Previous changes

September 2025 — minor update. Doxycycline has been added as a first-line alternative for people allergic to penicillin in line with the updated BLS/LSN Guidelines on the management of cellulitis in lymphoedema.

June 2025 — minor update. Minor typographical error corrected.

November 2024 — minor update. A recommendation to advise people to use emollients to prevent dry and cracking skin has been added to the management section.

August 2024 — minor update. Adverse effects of co-amoxiclav updated in line with manufacturer's SPC.

May 2024 — minor update. A typographical error has been corrected. Information added stating that concomitant treatment with clarithromycin and ivabradine is now contraindicated and caution is now advised when co-administering clarithromycin with edoxaban, as per the manufacturer's updated SPC.

March 2024 — reviewed. A literature search was conducted in March 2024 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials (RCTs) published since the last revision of this topic. 

December 2023 — minor update. Update to drug interactions section for erythromycin to include information on interactions with lomitapide and corticosteroids, as per the manufacturer's Summary of Product Characteristics (SPC).

November 2023 — minor update. Interactions section for flucloxacillin updated in line with updated manufacturer's summary of product characteristics.

July 2023 — minor update. The manufacturer's SPC for metronidazole has been updated to note that QT prolongation has been reported (unknown frequency), particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval. The summary of the manufacturer’s product characteristics for clarithromycin was updated to include a warning regarding concomitant treatment with domperidone (due to the risk of QT prolongation and cardiac arrhythmias).

May 2023 — minor update. Added potential adverse effects of co-amoxiclav to include Kounis syndrome (an allergic reaction which can result in myocardial infarction), aseptic meningitis, linear IgA disease (renal deposition of IgA), and drug-induced enterocolitis syndrome (all of unknown frequency). These adverse effects were noted in an update to the manufacturer’s summary of product characteristics.

January 2023 — minor update. Revised recommendation on prescribing antibiotics in people with cellulitis and lymphoedema to align with the British Lymphology Society and Lymphoedema Support Network guideline, 2022  Guidelines on the Management of Cellulitis in Lymphoedema. 

January 2021 — minor update. Contraindications and drug interactions for erythromycin have been updated in line with an MHRA drug safety update. 

December 2019 — minor update. Text amended to clarify antibiotic choices for children with a true penicillin allergy.

October 2019 — minor update. The topic has been updated to align with the National Institute for Health and Care Excellence (NICE) guideline Cellulitis and erysipelas: antimicrobial prescribing.  

April 2019 — reviewed. A literature search was conducted in March 2019 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 the recommendations have been made. However, the topic has undergone minor restructuring, and a prescribing information section has been added for doxycycline, which is now recommended as the first-line treatment for a person with a penicillin allergy who is also taking a statin.

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

August 2016 — minor update. Information on the use of antibiotic treatment for cellulitis in children with varicella has been added.

July 2015 — minor update. The information on the concurrent use of clarithromycin with statins has been clarified.

March to June 2015 — reviewed. A literature search was conducted in March 2015 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials (RCTs) published since the last revision of this topic. No major changes to the recommendations have been made. However, the topic has undergone minor restructuring, and prescribing information sections for the recommended antibiotics have been added.

September 2014 — minor update. Text inserted to include recommendations on the management of people with cellulitis and varicella.

May 2014 — minor update. Minor correction to the basis for the recommendation on prescribing clarithromycin. Recommendations in prescribing information have been clarified and links amended.

June 2013 — minor update. Text regarding the risk of pseudomembranous colitis with flucloxacillin has been amended.

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.

September 2012 — revised. A literature search was conducted in November 2011 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of the topic. No major changes to clinical recommendations have been made.

July 2011 — minor update. More exact paracetamol dosing for children has been introduced by the Medicines and Healthcare products Regulatory Agency (MHRA). Prescriptions have been updated to reflect the revised dosing. 

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

January 2009 — minor update. Co-amoxiclav added as an antibiotic option for treatment of mild facial cellulitis that does not require admission, in line with Health Protection Agency (HPA) recommendations. 

July to September 2008 — 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. Recommendations and prescriptions on recurrent cellulitis have been removed, as they are now considered out of scope. Other than this, there have been no major changes to the recommendations.

October 2006 — minor update. Analgesia prescriptions updated because new doses of ibuprofen for children are recommended by the British National Formulary (BNF). 

June 2005 — written. Validated in September 2005 and issued in November 2005.

New evidence

Evidence-based guidelines

No new evidence-based guidelines published since 1 March 2024.

HTAs (Health Technology Assessments)

No new HTAs since 1 March 2024.

Economic appraisals

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

Systematic reviews and meta-analyses

No new systematic review or meta-analyses since 1 March 2024.

Primary evidence

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

New policies

No new national policies or guidelines since 1 March 2024.

New safety alerts

No new safety alerts since 1 March 2024.

Changes in product availability

No changes in product availability since 1 March 2024.

