Previous changes

May 2024 — minor update. Information added stating that concomitant treatment with clarithromycin and ivabradine is now contra-indicated and caution is now advised when co-administering clarithromycin with edoxaban, as per the manufacturer's updated SPC.

February 2024 — reviewed. A literature search was conducted in December 2023 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. No major changes to recommendations have been made, but the topic has been restructured.

November 2023 — minor update. The drug interaction section for flucloxacillin has been updated in line with the updated manufacturer's summary of product characteristics (SPC).

August 2023 — minor update. The recommendation that children and adults should stay away from school and other childcare facilities or work until lesions are healed, dry, and crusted over or until 48 hours after initiating antibiotic treatment has been updated to include treatment with hydrogen peroxide cream. 

July 2023 — minor update. The SPC for clarithromycin has been updated to include a warning regarding concurrent treatment with domperidone (due to the risk of QT prolongation and cardiac arrhythmias). A minor typographical error has been corrected. 

August 2022 – minor update. A minor typographical error has been corrected.

February 2020 – minor update. The treatment recommendations section has been updated in line with the National Institute for Health and Care Excellence (NICE) guideline Impetigo: antimicrobial prescribing.

September 2018 — reviewed. A literature search was conducted in July 2018 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials (RCTs) published since the last revision of this topic. Changes to recommendations include a change in the duration of treatment of mild localized impetigo with fusidic acid from 7 to 5 days based on recommendations by Public Health England (PHE) to reduce the risk of bacterial resistance.

December 2016 — minor update. The dose of clarithromycin for people with severe renal impairment has been clarified, in line with the manufacturer's SPC.

July 2015 — minor updates. The text regarding the basis for prescribing oral erythromycin as an option if there is a history of penicillin allergy has been amended to remove the relative cost of erythromycin compared with clarithromycin. The information on the concurrent use of clarithromycin or erythromycin with statins has been clarified.

July 2014 — minor update. The text was changed in the prescribing information section to reflect the manufacturer's recommendation that topical fusidic acid can be used during pregnancy. It can also be used during breastfeeding but should not be applied to the breast.

July 2013 — reviewed. A literature search was conducted in June 2013 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of this topic. No major changes to recommendations have been made.

February 2013 — minor update. The 2013 QIPP options for local implementation have been added to this topic.

October 2012 — minor update. The 2012 QIPP options for local implementation have been added to this topic.

June 2011 — minor update. The 2010/2011 QIPP options for local implementation have been added to this topic. 

August 2010 — minor update. The Health Protection Agency (HPA) advises that children (and adults) should stay away from school (or work) until the lesions have scabbed over or for 48 hours after starting antibiotic treatment. 

December 2008 to June 2009 — converted from CKS guidance to CKS topic structure. The evidence base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence. Retapamulin has been included as a second-line treatment for localized areas of impetigo.

December 2008 — minor update. Clarithromycin has been added as an antibiotic option if a person is penicillin allergic. 

September 2008 — minor correction to the Changes section. 

October to December 2005 — reviewed. Validated in March 2006 and issued in May 2006.

September 2002 — written. Validated in October 2002 and issued in December 2002.

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 January 2024.

HTAs (Health Technology Assessments)

No new HTAs since 1 January 2024.

Economic appraisals

No new economic appraisals relevant to England since 1 January 2024.

Systematic reviews and meta-analyses

No new systematic reviews or meta-analyses which reach the CKS threshold for inclusion since 1 January 2024.

Primary evidence

No new primary evidence which reaches the CKS threshold for inclusion published since 1 January 2024.

New policies

No new national policies or guidelines since 1 January 2024.

New safety alerts

No new safety alerts since 1 January 2024.

Changes in product availability

No changes in product availability since 1 January 2024.

Basis for recommendation

These recommendations are based on the Primary Care Dermatology Society (PCDS) guideline Impetigo [PCDS, 2022a], the Centers for Disease Prevention and Control (CDC) guideline Impetigo [CDC, 2022], and on expert opinion in review articles Impetigo [BMJ Best Practice, 2020] and Impetigo [Quirke, 2022].

• Expert opinion in the PCDS guideline is that [PCDS, 2022a]:
  • Impetigo is usually diagnosed based on the clinical appearance.
  • Poorly responsive or recurrent cases of impetigo should be swabbed for culture and sensitivity to identify possible methicillin-resistant Staphylococcus aureus (MRSA). Swabs are best taken from a moist lesion or, in cases of bullous impetigo, from a de-roofed blister.
• Expert opinion in the CDC guideline is that [CDC, 2022]:
  • Impetigo is diagnosed by physical examination, but physical examination cannot reliably differentiate between streptococcal and staphylococcal non-bullous impetigo.
  • Gram stain or culture of the exudate or pus from an impetigo lesion can identify the bacterial cause; however, laboratory testing is not necessary or routinely performed in clinical practice.

Basis for recommendation

• The information on the differential diagnoses of impetigo is based on expert opinion in review articles Impetigo: diagnosis and treatment [Hartman-Adams, 2014], Common skin rashes in children [Allmon, 2015], Impetigo [BMJ Best Practice, 2020], and Impetigo [Quirke, 2022].
• The information on the clinical features of Staphylococcal Scalded Skin syndrome is based on expert opinion in the Primary Care Dermatology Society (PCDS) guideline Staphylococcal Scalded Skin Syndrome (syn. Ritter disease; staphylococcal epidermal necrolysis) [PCDS, 2022b].

When should I refer a person with non-bullous impetigo?

