Antibiotics: what are the main drug interactions?

What are antibiotics? What are they used for?

Definition and antibiotics classification

Contrary to antiviral medicines, antibiotics are molecules whose scope of action targets bacteria. They are divided into several families depending on their chemical classification, their mode of operation or their therapeutic target. Some antibiotics aim at blocking the development of bacteria, and therefore compromising their survival while others simply destroy these bacteria (these are called bactericidal).

Each antibiotic family, or even each antibiotic, often has a preferred target: bacteria are either sensitive or resistant to them. Indeed, some bacteria are anaerobic, meaning they don't need oxygen to survive, contrary to aerobic bacteria. If the antibiotic's mechanism of action lies in oxygen deprivation, an anaerobic bacterium could possibly avoid its scope of action.

It must be noted that bacterial resistances to antibiotics are not always natural: they are acquired in part because of the excessive use of antibiotics.

Antibiotics are categorised into several families:

• β-lactam: including carbapenems, penicillin derivatives, cephalosporins, 
• Glycopeptides,
• Aminoglycosides, 
• Macrolides, 
• Tetracyclines,
• Quinolones and fluoroquinolones,
• Sulfonamides,
• Nitrovasodilators (imidazoles),
• Antitubercular medications.

Uses and limitations

The massive use of antibiotics has caused the emergence of preoccupying bacterial resistances. Their use should be limited to preserve their efficiency: antibiotic resistance is highly related to the overconsumption and an improper use of antibiotics.

The massive consumption of antibiotics puts an evolutionary pressure on the different species of bacteria, favouring the survival of resistant species rather than sensitive species.

Innovation and novelties in the field of antibiotics are rare, and the number of available molecules has even decreased by 20% since the 2000's. The therapeutic option of molecules is thinning out for healthcare professionals, making the care for some infectious diseases more difficult.

To face this public health problem and the problem of worldwide expansion on men and animals, European health authorities have implemented an action plan whose objective is a reasonable use of antibiotics.

Some classifications of antibiotics have even been identified at risk to create an antibiotic resistance, which entails an important monitoring of their use. Among them: Augmentin (an association of amoxicillin and clavulanic acid), which is highly prescribed and not always advisedly; orally taken cephalosporins; or even fluoroquinolones.

What is a drug interaction?

Definition (how does it happen?)

A medicine follows a life cycle in the body (pharmacodynamics) and relies on the body's physiological mechanisms that influence its efficiency. Two medicines taken at the same time can consequently interact, even more so if they use the same metabolization process. A drug interaction is therefore the modification of the main or secondary therapeutic effect of a medicine caused by the intake of another molecule.

There are 4 main types of described interactions: 

• Increased effect of one of the two medicines: a substance is said to be an enzyme inhibitor when it slows down or stops the destruction of the other medicine by the body, increasing its blood level and therefore its effect;  
• Mutual amplification of both of the medicines' effects: their effects are said to be mutually potentiated by the intake of another medicine (for example, the use of benzodiazepines along with antihistamines increases the sedative effect of both therapeutic families).
• Decrease or even complete suppression of a medicine's effects: a substance is said to be an enzyme inducer when it accelerates the destruction of the other medicine by the body, decreasing its blood level and therefore its effect;
• No detected interaction between two substances when they coexist in the body, which can be explained by different metabolization processes that do not interfere.

Knowing how medicines interact in the body is not trivial: it allows making sure that a treatment is efficient, or avoiding a potential danger for the patient. Most interactions are known and subject to recommendations, allowing to classify them by severeness. There are 4 levels of recommendations:

• Contraindication: interdiction. 
• Association not recommended: drug association should be avoided.
• Caution of use: drug association can happen if some precautions are taken.
• To consider: there can be some side effects that should be taken into account.

Indeed, a doctor can deem that the risk of associating two molecules is largely inferior to the benefit it will bring to the patient, and decide to go against these recommendations. However, when interactions make up a contraindication, it is highly advised to follow the restriction.