Classification of cellulitis

• The severity of cellulitis can be categorized using the Eron classification system, to help guide management decisions [Eron, 2003; CREST, 2005; BMJ Best Practice, 2023].
  • Class I — there are no signs of systemic toxicity and the person has no uncontrolled comorbidities.
  • Class II — the person is either systemically unwell or systemically well but with a comorbidity (for example peripheral arterial disease, chronic venous insufficiency, or morbid obesity) that may complicate or delay the resolution of infection.
  • Class III — the person has significant systemic upset, such as acute confusion, tachycardia, tachypnoea, hypotension, or unstable comorbidities that may interfere with a response to treatment, or a limb-threatening infection due to vascular compromise.
  • Class IV — the person has sepsis or a severe life-threatening infection, such as necrotizing fasciitis.

Basis for recommendation

These recommendations are based on the Clinical Resource Efficiency Support Team (CREST) Guidelines on the management of cellulitis [CREST, 2005], the Primary Care Dermatology Society (PCDS) guideline Cellulitis, erysipelas, and necrotising fasciitis [PCDS, 2022a], the BMJ Best Practice guide Cellulitis and erysipelas [BMJ Best Practice, 2023], and expert opinion in a narrative review Cellulitis [Bystritsky, 2021]. 

Basis for recommendation

This information is based on the Clinical Resource Efficiency Support Team (CREST) Guidelines on the management of cellulitis [CREST, 2005], the Primary Care Dermatology Society (PCDS) guidelines Cellulitis, erysipelas, and necrotising fasciitis [PCDS, 2022a], Panniculitis [PCDS, 2021], Pyoderma gangrenosum [PCDS, 2023], and Erythema nodosum [PCDS, 2022b], the BMJ Best Practice guide Cellulitis and erysipelas [BMJ Best Practice, 2023], and the DermNet topic on Carcinoma erysipeloides [DermNet, 2013].

When should I admit or refer a person with cellulitis?

• Refer people to hospital (urgency depending on clinical judgement) if they:
  • Have signs or symptoms suggesting a more serious condition, such as: 
    • Necrotizing fasciitis.
    • Orbital cellulitis. 
    • Osteomyelitis.
    • Sepsis — for more information see the CKS topic on Sepsis.
    • Septic arthritis.
  • Have signs of systemic illness (such as confusion, tachycardia, tachypnoea, or hypotension).
  • Have a comorbidity that may complicate or delay recovery, or that is unstable. 
  • Have a limb-threatening infection due to vascular compromise. 
  • Are severely immunocompromised. 
• Consider referring people to hospital, or seek specialist advice, if they: 
  • Are severely unwell, frail, immunocompromised, elderly, or very young. 
  • Have facial cellulitis (unless very mild). 
  • Have infection near the eyes or nose (including periorbital cellulitis). 
  • Have a spreading infection that is not responding to an oral antibiotic. 
  • Have lymphangitis. 
  • Cannot take oral antibiotics. 
    • Explore locally available options for giving intravenous antibiotics at home or in the community, rather than in hospital, where appropriate. 
  • Could have uncommon pathogens, for example, after a penetrating injury, exposure to water-borne organisms, or an infection acquired outside the UK. 
• If a person has recurrent episodes of cellulitis (two separate episodes in the previous 12 months), consider routine referral to secondary care for advice on the use of prophylactic antibiotics. 

How should I manage acute cellulitis in primary care?

For people with cellulitis who do not require admission: 

• Offer oral antibiotic treatment. 
  • Before starting treatment, consider drawing around the extent of the infection with a single-use surgical marker pen to monitor progress. This may be difficult in people with lymphoedema as the rash is often blotchy. 
• Advise the person to:
  • Take paracetamol or ibuprofen for pain and fever — for detailed information on prescribing these analgesics, see the CKS topic on Analgesia - mild-to-moderate pain.
  • Drink adequate fluids. 
  • Seek medical help if symptoms worsen rapidly or significantly at any time, or do not start to improve within 2–3 days. 
  • Elevate the leg for comfort and to relieve oedema (where applicable). 
  • Avoid the use of compression garments during acute cellulitis.
  • Use emollients to prevent dry and cracking skin.
• Identify and manage any underlying risk factors for cellulitis, for example: 
  • Diabetes mellitus — see the CKS topics on Diabetes - type 1, and Diabetes - type 2 for management information. 
  • Eczema — see the CKS topics on Eczema - atopic, Venous eczema and lipodermatosclerosis, for management information.
  • Leg ulcer — see the CKS topic on Leg ulcer - venous for management information. 
  • Lymphoedema — consider referring these people to a specialist clinic.  
  • Tinea pedis — see the CKS topic on Fungal skin infection - foot for management information.
  • Venous insufficiency — see the CKS topic on Venous eczema and lipodermatosclerosis for management information. 
• Give advice on preventative measures to reduce the risk of recurrence, including management of risk factors, for example:
  • Weight management advice for people living with obesity — for more information, see the CKS topic on Obesity.
  • Foot care advice for people with diabetes. 
  • Use of emollients for people with dry skin.      
• Provide patient information on cellulitis. For example:  
  • The British Association of Dermatologists (BAD) leaflet Cellulitis and erysipelas.  
  • The Lymphoedema Support Network information About cellulitis.
  • The NHS information on Cellulitis. 
• Reassess the person if:
  • Symptoms worsen rapidly or significantly at any time, or do not start to improve within 2–3 days.
  • They become systemically unwell.
  • They have severe pain out of proportion to the infection.
  • Redness or swelling beyond the initial presentation develops — take into account that some initial spreading may occur, and that redness may be less visible on darker skin tones.
• If a person has recurrent episodes of cellulitis (two separate episodes in the previous 12 months), consider routine referral to secondary care for advice on the use of prophylactic antibiotics. 