• Refer the person to hospital (the urgency depending on clinical judgement) if:
  
  • A serious complication of impetigo is suspected, such as a deep soft tissue infection or sepsis. See the CKS topic on Sepsis for more information. 
  • The person is immunosuppressed, and the infection is widespread.
• Consider referral or seek specialist advice (urgency depending on clinical judgement) if:
  • The person is systemically unwell.
  • Impetigo recurs frequently.
  • The person is at high risk of complications.
  • The diagnosis is uncertain, and differential diagnoses have been considered.
• Consult a local microbiologist if:
  • Meticillin-resistant Staphylococcus aureus (MRSA) is suspected. For more information, see the CKS topic on MRSA in primary care. 

How should I manage a person with non-bullous impetigo?

If admission or referral is not indicated:

• Advise on:
  • The usual course of impetigo.
    • Impetigo is usually a self-limiting condition.
    • Without treatment, the infection heals in 7–21 days. However, appropriate treatment may lead to quicker resolution of infection and a reduced infective period. 
    • Impetigo usually heals completely without scarring, and complications are rare.
    • What to do if symptoms worsen rapidly at any time, or do not improve after completing a course of treatment.
    • Patient information leaflets on impetigo are available from the British Association of Dermatologists (BAD) and the NHS website.
  • Hygiene measures to aid healing and reduce the spread of impetigo. They should:
    • Wash affected areas with soap and water.
    • Avoid touching or scratching patches of impetigo.
    • Wash hands regularly, including after touching affected areas.
    • Cover affected areas where possible.
    • Not share towels, facecloths, and other personal care products.
    • Clean equipment, including toys and play equipment, daily. 
    • Wash clothing and bedding on the hottest available setting (at least 60 degrees). Clothing and bedding should be washed and changed daily during the first few days of treatment. 
  • Exclusion recommendations for people with impetigo.
    • People with impetigo should not attend a setting (such as school, other childcare facilities, or work) until all lesions (sores or blisters) are healed, dry, and crusted over or until 48 hours after commencing treatment (hydrogen peroxide cream or antibiotics).
    • Food handlers are required by law to inform employers immediately if they have a disease likely to be transmitted (through food or afflicted), for example, infected wounds, skin infections, or sores. 
• Ensure optimal treatment of pre-existing skin conditions, such as eczema, head lice, scabies, or insect bites.
  • For more information, see the CKS topics on Eczema - atopic, Head lice, Insect bites and stings, and Scabies.
• If the person has localized non-bullous impetigo and is not systemically unwell or at high risk of complications:
  
  • Consider offering hydrogen peroxide 1% cream (to be applied two to three times daily for 5 days). 
    
    • If hydrogen peroxide 1% cream is unsuitable, offer topical fusidic acid 2% (to be applied three times daily for 5 days).
    • If fusidic acid resistance is suspected or confirmed, offer topical mupirocin 2% (to be applied three times daily for 5 days).
  • Reassess the person if symptoms worsen rapidly or significantly at any time or do not improve after completing the course of treatment. 
• If the person has widespread non-bullous impetigo and is not systemically unwell or at high risk of complications:
  
  • Offer one of the following:
    • Topical fusidic acid 2% (to be applied three times daily for 5 days) — if fusidic acid resistance is suspected or confirmed, offer topical mupirocin 2% (to be applied three times daily for 5 days). 
    • An oral antibiotic.  
  • Take into account:
    • That topical and oral antibiotics are both effective at treating impetigo.
    • The preferences of the person and/or their parents/carers, including the practicalities of administration (particularly to large areas) and possible adverse effects.
    • Previous use of topical antibiotics (because antimicrobial resistance can develop rapidly with extended or repeated use). 
  • Do not offer combination treatment with a topical and oral antibiotic. 
  • Reassess the person if symptoms worsen rapidly or significantly at any time or do not improve after completing the course of treatment. 
• If the person has localized or widespread non-bullous impetigo and is systemically unwell or at high risk of complications:
  • Offer a short course of an oral antibiotic.  
  • Reassess the person if symptoms worsen rapidly or significantly at any time or do not improve after completing the course of treatment. 

Which antibiotic should I prescribe?

If an oral antibiotic is indicated for non-bullous impetigo, prescribe as follows. A 5-day treatment course is usually appropriate but can be increased to 7 days based on clinical judgement, depending on the severity and number of lesions. 

For adults aged 18 years and over:

• Prescribe flucloxacillin 500 mg four times daily for 5 days.
• If the person is allergic to penicillin or if flucloxacillin is unsuitable (for people who are not pregnant):
  • Prescribe clarithromycin 250 mg twice daily for 5 days. For severe infections, the dosage can be increased to 500 mg twice daily.
• If the person is pregnant and allergic to penicillin:
  • Prescribe erythromycin 250 mg to 500 mg four times daily for 5 days.
• If meticillin-resistant Staphylococcus aureus (MRSA) is suspected or confirmed:
  • Consult a local microbiologist. 

For children and young people under 18 years: 

• Prescribe flucloxacillin (oral solution or capsules): 
  • Age 1 month to 1 year — 62.5 mg to 125 mg four times daily for 5 days.
  • Age 2–9 years — 125 mg to 250 mg four times daily for 5 days. 
  • Age 10 –17 years — 250 mg to 500 mg four times daily for 5 days.
• If the child or young person is allergic to penicillin or if flucloxacillin is unsuitable (for example, if an oral solution is unpalatable and the child is unable to swallow capsules), prescribe clarithromycin.
  
