dozen reports of suspected interaction have been filed with the Committee on Safety of Medicines in the U.K. since 1999, including one fatality. In the fatal case, the patient's INR increased dramatically (greater than 50) six weeks after he started drinking cranberry juice, and he died from gastrointestinal and pericardial hemorrhage. However, the patient was also taking cephalexin for a chest infection and had not eaten for two weeks prior to hospitalization, which may have been contributing factors. Other cases involved less dramatic increases or instabilities in INR following cranberry juice consumption, and a decrease was reported in one, although details are generally lacking. In a rare published report, a 71-year-old patient developed hemoptysis, hematochezia, and shortness of breath two weeks after he started drinking 24 ounces of cranberry juice a day. Laboratory test results on admission revealed a decrease in hemoglobin, an INR greater than 18, and prothrombin time exceeding 120 seconds. The patient recovered after warfarin doses were withheld for several days and he was given packed red blood cells, fresh-frozen plasma, and subcutaneous vitamin K. It is not known if variations in the constituents of different brands of cranberry juice may affect the potential for drug interactions.
There have been several case reports in the medical literature of patients consuming grapefruit, grapefruit juice, or grapefruit seed extract who experienced increases in INR. R(+) warfarin, the less active of the two enantiomers of warfarin, is partially metabolized by CYP450 3A4. Depending on brand, concentration, dose and preparation, grapefruit juice may be considered a moderate to strong inhibitor of CYP450 3A4, thus coadministration with warfarin may decrease the clearance of R(+) warfarin. However, the clinical significance of this effect has not been established. A pharmacokinetic study found no effect on the PT or INR values of nine warfarin patients given 8 oz of grapefruit juice three times a day for one week.
A patient who was stabilized on warfarin developed a large hematoma in her calf in association with an elevated INR of 14 following consumption of approximately 3 liters of pomegranate juice in the week prior to admission. In vitro data suggest that pomegranate juice can inhibit CYP450 2C9, the isoenzyme responsible for the metabolic clearance of the biologically more active S(-) enantiomer of warfarin. In rats, pomegranate juice has also been shown to inhibit intestinal CYP450 3A4, the isoenzyme that contributes to the metabolism of R(+) warfarin.
Black currant juice and black currant seed oil may theoretically increase the risk of bleeding or bruising if used in combination with anticoagulants. The proposed mechanism is the antiplatelet effects of the gamma-linolenic acid constituent in black currants.
Soy protein in the form of soy milk was thought to be responsible for a case of possible warfarin antagonism in an elderly male stabilized on warfarin. The exact mechanism of interaction is unknown, as soy milk contains only trace amounts of vitamin K. Subtherapeutic INR values were observed approximately 4 weeks after the patient began consuming soy milk daily for the treatment of hypertriglyceridemia. No other changes in diet or medications were noted during this time. The patient's INR returned to normal following discontinuation of the soy milk with no other intervention.
An interaction with chewing tobacco was suspected in a case of warfarin therapy failure in a young male who was treated with up to 25 to 30 mg/day for 4.5 years. The inability to achieve adequate INR values led to eventual discontinuation of the chewing tobacco, which resulted in an INR increase from 1.1 to 2.3 in six days. The authors attributed the interaction to the relatively high vitamin K content in smokeless tobacco.
MANAGEMENT: Intake of vitamin K through supplements or diet should not vary significantly during oral anticoagulant therapy. The diet in general should remain consistent, as other foods containing little or no vitamin K such as mangos and soy milk have been reported to interact with warfarin. Some experts recommend that continuous enteral nutrition should be interrupted for one hour before and one hour after administration of the anticoagulant dose and that enteral formulas containing soy protein should be avoided. Patients should also consider avoiding or limiting the consumption of cranberry juice or other cranberry formulations (e.g., encapsulated dried cranberry powder), pomegranate juice, black currant juice, and black currant seed oil.