Which oral antibiotics should I prescribe?

Before treatment, consider drawing around the extent of the infection with a single-use surgical marker pen to monitor progress. This may be difficult in people with lymphoedema as the rash is often blotchy. 

• When choosing an antibiotic, take into account: 
  • The severity of symptoms.
  • The site of infection (for example near the eyes or nose).
  • The risk of uncommon pathogens (for example from a penetrating injury, after exposure to water-borne organisms, or an infection acquired outside the UK).
  • Previous microbiological results from a swab.
  • The person's meticillin-resistant Staphylococcus aureus (MRSA) status if known.
• For adults with cellulitis:
  • Prescribe flucloxacillin 500–1000 mg four times daily for 5–7 days.
  • If this is unsuitable, or the person has a penicillin allergy, prescribe either: 
    • Clarithromycin 500 mg twice daily for 5–7 days.
    • Doxycycline 200 mg on the first day then 100 mg once daily, for a total of 5–7 days.
    • Erythromycin (in pregnancy) 500 mg four times daily for 5–7 days.
• For adults with an infection near the eyes or nose, consider seeking specialist advice and prescribe co-amoxiclav 500/125 mg three times daily for 7 days.
  • If this is unsuitable, or the person has a penicillin allergy, prescribe clarithromycin 500 mg twice daily for 7 days plus metronidazole 400 mg three times daily for 7 days.
• For adults with known lymphoedema who develop cellulitis but do not require admission or referral:
  • Prescribe flucloxacillin 500-1000 mg four times daily for 14 days. 
  • If this cannot be tolerated, prescribe:
    • Amoxicillin 500 mg three times daily for 14 days.
  • If the person has a penicillin allergy, prescribe doxycycline 100 mg twice daily. If this is unsuitable, prescribe clarithromycin 500 mg twice daily for 14 days. 
  • Note: skin changes (such as discolouration) may persist for months or longer following severe cellulitis and do not necessarily require ongoing antibiotics.
• For children aged 1 month and over with cellulitis: 
  • Prescribe flucloxacillin for 5–7 days.
    • Aged 1 month to 1 year — 62.5–125 mg four times daily.
    • Aged 2–9 years — 125–250 mg four times daily.
    • Aged 10–17 years — 250–500 mg four times daily.
  • If this is unsuitable prescribe co-amoxiclav for 5–7 days.
    • Aged 1–11 months — 0.25 ml/kg of 125/31 suspension three times daily (double dose in severe infection).
    • Aged 1–5 years — 0.25 ml/kg or 5 ml of 125/31 suspension three times daily (double dose in severe infection).
    • Aged 6–11 years — 0.15 ml/kg or 5 ml of 250/62 suspension three times daily (double dose in severe infection).
    • Aged 12–17 years — 250/125 mg or 500/125 mg three times daily.
  • If the person has a penicillin allergy, prescribe clarithromycin for 5–7 days.
    • Under 8 kg — 7.5 mg/kg twice daily
    • 8–11 kg — 62.5 mg twice daily.
    • 12–19 kg — 125 mg twice daily.
    • 20–29 kg — 187.5 mg twice daily.
    • 30–40 kg — 250 mg twice daily.
    • 12–17 years — 250–500 mg twice daily, or erythromycin (in pregnancy) 250–500 mg four times daily for 5–7 days.
• For children aged 1 month and over with infection near the eyes or nose, consider seeking specialist advice and prescribe co-amoxiclav three times daily for 7 days. 
  • If this is unsuitable, or the person has a penicillin allergy, prescribe clarithromycin twice daily for 7 days.
  • If the presence of anaerobes is suspected prescribe clarithromycin plus metronidazole twice daily for 7 days:
    • Aged 1 month — 7.5 mg/kg twice daily.
    • Aged 2 months to 11 years — 7.5 mg/kg three times daily (maximum per dose 400 mg).
    • Aged 12–17 years — 400 mg three times daily.
• Give advice about: 
  • Possible adverse effects of antibiotics.
  • The skin taking some time to return to normal after the course of antibiotics has finished.
  • Seeking medical help if symptoms worsen rapidly or significantly at any time, or do not start to improve within 2–3 days.

How should I follow up a person on oral antibiotic treatment?

• Reassess the person after 2–3 days depending on clinical judgement. 
• Take into account: 
  • Other possible diagnoses, such as an inflammatory reaction to an immunization or an insect bite, gout, superficial thrombophlebitis, eczema, allergic dermatitis or deep vein thrombosis.
  • Any underlying conditions that may predispose to cellulitis or erysipelas, such as oedema, diabetes, venous insufficiency, or eczema.
  • Any symptoms or signs suggesting a more serious illness or condition, such as lymphangitis, orbital cellulitis, osteomyelitis, septic arthritis, necrotising fasciitis, or sepsis.
  • Any results from microbiological testing.
  • Any previous antibiotic use, which may have led to resistant bacteria.
• Consider taking a swab for microbiological testing if the skin is broken and this has not been done already. 
• If a swab has been sent for microbiological testing: 
  • Review the choice of antibiotic(s) when results are available. 
  • Change the antibiotic(s) according to results if symptoms or signs of the infection are not improving, using a narrow-spectrum antibiotic if possible.
• Refer the person to hospital, or seek specialist advice, if the infection is spreading and not responding to oral antibiotic treatment.   