  • Age 1 month to 11 years:
    • Under 8 kg — 7.5 mg/kg twice daily for 5 days.
    • 8–11 kg — 62.5 mg twice daily for 5 days.
    • 12–19 kg — 125 mg twice daily for 5 days.
    • 20–29 kg — 187.5 mg twice daily for 5 days.
    • 30–40 kg — 250 mg twice daily for 5 days.
  • Ages 12–17 years — 250 mg twice daily for 5 days. For severe infections, the dosage can be increased to 500 mg twice daily.
• If the person is pregnant and allergic to penicillin:
  • Ages 8-17 years — prescribe erythromycin 250 mg to 500 mg four times daily for 5 days.
• If MRSA is suspected or confirmed, consult a local microbiologist. 

For information on contraindications and cautions, adverse effects, and drug interactions, see the section on Prescribing information.

How should I follow up a person with non-bullous impetigo?

• If symptoms worsen rapidly or significantly at any time or have not improved after completing a course of treatment: 
  
  • Reassess the person.
    
    • Check compliance with initial treatment (hydrogen peroxide cream or antibiotics) and hygiene measures.
    • Consider alternative diagnoses, risk factors, and possible complications of impetigo.
    • Consider previous antibiotic use (which may have led to resistant bacteria).
  • If topical hydrogen peroxide 1% was used, offer:
    • A short course of a topical antibiotic if the impetigo remains localized, or
    • A short course of a topical or oral antibiotic if the impetigo has become widespread.
  • If a topical antibiotic was used:  
    • Offer a short course of an oral antibiotic, and
    • Consider sending a skin swab for microbiological testing.
  • If an oral antibiotic was used, consider sending a swab for microbiological testing.
    • When results are available, adjust the antibiotic based on swab results, using a narrow-spectrum antibiotic if possible.
    • If the infection is confirmed to be due to meticillin-resistant Staphylococcus aureus (MRSA), see the prodigy topic on MRSA in primary care for more information.
• If symptoms are recurrent:
  • Send a skin swab for microbiological testing.
    • When results are available, adjust the antibiotic based on swab results, using a narrow-spectrum antibiotic if possible.
    • If the infection is confirmed to be due to MRSA, see the prodigy topic on MRSA in primary care for more information.
  • Consider taking a nasal swab and starting treatment for decolonization.  
    • For information on decolonization, see the section on Staphylococcal carriage in the CKS topic on Boils, carbuncles, and staphylococcal carriage.
• If the person is systemically unwell or serious complications of impetigo have developed:
  • Consider the need for referral/specialist advice.

When should I refer a person with bullous impetigo?

• Refer the person to hospital (the urgency depending on clinical judgement) if:
  
  • A serious complication of impetigo is suspected, such as a deep soft tissue infection, or sepsis. See the CKS topic on Sepsis for more information. 
  • The person is immunosuppressed and the infection is widespread.
• Consider referral or seek specialist advice (urgency depending on clinical judgement) if:
  • The person is systemically unwell.
  • Impetigo recurs frequently.
  • The person is at high risk of complications.
  • The diagnosis is uncertain and differential diagnoses have been considered.
• Consult a local microbiologist if:
  • Meticillin-resistant Staphylococcus aureus (MRSA) is suspected. For more information, see the CKS topic on MRSA in primary care. 

How should I manage a person with bullous impetigo?

If referral is not indicated:

• Advise on:
  • The usual course of impetigo.
    • Impetigo is usually a self-limiting condition.
    • Without treatment, the infection heals in 7–21 days. However, appropriate treatment may lead to quicker resolution of infection and a reduced infective period. 
    • Impetigo usually heals completely without scarring, and complications are rare.
    • What to do if symptoms worsen rapidly at any time, or do not improve after completing a course of treatment.
    • Patient information leaflets on impetigo are available from the British Association of Dermatologists (BAD) and the NHS website.
  • Hygiene measures to aid healing and reduce the spread of impetigo. They should:
    • Wash affected areas with soap and water.
    • Avoid touching or scratching patches of impetigo.
    • Wash hands regularly, including after touching affected areas.
    • Cover affected areas where possible.
    • Not share towels, facecloths, and other personal care products.
    • Clean equipment, including toys and play equipment, daily. 
    • Wash clothing and bedding in the hottest setting (at least 60 degrees). During the first few days of treatment, clothing and bedding should be washed and changed daily. 
  • Exclusion recommendations for people with impetigo.
    • People with impetigo should not attend a setting (such as school, other childcare facilities, or work) until all lesions (sores or blisters) are healed, dry, and crusted over or until 48 hours after commencing treatment (hydrogen peroxide cream or antibiotics).
    • Food handlers are required by law to inform employers immediately if they have a disease likely to be transmitted (through food or afflicted), for example, infected wounds, skin infections, or sores. 
• Ensure optimal treatment of any pre-existing skin conditions, such as eczema, head lice, scabies, or insect bites.
  • For more information, see the CKS topics on Eczema - atopic, Head lice, Insect bites and stings, and Scabies.
• Offer a short course of an oral antibiotic.
  • Reassess the person if symptoms worsen rapidly or significantly at any time or do not improve after completing the course of treatment. 

Which antibiotic should I prescribe?

The recommended oral antibiotics for bullous impetigo are as follows. A 5-day treatment course is usually appropriate but can be increased to 7 days based on clinical judgement, depending on the severity and number of lesions. 