What are the main drug interactions with antibiotics?

The most meaningful example is the interaction related to the intake of two molecules from the same family: the therapeutic effects, but most importantly the adverse effects of these medicines will add up.

However, antibiotics are a class of medicines with which the simultaneous intake of other substances must be highly monitored. They are indeed often classified as 'enzyme inhibitors', or conversely 'enzyme inducers' and can harm the effect of an underlying treatment.

What precautions must be taken when on antibiotic therapy?

Which associations must be avoided?

Some antibiotics use the same degradation mechanism as other medicines, or are simply known to disrupt the intestinal bacterial flora, and therefore lead to a change in the expected effects.

Antibiotics and anticoagulants

Haemorrhagic strokes are not rare and patients on anticoagulants must be warned to avoid an overdose. Indeed, the patient learns about his treatment's specificities in regards to potential interferences with food, or the drug interactions that might exist because of their narrow therapeutic range (small difference between the toxic dose and the efficient dose).

The following table summarises the expected effects when associating some antibiotics with coumarin, a class of vitamin K antagonist anticoagulants gathering: acenocoumarol, warfarin, phenprocoumon. An increased monitoring of the International Normalized Ratio (INR, reflecting the functioning of blood coagulation) is recommended during the treatment.

Figure 2. Table gathering the antibiotics reacting with Coumarin anticoagulants

Antibiotics and oral contraception

The contraceptive effect of some hormonal treatments can be decreased to a great extent, which is why some additional preventive measures can sometimes be needed.

Figure 3. Table gathering the antibiotics interacting with oral contraception

Antibiotics and anti-diabetic medication

Sulfonamide antibiotics such as Bactrim can expose patients on oral anti-diabetics to an increased risk of hypoglycaemia.

Noteworthy interactions of macrolides (erythromycin, clarithromycin, azithromycin) with:

• Digoxin: increased toxicity of digoxin.
• Statin: potentiation of the risk of rhabdomyolysis (abnormal destruction of muscular cells, one of the main adverse effects of statins).
• Antiarrhythmic agents (amiodarone, sotalol, neuroleptics such as haloperidol or even antihistamines such as mizolastine): increased risk of ventricular arrhythmia (torsades de pointes).

Caution (how to avoid drug interactions?)

Why is alcohol consumption often advised against when on antibiotics?

When associated with alcohol, some antibiotics, mainly metronidazole (or even some cephalosporins such as ceftriaxone, cefamandole or cefazolin) provoke an Antabuse reaction. What is it? The Antabuse reaction gathers all the reactions of the body to the accumulation of a vasodilator molecule lowering the hepatic metabolism: acetaldehyde. This reaction manifests through red patches on the face, hot flashes, headaches, tachycardia, hypotension, excessive sweating, nausea, vomiting, diarrhoea, sometimes confusions, convulsions. As a matter of fact, these substances have the same liver degradation as alcohol! Some other anti-infectious medicines were identified to cause an Antabuse reaction: antifungal (griseofulvin and ketoconazole) and anti-parasite medicines from the same family as metronidazole (ornidazole, secnidazole and tinidazole).

Other antibiotics such as erythromycin or clarithromycin (enzyme inhibitors) lower the alcohol degradation, and therefore cause an early alcohol level peak.

Sun 

Some antibiotics are 'photosensitising', meaning they cause an increased skin sensitivity to UV rays, which manifests as skin burns. This is particularly true of quinolone antibiotics for which an increased protection from the sun is required during treatment, and even a few days after the end of the treatment.

The importance of observance

An antibiotic prescription will most often include the intake hour: before or during meals, or hours before or after having eaten. As a matter of facts, food intake influences the absorption of the medicine, or can sometimes protect the patient from the digestive discomfort caused by some products. This is why it is important to follow the intake instructions and the duration of the treatment.

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