Contraindications and cautions

• Do not prescribe amoxicillin 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, 2018; Devchand, 2019; Stone, 2020].
  • A history of severe immediate hypersensitivity reaction to cephalosporins — there is some evidence of partial cross-allergenicity. 
• Prescribe amoxicillin with caution to people with:
  • Chronic kidney disease (CKD) — reduce the dose of amoxicillin based on the estimated glomerular filtration rate (eGFR):
    • If the eGFR is 10–30 mL/minute/1.73 m², prescribe a maximum of 500 mg twice daily.
    • If the eGFR is less than 10 mL/minute/1.73 m², prescribe a maximum of 500 mg once daily.
  • Glandular fever (infective mononucleosis) — erythematous rashes common.
  • Acute lymphocytic leukaemia and chronic lymphocytic leukaemia — increased risk of erythematous rashes.
  • Cytomegalovirus infection — increased risk of erythematous rashes.

[BNF, 2024; EMC, 2024a]

Adverse effects

• Gastrointestinal
  • Common: nausea and diarrhoea.
  • Uncommon: vomiting.
  • Very rarely: antibiotic-associated colitis. For more information, see the CKS topic on Diarrhoea - antibiotic associated.
• Skin and subcutaneous tissue 
  • Common: skin rash.
  • Uncommon: urticaria and pruritus.
  • Very rarely: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis, acute generalised exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS).
• Other very rare adverse effects include: 
  • Aseptic meningitis.
  • Crystalluria.
  • Hepatitis and cholestatic jaundice.
  • Hyperkinesia, dizziness, and convulsions.
  • Interstitial nephritis.
  • Jarisch–Herxheimer reaction.
  • Kounis syndrome.
  • Leucopenia, thrombocytopenia, and haemolytic anaemia.
  • Severe allergic reactions.

[BNF, 2024; EMC, 2024a]

Drug interactions

• Possible drug interactions for amoxicillin include:
  • Allopurinol — concurrent use with amoxicillin may increase the incidence of skin rashes. However, there is no need to avoid concurrent use.
  • Coumarin anticoagulants (for example, warfarin) — isolated cases of increased prothrombin time have been reported in people taking amoxicillin concurrently. Consider monitoring INR more frequently if penicillins are started or stopped.  
  • 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.
  • Live cholera vaccine — efficacy of the vaccine may be reduced.
    • Avoid antibiotics from 14 days before to 10 days after receiving live cholera vaccine.
  • Live typhoid vaccine — immune response to the vaccine may be reduced.
    • Avoid antibiotics from 3 days before to 3 days after receiving live typhoid vaccine.

[Preston, 2024]

Pregnancy and breastfeeding

• Pregnancy
  • Amoxicillin is not known to be harmful in pregnancy. 
• Breastfeeding
  • Trace amounts of amoxicillin are found in breastmilk, but it is appropriate to use in women who are breastfeeding.

[BNF, 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. Maximum duration 14 days. 
    • 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.

[EMC, 2023a; BNF, 2024]

Adverse effects

• Cardiac 
  • Uncommon: cardiac arrest, atrial fibrillation, and QT interval prolongation.
  • Unknown: torsades de pointes, ventricular tachycardia, and ventricular fibrillation.
• Gastrointestinal 
  • Common: diarrhoea, vomiting, dyspepsia, nausea, and abdominal pain. 
  • Uncommon: gastroesophageal reflux disease, gastritis, proctalgia, stomatitis, glossitis, abdominal distension, constipation, dry mouth, eructation, and flatulence.
  • Unknown: pancreatitis and pseudomembranous colitis. For more information, see the CKS topic on Diarrhoea - antibiotic associated.
• Hepatobiliary
  • Common: abnormal liver function test.
  • Uncommon: cholestasis, hepatitis, and raised liver enzymes. 
  • Unknown: hepatic failure and jaundice.
• Nervous system 
  • Common: headache and dysgeusia.
  • Uncommon: dizziness, somnolence, and tremor.
  • Unknown: convulsions and paraesthesia.
• Psychiatric 
  • Common: insomnia.
  • Uncommon: anxiety and nervousness. 
  • Unknown: psychotic disorders, depression, mania, hallucination, and abnormal dreams.
• Skin 
  • Common: rash and hyperhidrosis.
  • Uncommon: pruritus and urticaria.
  • Unknown: drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalised exanthematous pustulosis (AGEP).
• Other adverse effects include: 
  • Anaphylaxis.
  • Asthma,
  • Deafness.
  • Epistaxis.
  • Hepatic failure and jaundice.
  • Pancreatitis. 
  • Renal failure and interstitial nephritis.
  • Rhabdomyolysis, muscle spasms, and myopathy.
  • Vasodilation and haemorrhage.