For adults aged 18 years and over:

• Prescribe flucloxacillin 500 mg four times daily for 5 days.
• If the person is allergic to penicillin or if flucloxacillin is unsuitable (for people who are not pregnant):
  • Prescribe clarithromycin 250 mg twice daily for 5 days. For severe infections, the dosage can be increased to 500 mg twice daily.
• If the person is pregnant and allergic to penicillin:
  • Prescribe erythromycin 250 mg to 500 mg four times daily for 5 days.
• If meticillin-resistant Staphylococcus aureus (MRSA) is suspected or confirmed:
  • Consult a local microbiologist. 

For children and young people under 18 years: 

• Prescribe flucloxacillin (oral solution or capsules): 
  • Age 1 month to 1 year — 62.5 mg to 125 mg four times daily for 5 days.
  • Age 2–9 years — 125 mg to 250 mg four times daily for 5 days. 
  • Age 10 –17 years — 250 mg to 500 mg four times daily for 5 days.
• If the child or young person is allergic to penicillin or if flucloxacillin is unsuitable (for example, if an oral solution is unpalatable and the child is unable to swallow capsules), prescribe clarithromycin.
  
  • Age 1 month to 11 years:
    • Under 8 kg — 7.5 mg/kg twice daily for 5 days.
    • 8–11 kg — 62.5 mg twice daily for 5 days.
    • 12–19 kg — 125 mg twice daily for 5 days.
    • 20–29 kg — 187.5 mg twice daily for 5 days.
    • 30–40 kg — 250 mg twice daily for 5 days.
  • Ages 12–17 years — 250 mg twice daily for 5 days. For severe infections, the dosage can be increased to 500 mg twice daily.
• If the person is pregnant and allergic to penicillin:
  • Ages 8-17 years — prescribe erythromycin 250 mg to 500 mg four times daily for 5 days.
• If MRSA is suspected or confirmed, consult a local microbiologist. 

For information on contraindications and cautions, adverse effects, and drug interactions, see the section on Prescribing information.

How should I follow up a person with bullous impetigo?

• If symptoms worsen rapidly or significantly at any time or have not improved after completing a course of treatment: 
  
  • Reassess the person.
    
    • Check compliance with initial treatment and hygiene measures.
    • Consider alternative diagnoses, risk factors, and possible complications of impetigo.
    • Consider previous antibiotic use (which may have led to resistant bacteria).
  • Consider sending a swab for microbiological testing.
    
    • When results are available, adjust the antibiotic based on swab results, using a narrow-spectrum antibiotic if possible.
    • If the infection is confirmed to be due to meticillin-resistant Staphylococcus aureus (MRSA), see the CKS topic on MRSA in primary care for more information.
• If symptoms are recurrent:
  • Send a skin swab for microbiological testing.
    • When results are available, adjust the antibiotic based on swab results, using a narrow-spectrum antibiotic if possible.
    • If infection is confirmed to be due to MRSA, see the prodigy topic on MRSA in primary care for more information.
  • Consider taking a nasal swab and starting treatment for decolonization.  
    • For information on decolonization, see the section on Staphylococcal carriage in the CKS topic on Boils, carbuncles, and staphylococcal carriage.
• If the person is systemically unwell or serious complications of impetigo have developed:
  • Consider the need for referral/specialist advice.

Contraindications and cautions

• Do not prescribe flucloxacillin to people with:
  • A true penicillin hypersensitivity — gastrointestinal adverse effects alone (such as nausea, vomiting, or diarrhoea) do not constitute a true penicillin allergy [NICE, 2014; Devchand, 2019; Stone, 2020].
  • History of urticaria or rash immediately after penicillin administration — risk of immediate hypersensitivity to penicillins.
  • History of a severe immediate hypersensitivity reaction (for example, anaphylaxis) to cephalosporins — there is some evidence of partial cross-allergenicity between cephalosporins and penicillins. 
  • History of flucloxacillin-associated jaundice/hepatic dysfunction.
• Prescribe flucloxacillin with caution to people with:
  • History of a minor rash (non-confluent, non-pruritic rash restricted to a small area of the body) or a rash that occurs more than 72 hours after administration of a penicillin — possibility of an allergic reaction to penicillin.
  • History of allergy to cephalosporins or other medications.
  • History of atopic allergy (including asthma, eczema, or hay fever) — high risk of anaphylactic reactions to penicillins.
  • Hepatic impairment, especially if they have a serious underlying disease.
  • Severe renal impairment (creatinine clearance less than 10 ml/minute) — consider a dose reduction or an extension of the dosing interval due to the risk of neurotoxicity.

[EMC, 2023c; BNF, 2024]

Adverse effects

• For all penicillins
  • The most common adverse effects are:
    • Gastrointestinal adverse effects, such as diarrhoea, nausea, and vomiting.
    • Skin reactions.
    • Thrombocytopenia.
  • The most significant adverse effect is hypersensitivity, which causes rashes and anaphylaxis and can be fatal.
    
