Which antibiotic with warfarin

Flagyl [prescribing information]. Chicago, IL: Pharmacia Corp; Rifater [prescribing information]. Rifadin [prescribing information]. Tetracycline [prescribing information]. Unasyn [prescribing information]. PL Detail-Document. Antimicrobial drug interactions and warfarin. August Drug interactions involving warfarin: practice tool and practical management tips. Matthew Grissinger, RPh, FISMP, FASCP, director of Error Reporting Programs, Institute for Safe Medication Practices, discusses how human error, various at-risk behaviors, as well as workarounds taken by staff members all impact outcomes and decision-making processes in pharmacy, and why it is important to appropriately use the technology functionalities that are available in practice.

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This review attempts to summarise current knowledge and, with reference to basic science, suggest possible management strategies when faced with a prescribing dilemma. There are two types of oral anticoagulant, the coumarins and indanediones. By far the most commonly used are the coumarin derivatives, of which warfarin is a member, due to their lower incidence of side effects compared with the indanediones.

These factors are synthesised in the liver in precursor form and are activated by carboxylation of specific glutamic acid residues which require vitamin K in its reduced form as a cofactor. Warfarin acts by inhibiting the reductase that converts the epoxide form of vitamin K to its reduced form by competitive antagonism due to the molecular similarity of warfarin and vitamin K.

A reduction in the activity and concentration of all four factors is embraced by the portmanteau term 'hypoprothrombinaemia'. Due to its mechanism of action the anticoagulant effect of warfarin is delayed until the previously synthesised normal factors are metabolised.

On administration, therefore, one can expect the prothrombin time, in the form of the International Normalised Ratio INR , to reach its therapeutic target approximately 48—72 hours later. Warfarin is used in the treatment of a number of conditions and the target INR varies in each situation. An understanding of a patient's medical history, therefore, can give greater initial insight into their degree of anticoagulation than simple knowledge of the dose.

Indeed the individual response to warfarin varies between patients and the final therapeutic dose is determined by repeated INR measurements. The main indication for oral anticoagulant therapy is in the prophylaxis of deep vein thrombosis DVT.

Several mechanisms are of relevance when considering the interaction of antibiotics with warfarin; however, controversy exists in some cases as to their relative importance. Commonly cited mechanisms are:. Although penicillins have not been shown in studies to interact with warfarin, 2 isolated cases have been reported associated with broad-spectrum penicillins.

There does not appear to be significant evidence to suggest that narrow-spectrum penicillins commonly used in dentistry interact with warfarin.

However, one isolated report did describe hypoprothrombinaemia in one patient on warfarin given 24 million units of benzylpenicillin penicillin-G daily, intravenously. Bearing in mind how frequently penicillins are used in patients taking warfarin documented reports of interactions are relatively rare. Consequently the broad picture suggests that no clinically relevant interaction normally occurs.

Despite this one must always consider that atypical effects can occur and exercise caution when prescribing for patients taking warfarin. Buckley suggested the use of orally administered penicillins in patients taking warfarin is safe, provided the patients vitamin K intake is normal. Amoxycillin prophylaxis American Heart Association had been given followed by a further course of mg tds for 1 week.

Wood et al. In one of these cases the elevated INR 6. Alteration in the oral flora by broad spectrum antibiotics such as amoxycillin has been suggested to decrease gut floral production and absorption of vitamin K.

In the synthesis of certain blood coagulation factors vitamin K is required in its reduced form to act as a cofactor and warfarin, being structurally similar to vitamin K, competes for binding sites in this reduction process.

Thus if the available vitamin K decreases then a greater percentage of binding sites will be occupied by warfarin leading to inactive reductants and decreased synthesis of coagulation factors. Most vitamin K is ingested and absorbed from the normal diet 7 and, although it is accepted that continuous intrinsic synthesis in the colon by bacterial activity occurs, 8 there is controversy regarding the importance of this on the coagulation process. It would seem sensible to prescribe single-dose penicillin wherever possible for patients on warfarin, as it may be the case that longer courses would have more of an effect on the gut flora, if indeed this is significant.

This is not, of course, foolproof, as the above cases illustrate, and individual clinical judgement is required with particular care in the under or malnourished patient 11 where the role of intrinsically produced vitamin K may be more significant.

When considering antibiotic prophylaxis for patients taking warfarin it may, therefore, be prudent to consider clindamycin as a first-line. There is, currently, only one case report of clindamycin interacting with warfarin and, in that instance, in addition to the prophylactic dose, it had been used as a 7-day therapeutic dose for local infection.

In the cases described, the increases in INR occurred a few days post-operatively and in one patient was not associated with signs of bleeding. This indicates that initial haemostasis may not be a reliable indicator in predicting problems so the following protocol would be prudent for the post-operative management of patients receiving concurrent penicillin and warfarin.