 [EMC, 2023a; BNF, 2024]

Drug interactions

• Drug interactions for clarithromycin include:
  • 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 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.
    • Edoxaban — decrease the edoxaban dose to 30 mg once daily. 
  • 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 about 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.
    • Salmeterol — avoid concurrent use. 
  • 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 contraindicated, 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 — concurrent use is contraindicated. If clarithromycin treatment cannot be avoided, withhold simvastatin for the duration of the clarithromycin course.
    • Atorvastatin — avoid concurrent use. If concurrent use cannot be avoided, withhold statin, or give the lowest dose possible, and advise the person to report any muscle pain, tenderness, or weakness.
    • Pravastatin — advise the person to report any muscle pain, tenderness, or weakness.
    • Rosuvastatin — advise the person to report any muscle pain, tenderness, or weakness.
  • Drugs metabolized by CYP3A4 — concurrent use with clarithromycin may increase plasma levels of these drugs, leading to increased or prolonged therapeutic and adverse effects.
    • Daridorexant or rimegepant — avoid concurrent use. 
    • Domperidone, dronederone, pimozide, or terfenadine — concurrent use is contraindicated due to the risk of QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes.
    • Ergot alkaloids, oral midazolam, colchicine, eplerenone,  ticagrelor, or ranolazine — concurrent use is contraindicated.
    • 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 — few patients have a clinically significant interaction. Consider increased monitoring of INR, especially in the first 3 days of starting clarithromycin. 
  • Live cholera vaccine — efficacy of the vaccine may be reduced.
    • Avoid antibiotics from 14 days before to 10 days after receiving live cholera vaccine.
  • Live typhoid vaccine — immune response to the vaccine may be reduced.
    • Avoid antibiotics from 3 days before to 3 days after receiving live typhoid vaccine.

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

Pregnancy and breastfeeding

• Pregnancy
  • The manufacturer advises that the use of clarithromycin is not advised in pregnancy, particularly in the first trimester, unless the potential benefit outweighs the risk.
• Breastfeeding
  • Clarithromycin is excreted into breast milk. Epidemiologic evidence indicates that the risk of hypertrophic pyloric stenosis in infants might be increased by use of maternal macrolides, especially in infants exposed in the first 2 weeks after birth.
  • The manufacturer advises avoiding clarithromycin unless the potential benefit outweighs the risk.

[SPS, 2020a; BNF, 2024]

Contraindications and cautions

• Do not prescribe co-amoxiclav 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, 2018; Devchand, 2019; Stone, 2020].
  • History of urticaria or rash immediately after penicillin administration — risk of immediate penicillin hypersensitivity.
  • 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 co-amoxiclav-associated jaundice or hepatic dysfunction. 
  • History of penicillin-associated jaundice or hepatic dysfunction.
• Prescribe co-amoxiclav 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 penicillin administration — possibility of an allergic reaction to penicillins.
  • 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 — monitor hepatic function regularly.
  • Acute or chronic lymphocytic leukaemia — increased risk of erythematous rashes.
  • Cytomegalovirus infection — increased risk of erythematous rashes.
  • Glandular fever — erythematous rashes are common.
  • Renal impairment — dosage reduction may be indicated:
    • For adults and children weighing 40 kg or more: if creatinine clearance (CrCl) is 10–30 ml/minute, prescribe 500 mg/125 mg twice daily. If CrCl is less than 10 ml /minute, prescribe 500 mg/125 mg once daily.
    • For children weighing less than 40 kg: if CrCl is 10–30 ml/minute, prescribe 15 mg/3.75 mg/kg twice daily (maximum 500 mg/125 mg twice daily). If CrCl is less than 10 ml /minute, prescribe 15 mg/3.75 mg/kg as a single daily dose (maximum 500 mg/125 mg).

[BNF, 2024; EMC, 2024c]

Adverse effects

• Gastrointestinal
  • Common: nausea, diarrhoea, and vomiting.
  • Uncommon: indigestion.
  • Very rarely: antibiotic-associated colitis. For more information, see the CKS topic on Diarrhoea - antibiotic associated.
• Skin and subcutaneous tissue 
  • Common: skin rash.
  • Uncommon: urticaria and pruritus.
  • Very rarely: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis, acute generalised exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS), and linear IgA disease.
• Other very rare adverse effects include: 
  • Aseptic meningitis.
  • Black hairy tongue. 
  • Crystalluria.
  • Hepatitis, cholestatic jaundice, and cholangitis.
  • Hyperkinesia, akathisia, dizziness, and convulsions.
  • Interstitial nephritis.
  • Jarisch–Herxheimer reaction.
  • Kounis syndrome.
  • Leucopenia, thrombocytopenia, and haemolytic anaemia.
  • Severe allergic reactions.
• Symmetrical Drug-related Intertriginous and Flexural Exanthema (SDRIFE) are adverse effects of unknown frequency.