    • Allergic reactions occur in 1–10% of people treated with penicillin; anaphylactic reactions occur in fewer than 0.05% of people. 
    • People with a history of atopic allergy (for example, asthma, eczema, and hay fever) are at a higher risk of anaphylactic reactions to penicillin.
    • People with a history of anaphylaxis, urticaria, or rash immediately after penicillin administration are at risk of immediate hypersensitivity and should not take flucloxacillin.
    • People with a history of a minor rash (non-confluent, non-pruritic rash restricted to a small area of the body) or a rash that occurs more than 72 hours after penicillin administration are probably not allergic to penicillin. Flucloxacillin should not be withheld unnecessarily for serious infections, but the possibility of an allergic reaction should be noted. Other beta-lactam antibiotics (including cephalosporins) can be used.
    • People allergic to one penicillin will be allergic to all because the hypersensitivity is related to the basic penicillin structure.
    • People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta-lactam antibiotics, and so should not receive these antibiotics. There is some evidence of partial cross-allergenicity of penicillins and cephalosporins. 
    • If a penicillin (or another beta-lactam) antibiotic is essential in a person with immediate hypersensitivity to penicillins, specialist advice should be sought on hypersensitivity testing or using a beta-lactam antibiotic with a different structure to the penicillin that caused the hypersensitivity.
  • Antibiotic-associated colitis has been reported and may range in severity from mild to life-threatening.
    • Consider this diagnosis in people who present with diarrhoea during or after treatment with any antibiotic.
    • The risk is increased with longer durations of antibiotic treatments, multiple antibiotics prescribed concurrently, or multiple courses of antibiotics.
    • See the CKS topic on Diarrhoea - antibiotic associated for more information. 
  • Other possible adverse effects include:
    • Uncommon — arthralgia and leucopenia.
    • Rare or very rare — agranulocytosis, angioedema, haemolytic anaemia, hepatic disorders, nephritis tubulointerstitial, neutropenia, seizure, and severe cutaneous adverse reactions (SCARs).
• For flucloxacillin
  • Hepatitis and cholestatic jaundice have been reported.
    • These reactions are unrelated to the dose or route of administration of flucloxacillin.
    • The onset of these hepatic effects may be delayed for up to two months post-treatment; in several cases, the course of the reactions has been protracted and lasted for some months.
    • In very rare cases, a fatal outcome has been reported. Most reports of deaths have been in people aged 50 years and older and people with serious underlying disease.
  • Other possible adverse effects include:
    
    • Rare or very rare — eosinophilia, fever, and myalgia.
    • Frequency not known  — hypokalaemia, oesophageal disorder, oral pain, oropharyngeal pain, and throat irritation.

[EMC, 2023c; BNF, 2024]

Drug interactions

• Drug interactions of flucloxacillin include:
  • Live cholera vaccine — efficacy of the vaccine may be reduced.
    • Avoid flucloxacillin from 14 days before to 10 days after receiving live cholera vaccine.
  • Live typhoid vaccine — immune response to the vaccine may be reduced.
    • Avoid flucloxacillin from 3 days before to 3 days after receiving live typhoid vaccine.
  • Methotrexate — reduced clearance and acute methotrexate toxicity have been attributed to concurrent use with some penicillins. Serious interactions are uncommon, but risk factors are as yet unknown. People taking low-dose methotrexate have been affected.
    • High-dose methotrexate: standard routine monitoring will identify any decreases in elimination, which should be managed according to local guidelines.
    • Low-dose methotrexate: consult local or national guidelines for recommendations on appropriate monitoring and management.
  • Paracetamol — paracetamol has been reported to cause high anion gap metabolic acidosis (HAGMA) when given with flucloxacillin.
    • Be alert for signs and symptoms of HAGMA.
    • Risk factors include severe renal impairment, sepsis, or malnutrition, especially if the maximum daily doses of paracetamol are used.
    • On stopping paracetamol, HAGMA may persist with flucloxacillin alone.
  • Phenindione — flucloxacillin is predicted to increase the risk of bleeding when given with phenindione.
    • Consider increased monitoring of the international normalized ratio (INR) if flucloxacillin is started or stopped.
  • Posaconazole and voriconazole — flucloxacillin (particularly high doses) appear to greatly decrease the concentrations of these antifungals.
    • If concurrent use is unavoidable, monitor for decreased efficacy and consider increasing the dose of the azole (although this may not resolve the issue). 
  • Probenecid — probenecid reduces the excretion of penicillins and usually increases their concentrations.
    • Concurrent use with flucloxacillin can be beneficial. However, consider any detrimental effect elevated flucloxacillin concentrations may have on the person.
  • Warfarin — flucloxacillin decreases the INR in people taking warfarin.
    • Consider an interaction if otherwise unexplained decreases in INR occur.
    • Monitor and adjust the warfarin dose accordingly.

[BNF, 2024; Preston, 2024]

Contraindications and cautions

• Do not prescribe clarithromycin to people with:
  
  • Electrolyte disturbances (hypokalaemia or hypomagnesaemia) — risk of prolongation of the QT interval.
  • A history of QT prolongation or ventricular cardiac arrhythmia, including torsades de pointes arrhythmias.
  • Severe hepatic impairment in combination with renal impairment.
• Prescribe clarithromycin with caution to people with:
  • Impaired hepatic function (or concurrently taking potentially hepatotoxic drugs) — clarithromycin is principally excreted by the liver. 
  • Coronary artery disease, severe cardiac insufficiency, conduction disturbances, or clinically relevant bradycardia — risk of QT interval prolongation.
  • Myasthenia gravis — may aggravate symptoms.
  • Renal impairment — dose reduction may be indicated based on creatinine clearance (CrCl): 
    • For immediate-release preparations, use half the usual dosage if CrCl is less than 30 mL/minute.
    • For modified-release preparations, use half the usual dosage if CrCl is 30–60 mL/minute. Avoid if CrCl is less than 30 mL/minute.
• Be aware of severe drug interactions with clarithromycin.