Consider reviewing patients routinely at 3 days post-op, to check INR, taking appropriate action if it is elevated. Remember the absence of bleeding does not rule out an elevated INR.

In the undernourished patient or those with malabsorptive disorders consider closer liaison with medical colleagues. In multiple extraction cases be aware that problems with eating may compound antibiotic-induced decrease in vitamin K availability. It has been shown that low dose 1 mg oral vitamin K can effectively reduce INR within 24 hours in warfarinised patients who develop asymptomatic increases in INR. It is generally accepted that erythromycin has the potential to enhance the anticoagulant effect of warfarin but most patients are unlikely to develop a clinically important reaction.

Bartle described the case of a year-old woman on warfarin who developed an increased prothrombin time with haematuria and bruising within a week after being given 2 g of erythromycin stearate. Bartle suggested that some of the most clinically significant drug interactions are those that involve an alteration in the metabolism of warfarin.

Erythromycin is thought to be involved in this process by stimulating liver enzymes to produce metabolites that bind to cytochrome P, forming inactive complexes and, thereby, reducing the metabolism of warfarin which enhances its effect.

Concurrent use should be avoided if possible. However, it is worth noting that the effect is unpredictable and by no means occurs in all individuals. Erythromycin is an important antibiotic in the management of dental infections when a patient is allergic to penicillin and its use is justified in patients taking warfarin, however, monitoring of the INR is a sensible precaution.

It has been reported that in most cases the effect may not be significant, however, the potential for serious effects in some individuals justifies caution. Kazmier 27 and Dean 28 reported in separate cases significant bleeding in patients taking metronidazole and warfarin. These clinical findings reinforce the study by O'Reilly 29 who found that a daily dose of mg of metronidazole for 1 week increased the half-life of warfarin by approximately one third in 8 normal subjects.

As with erythromycin the inhibition of warfarin metabolism, albeit by a different mechanism, results in a clinically significant drug interaction. Concurrent use should be avoided. If this is not possible then the warfarin dose should be reduced with close monitoring of the INR and current research suggests the warfarin reduction should be in the order of one third to one half.

Reports have suggested that tetracycline's can enhance the effect of warfarin although this is by no means the normal outcome. Westfall reported a woman who bled menorrhagia while taking warfarin and doxycycline mg daily for 8 days. Danos reported a marked increase in INR 2 to 7. The mechanism is not fully understood, however, it has been reported that tetracycline's alone can reduce prothrombin activity.

Concurrent use need not necessarily be avoided as it is an apparently uncommon interaction. However, due to the occasional patient showing increased anticoagulant effects which may be severe, close monitoring of the INR, is indicated. Clindamycin has been reported, in one isolated case report, to enhance the effect of warfarin. The risk of an interaction appears to exist when given therapeutically as an extended course, as opposed to when given as a single dose.

Aldous et al. The mechanism is unclear, however, it was suggested in the above case that extended administration of clindamycin resulted in decreased production of vitamin K from gut flora, enhancing the effect of warfarin. A pre-operative single dose for the prevention of endocarditis is not thought to pose a risk. When clindamycin is used therapeutically, or indeed combined with a prophylactic dose, the likelihood of the INR increasing appears to be enhanced.

Thus, in this situation, caution is advised and the INR should be closely monitored. The drug classes are listed in this chart, along with their risk of interaction 4. Warfarin levels are gauged by checking your prothrombin or clotting time, which is measured using the international normalized ratio INR. The higher the INR, the longer it takes for blood to clot.

If you take warfarin, an INR of 2 to 3 is often ideal, although the best range for you will be based on your individual condition. Antibiotics may cause this level to rise or fall, putting you in danger. At this level, the risk of gastrointestinal bleeding increases, and a bump on the head could become a bleed in the brain," says Dr. Because the effect of an antibiotic on any individual cannot be predicted, guidelines recommend everyone taking warfarin be managed by a medical professional who can gauge risk and know when to take appropriate action.

If we see a small rise in INR with a two to three day course of prophylactic antibiotics before dental work, we may not worry, because the antibiotic leaves the system quickly. However, if we see an upward rise in INR with a common, broad-spectrum antibiotic such as erythromycin or ciprofloxacin, we must decide whether we need to adjust the dose downward and continue monitoring the patient," says Lynn Oertel, clinical nurse specialist for the anticoagulation management service at Massachusetts General Hospital.

Many patients think drug interactions are only caused by pills, but topical antibiotics are absorbed into the bloodstream and can interfere with warfarin, too. This includes ointments, creams, and suppositories.

Most physicians are aware of the potential for warfarin-antibiotic interactions, and they discuss the risk with patients when warfarin is prescribed. Nevertheless, there are plenty of opportunities for error:. A patient may not understand the potential significance of this drug-drug interaction, or may simply forget.

A provider who prescribes the antibiotic may fail to inform the clinician managing the patient's warfarin.