[BNF, 2024; EMC, 2024c; EMC, 2024d]

Drug interactions

• Drug interactions for co-amoxiclav include:
  • Allopurinol — concurrent use with amoxicillin may increase the incidence of skin rashes. However, there is no need to avoid concurrent use.
  • Coumarin anticoagulants (for example, warfarin) — isolated cases of increased prothrombin time have been reported in people taking amoxicillin concurrently. Consider monitoring INR more frequently if penicillins are started or stopped.  
  • 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.
  • Mycophenolate — amoxicillin (given with clavulanic acid) reduces exposure to mycophenolate. Monitor mycophenolate efficacy.
  • Live cholera vaccine — efficacy of the vaccine may be reduced.
    • Avoid antibiotics from 14 days before to 10 days after receiving live cholera vaccine.
  • Live typhoid vaccine — immune response to the vaccine may be reduced.
    • Avoid antibiotics from 3 days before to 3 days after receiving live typhoid vaccine.

 [Preston, 2024]

Pregnancy and breastfeeding

• Pregnancy
  • Co-amoxiclav is not known to be harmful in pregnancy. 
  • Data do not support an increased risk of any adverse pregnancy outcomes associated with penicillin use in pregnancy.  
• Breastfeeding
  • Trace amounts of co-amoxiclav are found in breastmilk, but it is appropriate to use in women who are breastfeeding. 

[UKTIS, 2019; BNF, 2024]

Contraindications and cautions

• Do not prescribe doxycycline to:
  • Pregnant women.
  • Breastfeeding women.
  • Children younger than 12 years of age — tetracyclines can bind to calcium ions and be deposited in growing bone and teeth, causing staining. Enamel hypoplasia has also been reported.
    
    • In children aged under 8 years, use only in severe or life-threatening conditions (such as Rocky Mountain spotted fever) when there are no adequate alternatives.
    • In children aged 8–11 years, use only in acute or severe infections when there are no adequate alternatives.
• Prescribe doxycycline with caution to people with:
  • Hepatic impairment (or concurrently receiving potentially hepatotoxic drugs).
  • Myasthenia gravis — muscle weakness may be increased.
  • Systemic lupus erythematosus — symptoms may be exacerbated.
  • Alcohol dependence — alcohol may decrease the half-life of doxycycline.

[MHRA, 2023; BNF, 2024]

Adverse effects

• Blood disorders
  • Rare: haemolytic anaemia, thrombocytopenia, neutropenia, and eosinophilia.
• Gastrointestinal 
  • Common: diarrhoea, nausea, and vomiting
  • Uncommon: dyspepsia, abdominal discomfort, diarrhoea, and tooth discolouration and enamel hypoplasia in children
  • Rare: dysphagia, oesophagitis, oesophageal irritation, and pseudomembranous colitis. For more information, see the CKS topic on Diarrhoea - antibiotic associated.
• Hepatic disorders
  • Rare: hepatotoxicity, hepatitis, jaundice, and hepatic failure.
• Skin 
  • Common: photosensitivity and rash.
  • Rarely: toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiforme, exfoliative dermatitis, photo-onycholysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and fixed eruption.
• Other rare adverse effects include:
  • Anaphylaxis.
  • Anxiety.
  • Arthralgia and myalgia.
  • Blood urea increased.
  • Bulging fontanelles in infants.
  • Flushing.
  • Intracranial hypertension.
  • Jarisch-Herxheimer reaction.
  • Porphyria and reduced appetite.
  • Severe headache and/or visual disturbances — may be an early symptom of benign intracranial hypertension, a rare but serious adverse effect.
  • Tinnitus.

[MHRA, 2023; BNF, 2024]

Drug interactions

• Drug interactions for doxycycline include:
  • Antacids — the absorption of doxycycline may be impaired by concurrently administered antacids containing aluminium, calcium, or magnesium, or other drugs containing these cations, as well as oral zinc, iron salts, or bismuth preparations.
    • Separate the doses by at least 2–3 hours to avoid this interaction.
    • Histamine H2-receptor antagonists do not interact and could be a suitable alternative.
  • Carbamazepine and phenytoin — serum levels of doxycycline are reduced and may fall below the accepted therapeutic minimum in people on long-term treatment with carbamazepine or phenytoin. 
    • Doxycycline dose may need to be doubled.
  • Ciclosporin — doxycycline is predicted to increase ciclosporin concentrations.
    • Monitor ciclosporin concentrations and effects (for example, on renal function) more frequently when starting or stopping doxycycline, and adjust the ciclosporin dose as needed.
  • Lithium — doxycycline is predicted to increase the risk of lithium toxicity.
    • If concurrent use cannot be avoided, monitor for lithium toxicity (tremors, dysarthria, ataxia, and confusion), and adjust the lithium dose as needed.
  • Retinoids — there is a possible increased risk of benign intracranial pressure if tetracyclines are used concurrently with retinoids (such as isotretinoin). Concurrent use is contraindicated.
  • Rifampicin — doxycycline levels are markedly reduced, which may lead to treatment failure. Monitor the effects and increase doxycycline dose if necessary.
  • Coumarin anticoagulants (for example, warfarin) — doxycycline may increase the anticoagulant effect of warfarin. Consider increasing monitoring of INR.
  • Live cholera vaccine — efficacy of the vaccine may be reduced.
    • Avoid antibiotics from 14 days before to 10 days after receiving live cholera vaccine.
  • Live typhoid vaccine — immune response to the vaccine may be reduced.
    • Avoid antibiotics from 3 days before to 3 days after receiving live typhoid vaccine.