[EMC, 2023d; BNF, 2024]

Adverse effects

• For all macrolides
  • The most common adverse effects are:
    • Gastrointestinal adverse effects, such as diarrhoea, nausea, vomiting, abdominal discomfort, and dyspepsia.
    • Decreased appetite and altered taste.
    • Dizziness, headache, vasodilation, and vision disorders.
    • Hearing impairment.
    • Insomnia.
    • Pancreatitis.
    • Paraesthesia and skin reactions.
  • Antibiotic-associated colitis has been reported and may range in severity from mild to life-threatening.
    • Consider this diagnosis in people who present with diarrhoea during or after treatment with any antibiotic.
    • The risk is increased with longer durations of antibiotic treatment, multiple antibiotics prescribed concurrently, or multiple courses of antibiotics.
    • See the CKS topic on Diarrhoea - antibiotic associated for more information. 
  • Other possible adverse effects include:
    • Uncommon — angioedema, anxiety, arrhythmias, candidal infection, chest pain, constipation, drowsiness, eosinophilia, hepatic disorders, leucopenia, neutropenia, palpitations, QT interval prolongation, severe cutaneous adverse reactions (SCARs), tinnitus, and vertigo.
    • Rare or very rare — myasthenia gravis and nephritis tubulointerstitial.
    • Frequency not known — altered smell, hallucination, hypotension, seizure, thrombocytopenia, and tongue discolouration.
• For clarithromycin
  • Hepatic dysfunction has been reported.
    
    • This includes increased liver enzymes, and hepatocellular and/or cholestatic hepatitis with or without jaundice. 
    • Hepatic dysfunction may be severe and is usually reversible. Cases of fatal hepatic failure have been reported.
    • Advise people taking clarithromycin to stop treatment and seek medical advice if signs and symptoms of hepatic disease develop, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen.
  • Other possible adverse effects include:
    
    • Uncommon — burping, dry mouth, epistaxis, muscle complaints, oral disorders, thrombocytosis, and tremor.
    • Frequency not known — abnormal dreams, agranulocytosis, depersonalization, depression, mania, myopathy, psychotic disorder, renal failure, tooth discolouration, and urine discolouration.

 [EMC, 2023d; BNF, 2024]

Drug interactions

• Drug interactions of clarithromycin include:
  • Live cholera vaccine — efficacy of the vaccine may be reduced.
    • Avoid clarithromycin from 14 days before to 10 days after receiving live cholera vaccine.
  • Live typhoid vaccine — immune response to the vaccine may be reduced.
    • Avoid clarithromycin from 3 days before to 3 days after receiving live typhoid vaccine.
  • Antidiabetic drugs — concurrent use with oral hypoglycaemic drugs (such as sulfonylureas) or insulin can result in significant hypoglycaemia.
    
    • Monitor blood glucose levels closely, and adjust the antidiabetic dose if necessary.
  • Calcium channel blockers — clarithromycin possibly inhibits the metabolism of calcium channel blockers, such as verapamil and amlodipine, increasing the risk of hypotension and other adverse effects.
    • Monitor for hypotension and other adverse effects, and adjust the dose of the calcium channel blocker if necessary.
  • Digoxin — clarithromycin increases the plasma concentration of digoxin.  
    • Monitor for signs of digoxin adverse effects (bradycardia).
    • Measure digoxin concentrations, and adjust the dose if problems develop.
  • Direct oral anticoagulants (DOACs) — clarithromycin increases the exposure to dabigatran, slightly increases the exposure to apixaban, and is predicted to increase the exposure to edoxaban.
    
    • Monitor for signs and symptoms of bleeding or anaemia, especially in older people and people with renal impairment.
  • Drugs that prolong the QT interval — clarithromycin can prolong the QT interval. Concurrent use with other drugs that prolong QT intervals can increase the risk of QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes.
    • Concurrent use with domperidone, ivabradine, or pimozide is contraindicated. Seek advice from a medical microbiologist regarding a suitable alternative antibiotic.
    • Most manufacturers advise avoiding the use of two or more drugs that are associated with QT prolongation.
    • Increasing age, female sex, cardiac disease, and some metabolic disturbances (notably hypokalaemia) predispose to QT prolongation.
  • Drugs that cause hypokalaemia (such as diuretics) — concurrent use with clarithromycin can predispose to QT prolongation.
    