- Guo LQ, Yamazoe Y "Inhibition of cytochrome P450 by furanocoumarins in grapefruit juice and herbal medicines." Acta Pharmacol Sin 25 (2004): 129-36
- Bodiford AB, Kessler FO, Fermo JD, Ragucci KR "Elevated international normalized ratio with the consumption of grapefruit and use of warfarin." SAGE Open Med Case Rep 0 (2013): 1-3
- Suvarna R, Pirmohamed M, Henderson L "Possible interaction between warfarin and cranberry juice." BMJ 327 (2003): 1454
- Beckey NP, Korman LB, Parra D "Effect of the moderate consumption of olestra in patients receiving long-term warfarin therapy." Pharmacotherapy 19 (1999): 1075-9
- Lee M, Schwartz RN, Sharifi R "Warfarin resistance and vitamin K." Ann Intern Med 94 (1981): 140-1
- Sullivan DM, Ford MA, Boyden TW "Grapefruit juice and the response to warfarin." Am J Health Syst Pharm 55 (1998): 1581-3
- Brandin H, Myrberg O, Rundlof T, Arvidsson AK, Brenning G "Adverse effects by artificial grapefruit seed extract products in patients on warfarin therapy." Eur J Clin Pharmacol 63 (2007): 565-70
- Kempin SJ "Warfarin resistance caused by broccoli." N Engl J Med 308 (1983): 1229-30
- Harrell CC, Kline SS "Vitamin K-supplemented snacks containing olestra: Implication for patients taking warfarin." Jama J Am Med Assn 282 (1999): 1133-4
- Westfall LK "An unrecognized cause of warfarin resistance." Drug Intell Clin Pharm 15 (1981): 131
- Grant P "Warfarin and cranberry juice: an interaction?" J Heart Valve Dis 13 (2004): 25-6
- Walker FB "Myocardial infarction after diet-induced warfarin resistance." Arch Intern Med 144 (1984): 2089-90
- Pedersen FM, Hamberg O, Hess K, Ovesen L "The effect of dietary vitamin K on warfarin-induced anticoagulation." J Intern Med 229 (1991): 517-20
- Ge B, Zhang Z, Zuo Z "Updates on the clinical evidenced herb-warfarin interactions." Evid Based Complement Alternat Med 2014 (2014): 957362
- Griffith LD, Olvey SE, Triplett WC "Increasing prothrombin times in a warfarin-treated patient upon withdrawal of ensure plus." Crit Care Med 10 (1982): 799-800
- Kuykendall JR, Houle MD, Rhodes RS "Possible warfarin failure due to interaction with smokeless tobacco." Ann Pharmacother 38 (2004): 595-7
- Wells PS, Holbrook AM, Crowther NR, Hirsh J "Interactions of warfarin with drugs and food." Ann Intern Med 121 (1994): 676-83
- Ministerio de Sanidad y Consumo. Gobierno de España "AEMPS. Agencia Española de Medicamentos y Productos Sanitarios. Available from: URL: https://sinaem4.agemed.es/consaem/fichasTecnicas.do?metodo=detalleForm."
- Zallman JA, Lee DP, Jeffrey PL "Liquid nutrition as a cause of warfarin resistance." Am J Hosp Pharm 38 (1981): 1174
- Wohlt PD, Zheng L, Gunderson S, Balzar SA, Johnson BD, Fish JT "Recommendations for the use of medications with continuous enteral nutrition." Am J Health Syst Pharm 66 (2009): 1438-67
- Watson AJ, Pegg M, Green JR "Enteral feeds may antagonise warfarin." Br Med J 288 (1984): 557
- MHRA. Mediciines and Healthcare products Regulatory Agency. Committee on Safety of Medicines "Possible interaction between warfarin and cranberry juice. Available from: URL: http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/currentproblems/currentproblems.htm." ([2003 Sept]):
- Karlson B, Leijd B, Hellstrom K "On the influence of vitamin K-rich vegetables and wine on the effectiveness of warfarin treatment." Acta Med Scand 220 (1986): 347-50
- O'Reilly RA, Rytand DA ""Resistance" to warfarin due to unrecognized vitamin K supplementation." N Engl J Med 303 (1980): 160-1
- Kazmier FJ, Spittell JA Jr "Coumarin drug interactions." Mayo Clin Proc 45 (1970): 249-55
- Chow WH, Chow TC, Tse TM, Tai YT, Lee WT "Anticoagulation instability with life-threatening complication after dietary modification." Postgrad Med J 66 (1990): 855-7
- Hamann GL, Campbell JD, George CM "Warfarin-cranberry juice interaction." Ann Pharmacother 45 (2011): e17
- Andersen P, Godal HC "Predictable reduction in anticoagulant activity of warfarin by small amounts of vitamin K." Acta Med Scand 198 (1975): 269-70
- MacLeod SM, Sellers EM "Pharmacodynamic and pharmacokinetic drug interactions with coumarin anticoagulants." Drugs 11 (1976): 461-70
- Jarvis S, Li C, Bogle RG "Possible interaction between pomegranate juice and warfarin." Emerg Med J 27 (2010): 74-5
- Cambria-Kiely JA "Effect of soy milk on warfarin efficacy." Ann Pharmacother 36 (2002): 1893-6
- Monterrey-Rodriguez J "Interaction between warfarin and mango fruit." Ann Pharmacother 36 (2002): 940-1
- Roberts D, Flanagan P "Case report: Cranberry juice and warfarin." Home Healthc Nurse 29 (2011): 92-7
- Griffiths AP, Beddall A, Pegler S "Fatal haemopericardium and gastrointestinal haemorrhage due to possible interaction of cranberry juice with warfarin." J R Soc Health 128 (2008): 324-6
- Parr MD, Record KE, Griffith GL, et al "Effect of enteral nutrition on warfarin therapy." Clin Pharm 1 (1982): 274-6
- Howard PA, Hannaman KN "Warfarin resistance linked to enteral nutrition products." J Am Diet Assoc 85 (1985): 713-5
- Rindone JP, Murphy TW "Warfarin-cranberry juice interaction resulting in profound hypoprothrombinemia and bleeding." Am J Ther 13 (2006): 283-4
Therapeutic duplication warnings
No therapeutic duplications were found for your selected drugs.
Drug Interaction Classification
|Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.|
|Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.|
|Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.|
|No information available.|
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