[Preston, 2024]

Pregnancy and breastfeeding

• Pregnancy
  • Doxycycline is contraindicated in women who are pregnant. 
• Breastfeeding 
  • The manufacturer advises that doxycycline is contraindicated in breastfeeding women as it may cause permanent discolouration of the child's teeth (yellow-grey-brown), and affect skeletal development. 
  • The NHS Specialist Pharmacy Service (SPS) states that concerns about bone deposition of tetracyclines and possible staining of infant’s dental enamel have not been confirmed, and are unlikely during short-term use. In addition, absorption and therefore discolouration of teeth in the infant is also inhibited by calcium in the breastmilk.
    • If other antibiotics are not appropriate, tetracycline is the preferred drug from this group. Short-term use (less than 3 weeks duration) is acceptable for most tetracyclines, but long-term use (for example in acne) is not advisable.

[SPS, 2020b; MHRA, 2023; BNF, 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 renal 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 — they may be more susceptible to drug-associated effects on the QT interval.

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

Adverse effects

• Gastrointestinal 
  • Common or very common: diarrhoea, GI discomfort/disorders, nausea, vomiting, and pancreatitis.
  • Uncommon: constipation.
  • Rare or very rare: antibiotic-associated colitis. For more information, see the CKS topic on Diarrhoea - antibiotic associated. 
• Cardiovascular  
  • Uncommon: QTc interval prolongation, torsades de pointes, and palpitations and cardiac rhythm disorders, including ventricular tachyarrhythmias.
• Hepatobiliary
  • Uncommon: cholestatic hepatitis, jaundice, hepatic dysfunction, hepatomegaly, hepatic failure, and hepatocellular hepatitis.
• Skin and subcutaneous tissues 
  • Common or very common: skin reactions.
  • Uncommon: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme (uncommon), and acute generalised exanthematous pustulosis (AGEP).
• Other adverse effects include:
  • Dizziness.
  • Eosinophilia, leucopenia, and neutropenia.
  • Hallucinations.
  • Headache.
  • Hearing impairment, tinnitus.
  • Interstitial nephritis.
  • Myasthenia gravis.
  • Seizures, confusion, vertigo.
  • Vasodilation.
  • Vision disorders.
• 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.
  • Rare or very rare — hearing loss (can occur after large doses).

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

Drug interactions

• Drug interactions of erythromycin include:
  • 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.
  • 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. Monitor concurrent use for erythromycin adverse effects.
  • Digoxin — erythromycin may increase the plasma concentration of digoxin. Monitor for signs of digoxin adverse effects (bradycardia), measure digoxin concentrations, and adjust the dose if necessary.
  • 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.
    • Edoxaban — decrease the edoxaban dose to 30 mg once daily. 
  • 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, and 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 2 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 — concurrent use is contraindicated. If erythromycin treatment cannot be avoided, withhold simvastatin for the duration of the erythromycin course.
    • Atorvastatin — avoid concurrent use. If concurrent use cannot be avoided, withhold statin, or give the lowest dose possible, and advise the person to report any muscle pain, tenderness, or weakness.
    • Pravastatin  — 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 — few patients have a clinically significant interaction. Consider increased monitoring of INR, especially in the first 3 days of starting clarithromycin. 
  • Live cholera vaccine — efficacy of the vaccine may be reduced.
    • Avoid antibiotics from 14 days before to 10 days after receiving live cholera vaccine.
  • Live typhoid vaccine — immune response to the vaccine may be reduced.
    • Avoid antibiotics from 3 days before to 3 days after receiving live typhoid vaccine.

[MHRA, 2014; Preston, 2024]

Pregnancy and breastfeeding

Pregnancy

• The manufacturer advises that states that erythromycin should only be used during pregnancy if clinically needed and the benefit of treatment is expected to outweigh any small increased risks that may exist. 

Breastfeeding

• Erythromycin is excreted in breast milk in small amounts and it is not known to be harmful.

[EMC, 2023b; BNF, 2024]

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, 2018; 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 penicillins.
  • 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 increase in dosing interval.

[EMC, 2023c; BNF, 2024]

Adverse effects

• Gastrointestinal   
  • Common: diarrhoea, nausea, and gastrointestinal disturbances.
  • Very rarely: antibiotic-associated colitis. For more information, see the CKS topic on Diarrhoea - antibiotic associated.  
• Nervous system 
  • Uncommon: headache and dizziness.
• Skin and subcutaneous tissue 
  • Uncommon: skin rash, urticaria, and purpura. 
  • Very rarely: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis (AGEP).
• Other adverse effects include:
  • Anaphylaxis.
  • Arthralgia and myalgia — may sometimes develop more than 48 hours after the start of the treatment.
  • Fever — may sometimes develop more than 48 hours after the start of the treatment.
  • Hepatitis and cholestatic jaundice — this may occur up to several weeks after treatment with flucloxacillin has been stopped. Risk factors include treatment for more than 2 weeks, and increasing age.
  • Hypokalaemia
  • Interstitial nephritis.
  • Neutropenia, thrombocytopenia, and haemolytic anaemia.