    • Monitor potassium concentrations closely.
  • Drugs that induce cytochrome P450 (CYP3A4) enzyme — concurrent use may decrease plasma concentrations of clarithromycin, leading to sub-therapeutic levels and reduced efficacy.  
    • Monitor concurrent use of clarithromycin and CYP3A4 enzyme inducers, such as rifampicin, phenytoin, carbamazepine, phenobarbital, and St. John's wort.
    • It may also be necessary to monitor the plasma levels of the CYP3A4 inducer, which could be increased due to the inhibition of CYP3A4 by clarithromycin. For example, concurrent treatment with rifabutin and clarithromycin increases rifabutin levels and decreases clarithromycin levels.
  • Edoxaban — manufacturer advises caution with concurrent treatment with edoxaban, particularly in those with a high risk of bleeding.
  • Ivabradine — concomitant treatment is contra-indicated, owing to CYP3A4 inhibition by clarithromycin which can cause elevated levels of ivabradine.
  • Statins — clarithromycin is a CYP3A4 enzyme inhibitor. Concurrent use with a statin metabolized by CYP3A4 will increase the plasma concentration of the statin, leading to an increased risk of myopathy (including rhabdomyolysis). 
    • Simvastatin is extensively metabolized by CYP3A4. Concurrent use with clarithromycin is contraindicated. If clarithromycin treatment cannot be avoided, withhold simvastatin for the duration of the clarithromycin course.
    • Atorvastatin is moderately metabolized by CYP3A4. Avoid concurrent use with clarithromycin. If concurrent use cannot be avoided, do not exceed 20 mg of atorvastatin daily. Advise the person to report any muscle pain, tenderness, or weakness.
    • Pravastatin is not associated with cytochrome P450 interactions. However, the Medicines and Healthcare products Regulatory Agency (MHRA) advises caution with clarithromycin. Advise the person to report any muscle pain, tenderness, or weakness.
    • Rosuvastatin is not associated with cytochrome P450 interactions. Nevertheless, advise the person to report any muscle pain, tenderness, or weakness.
    • Fluvastatin is not dependent on CYP3A metabolism. Nevertheless, advise the person to report any muscle pain, tenderness, or weakness. 
  • Other drugs metabolized by CYP3A4 — concurrent use with clarithromycin may increase plasma concentrations of the concurrent drug, leading to increased or prolonged therapeutic and adverse effects of the concurrent drug.
    • Concurrent use with domperidone, pimozide, or terfenadine is contraindicated due to the risk of QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes.
    • Concurrent use with ergot alkaloids, oral midazolam, colchicine, ticagrelor, or ranolazine is contraindicated.
    • Concurrent use of clarithromycin with other drugs metabolized by CYP3A4 should be done with caution, especially if the other drug has a narrow safety margin (such as carbamazepine) or is extensively metabolized by CYP3A4. Dosage adjustments may be considered, and when possible, serum concentrations of the CYP3A4 substrate should be monitored closely.
  • Warfarin — clarithromycin may enhance the anticoagulant effect of warfarin.
    • Monitor the international normalized ratio (INR) closely, and adjust the warfarin dose if necessary.

[MHRA, 2014; BNF, 2024; Preston, 2024; EMC, 2024]

Contraindications and cautions

• Do not prescribe erythromycin to people with:
  • A history of QT interval prolongation or ventricular arrhythmia (including torsade de pointes) — risk of QT interval prolongation.
  • Electrolyte disturbances (hypokalaemia or hypomagnesaemia) — risk of QT interval prolongation. 
• Prescribe erythromycin with caution to:
  • People with:
    • Impaired hepatic function (or concurrently receiving potentially hepatotoxic drugs) — erythromycin is excreted principally in the liver.
    • Moderate to severe impairment — consider dosage reduction due to the risk of ototoxicity.
    • With cardiac disease or heart failure, conduction disturbances, or clinically relevant bradycardia (or concurrently receiving drugs associated with QT interval prolongation) — risk of QT interval prolongation.
    • Myasthenia gravis — macrolides may aggravate symptoms.
    • Acute porphyrias.
  • Older people — may be more susceptible to drug-associated effects on the QT interval.

[MHRA, 2020; EMC, 2023e; BNF, 2024]

Adverse effects

• For all macrolides
  • The most common adverse effects are:
    • Gastrointestinal adverse effects, such as diarrhoea, nausea, vomiting, abdominal discomfort, and dyspepsia.
    • Decreased appetite and altered taste.
    • Dizziness, headache, vasodilation, and vision disorders.
    • Hearing impairment.
    • Insomnia.
    • Pancreatitis.
    • Paraesthesia and skin reactions.
  • Antibiotic-associated colitis has been reported and may range in severity from mild to life-threatening.
    • Consider this diagnosis in people who present with diarrhoea during or after treatment with any antibiotic.
    • The risk is increased with longer durations of antibiotic treatment, multiple antibiotics prescribed concurrently, or multiple courses of antibiotics.
    • See the CKS topic on Diarrhoea - antibiotic associated for more information. 
  • Other possible adverse effects include:
    • Uncommon — angioedema, anxiety, arrhythmias, candidal infection, chest pain, constipation, drowsiness, eosinophilia, hepatic disorders, leucopenia, neutropenia, palpitations, QT interval prolongation, severe cutaneous adverse reactions (SCARs), tinnitus, and vertigo.
    • Rare or very rare — myasthenia gravis and nephritis tubulointerstitial.
    • Frequency not known — altered smell, hallucination, hypotension, seizure, thrombocytopenia, and tongue discolouration.
• For erythromycin
  • Increased risk of cardiotoxicity (QT interval prolongation) has been reported.
    • Therefore, erythromycin should not be given to people with a history of QT interval prolongation, ventricular arrhythmia (including torsade de pointes), or electrolyte disturbances. See the section on Contraindications and cautions for more information.
  • Infantile hypertrophic pyloric stenosis has been reported.
    • The risk is highest in the first 14 days after birth.
    • Assess the benefit-risk balance of erythromycin treatment in infants.
    • Advise parents and carers to seek medical attention if vomiting or irritability with feeding occurs in infants during treatment with erythromycin.
  • Other possible adverse effects include:
    • Uncommon — hepatic dysfunction, including increased liver enzymes and/or cholestatic hepatitis (with or without jaundice).
    • Rare or very rare — hearing loss (can occur after large doses).
    • Frequency not known — cerebral impairment.

[MHRA, 2020; EMC, 2023e; BNF, 2024]

Drug interactions

• Drug interactions of erythromycin include:
  • Live cholera vaccine — efficacy of the vaccine may be reduced.
    • Avoid erythromycin from 14 days before to 10 days after receiving live cholera vaccine.
  • Live typhoid vaccine — immune response to the vaccine may be reduced.
    • Avoid erythromycin from 3 days before to 3 days after receiving live typhoid vaccine.
  • Calcium channel blockers — erythromycin possibly inhibits the metabolism of calcium channel blockers, such as verapamil and amlodipine, increasing the risk of hypotension and other adverse effects.
    • Monitor for hypotension and other adverse effects, and adjust the dose of the calcium channel blocker if necessary.
    • Hypotension, bradyarrhythmias, and lactic acidosis have been observed in people receiving concurrent verapamil.
  • Ciclosporin — erythromycin significantly increases ciclosporin concentrations, and cases of toxicity have been reported. Erythromycin-related ototoxicity has also been reported.
    • Monitor the concentration and effects (for example, on renal function) of ciclosporin more frequently if erythromycin is started or stopped.
    • Adjust the ciclosporin dose as necessary.
  • Cimetidine — cimetidine may inhibit the metabolism of erythromycin, leading to an increased plasma concentration.
    • The general clinical importance of this interaction is uncertain.
    • Monitor concurrent use for erythromycin adverse effects.
    • Stop erythromycin if deafness occurs. 
  • Digoxin — erythromycin increases the plasma concentration of digoxin.
    • Monitor for signs of digoxin adverse effects (bradycardia).
    • Measure digoxin concentrations and adjust the dose if problems develop.
  • Direct oral anticoagulants (DOACs) — erythromycin is predicted to increase the exposure to DOACs, resulting in an increased risk of bleeding.
    • Monitor for signs and symptoms of bleeding or anaemia, especially in older people and people with renal impairment.
  • Drugs that prolong the QT interval — erythromycin can prolong the QT interval. Concurrent use with other drugs that prolong QT intervals can increase the risk of QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and torsades de pointes.
    
    • Concurrent use with domperidone, tolterodine, mizolastine, or amisulpride is contraindicated.
    • Most manufacturers advise avoiding the use of two or more drugs that are associated with QT prolongation.
    • Increasing age, female sex, cardiac disease, and some metabolic disturbances (notably hypokalaemia) predispose to QT prolongation.
  • Drugs that cause hypokalaemia (such as diuretics) — concurrent use with erythromycin can predispose to QT prolongation.
    
    • Monitor potassium concentrations closely.
  • Drugs that induce cytochrome P450 (CYP3A4) enzyme — concurrent use with drugs such as rifampicin, phenytoin, carbamazepine, phenobarbital, St John's Wort may induce the metabolism of erythromycin, leading to sub-therapeutic levels of erythromycin and a decreased effect. The induction decreases gradually two weeks after discontinued treatment with the CYP3A4 inducers.
    • Avoid erythromycin during (and for two weeks after) treatment with a CYP3A4 inducer. If concurrent use is unavoidable, be alert for decreased erythromycin efficacy.
    • It may also be necessary to monitor the plasma levels of the CYP3A4 inducer, which could be increased due to the inhibition of CYP3A4 by erythromycin. For example, concurrent treatment with rifabutin and erythromycin increases rifabutin levels and decreases erythromycin levels. 
  • Statins — erythromycin is a CYP3A4 enzyme inhibitor. Concurrent use with a statin metabolized by CYP3A4 will increase the plasma concentration of the statin, leading to an increased risk of myopathy (including rhabdomyolysis).
    • Simvastatin is extensively metabolized by CYP3A4. Concurrent use with erythromycin is contraindicated. If erythromycin treatment cannot be avoided, withhold simvastatin for the duration of the erythromycin course.
    • Atorvastatin is moderately metabolized by CYP3A4. Avoid concurrent use with erythromycin. If concurrent use cannot be avoided, withhold atorvastatin for the duration of the erythromycin course or consider a lower maximum dose of atorvastatin.
    • Pravastatin is not associated with cytochrome P450 interactions. However, the Medicines and Healthcare products Regulatory Agency (MHRA) advises caution with erythromycin. Advise the person to report any muscle pain, tenderness, or weakness.
    • Rosuvastatin is not associated with cytochrome P450 interactions. Nevertheless, advise the person to report any muscle pain, tenderness, or weakness.
    • Fluvastatin is not dependent on CYP3A4 metabolism. Nevertheless, advise the person to report any muscle pain, tenderness, or weakness. 
  • Other drugs metabolized by CYP3A4 — concurrent use with erythromycin may increase plasma concentrations of the concurrent drug, leading to increased or prolonged therapeutic and adverse effects of the concurrent drug.
    • Concurrent use with pimozide or terfenadine is contraindicated. Erythromycin significantly alters the metabolism of these drugs, and rare cases of serious, potentially fatal cardiovascular events, including cardiac arrest, torsade de pointes, and other ventricular arrhythmias, have been observed.
    • Concurrent use with ergot alkaloids is contraindicated.
    • For other medications, appropriate monitoring should be undertaken and dosages adjusted as necessary. 
  • Theophylline — erythromycin can reduce theophylline clearance, leading to raised theophylline levels and potential theophylline toxicity. Oral erythromycin exposure may be reduced by theophylline. Theophylline can cause hypokalaemia, increasing the risk of torsade de pointes, which might be additive with the effects of erythromycin.
    • Monitor theophylline levels and adjust the dose accordingly.
    • Monitor the effects of erythromycin to ensure they are adequate.
    • Monitor potassium concentrations closely.
  • Warfarin — erythromycin increases the anticoagulant effect of warfarin. 
    • Monitor the international normalized ratio (INR), and adjust the warfarin dose accordingly.

[MHRA, 2014; EMC, 2023f; EMC, 2023e; BNF, 2024; Preston, 2024]