[EMC, 2023c; BNF, 2024]

Drug interactions

• Drug interactions of flucloxacillin include:
  • 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, and malnutrition, especially if the maximum daily doses of paracetamol are used.
    • On stopping paracetamol, HAGMA may persist with flucloxacillin alone.
  • Azole antifungals (for example, posaconazole and voriconazole) — flucloxacillin (particularly high doses) appears 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). 
  • 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.
  • Live cholera vaccine — efficacy of the vaccine may be reduced.
    • Avoid antibiotics from 14 days before to 10 days after receiving live cholera vaccine.
  • Live typhoid vaccine — immune response to the vaccine may be reduced.
    • Avoid antibiotics from 3 days before to 3 days after receiving live typhoid vaccine.

[Preston, 2024]

Pregnancy and breastfeeding

Pregnancy

• Flucloxacillin is not known to be harmful in pregnancy. 

Breastfeeding

• Trace amounts of penicillins are found in breastmilk, but it is appropriate to use in women who are breastfeeding. 

[EMC, 2023c; BNF, 2024]

Contraindications and cautions

• Prescribe metronidazole with caution to people with:
  • Cockayne syndrome.
  • Active or chronic severe peripheral and central nervous system disease.
  • Severe liver disease or hepatic encephalopathy — prescribe one-third of the daily dosage once daily.

[BNF, 2024; EMC, 2024e]

Adverse effects

• Blood disorders 
  • Very rare: agranulocytosis, neutropenia, thrombocytopenia, and pancytopenia.
  • Unknown: leucopenia and bone marrow depression disorders such as aplastic anaemia.
• Gastrointestinal 
  • Unknown: nausea, vomiting, anorexia, epigastric pain, taste disturbances, furred tongue, and oral mucositis.
• Hepatobiliary
  • Very rare: abnormal liver function tests, cholestatic hepatitis, jaundice, and pancreatitis.
• Nervous system
  • Very rare: drowsiness, dizziness, convulsions, headaches, and encephalopathy.
  • Unknown: depression, paraesthesia, and peripheral sensory neuropathy.
• Psychiatric 
  • Very rare: psychotic disorders and hallucinations.
• Skin
  • Very rare: rash, pruritus, and flushing.
  • Unknown: erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis, and fixed drug eruption.
• Other rare, or very rare adverse effects include:
  • Anaphylaxis and angioedema.
  • Darkening of urine.
  • Diplopia or myopia.
  • Hearing impairment and tinnitus.
  • Liver enzyme increases, jaundice, and pancreatitis.
  • Myalgia and arthralgia.

[BNF, 2024; EMC, 2024e]

Drug interactions

• Alcohol — some people taking metronidazole experience a disulfiram-like reaction with alcohol.
  • Warn the person that they might experience this reaction if they drink alcohol whilst on metronidazole and for at least 48 hours afterwards. 
• Busulfan — plasma levels of busulfan increased potentially leading to toxicity. Avoid high doses of busulfan. If conventional doses of busulfan are given, monitor blood count weekly.
• Ciclosporin — levels of ciclosporin may be increased. If co-administration of metronidazole and ciclosporin is necessary, monitor serum ciclosporin and serum creatinine levels closely.
• Ergot alkaloids — levels may be increased, which may lead to ergotism. If concurrent use is unavoidable, advise the person to be alert for symptoms of ergotism (coldness, numbness, or tingling of the hands and feet), and advise them to stop treatment and seek medical advice.
• Fluorouracil — metronidazole reduces the clearance of fluorouracil, increasing the risk of toxicity. Monitor the person for increased toxicity.
• Lithium — seek specialist advice regarding the use of metronidazole with lithium, as metronidazole increases the risk of lithium toxicity. Lithium dose reduction may be required due to the risk of renal damage with concurrent use. Plasma concentrations of lithium, creatinine, and electrolytes should be monitored if metronidazole and lithium are used simultaneously.
• Phenobarbital — the metabolism of metronidazole is increased significantly. The dose of metronidazole may need to be increased.
• Coumarin anticoagulants (for example, warfarin) — the anticoagulant effects of warfarin are increased by metronidazole. 
  • Monitor the international normalized ratio (INR) and adjust the warfarin dose accordingly. 
• Live cholera vaccine — efficacy of the vaccine may be reduced.
  • Avoid antibiotics from 14 days before to 10 days after receiving live cholera vaccine.
• Live typhoid vaccine — immune response to the vaccine may be reduced.
  • Avoid antibiotics from 3 days before to 3 days after receiving live typhoid vaccine.

[Preston, 2024]

Pregnancy and breastfeeding

Pregnancy

• Metronidazole can be considered in pregnancy if clinically indicated.
• The manufacturer advises that it can be used in pregnancy if the potential benefit outweighs the possible risks, but high dose regimens should be avoided.  

Breastfeeding

• Significant amounts of metronidazole are excreted in breastmilk, however, it is compatible with breastfeeding, but the manufacturer advises against the use of high-dose regimens.

[UKTIS, 2022; BNF, 2024; EMC, 2024e]