Previous changes

May 2024 — minor update. 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. Additional information added to the basis for recommendation in the section on management about use of anaesthetic and analgesic drops.

February 2024 — reviewed. A literature search was conducted in January 2024 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of the topic. There have been minor structural changes to the topic, with no major changes to the clinical recommendations.

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).

July 2023 — minor update. The summary of 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 2021 — minor update. Contraindications and drug interactions for erythromycin have been updated in line with an MHRA drug safety update. 

July 2018 — reviewed. A literature search was conducted in May 2018 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, recommendations in the Acute otitis media - initial presentation and Persistent acute otitis media - treatment failure scenarios have been updated in line with the 2018 NICE guideline Otitis media (acute): antimicrobial prescribing, and individual prescribing information sections for the recommended antibiotics have been added.

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

May 2015 — minor update. Typographical errors corrected.

January to March 2015 — reviewed. A literature search was conducted in January 2015 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 prescribing information sections for the recommended antibiotics have been added.

May 2014 — minor update. Links to prescriptions have been removed from the scenarios.

August 2013 — minor update. In Scenario: Acute diffuse otitis externa, the management node has been slightly reworded to clarify that in children younger than 3 months there should be a low threshold for admitting the child or for prescribing antibiotics, as appropriate.

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.

July 2011 — minor update. More exact paracetamol dosing for children has been introduced by the Medicines and Healthcare products Regulatory Agency. 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. 

April to July 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.

The following important changes have been made to the previous CKS guidance:

• In line with the National Institute for Health and Care Excellence guideline, Prescribing of antibiotics for self-limiting respiratory tract infections in adults and children in primary care, immediate antibiotics are no longer routinely recommended for:
  • All children younger than 6 months of age.
  • Children aged between 6 months and 2 years of age in whom the diagnosis of AOM is reasonably certain.
  • Children older than 2 years of age where there is moderate or severe earache with a fever of 39°C or above or bilateral acute otitis media.
• In line with the National Institute for Health and Care Excellence guideline, Feverish illness in children — Assessment and initial management in children younger than 5 years, admission for specialist assessment is now recommended for:
  • Children younger than 3 months of age with a temperature of 38°C or higher.
  • Children 3–6 months of age with a temperature of 39°C or higher.

February 2009 — minor update. Azithromycin added as a second-line antibiotic option for people who are allergic to penicillin, in line with updated advice from the Health Protection Agency. 

January 2007 — updated. Macrolide choices for people with penicillin allergy changed to erythromycin and clarithromycin, in line with advice from the Health Protection Agency. 

July to September 2006 — reviewed. Validated in December 2006 and issued in January 2007.

June 2007 — minor update. Amoxicillin prescription corrected. 

November 2005 — minor technical update. 

March 2004 — updated the recommended dose of amoxicillin. Validated in March 2004 and issued in June 2004.

July 2003 — rewritten. Validated in September 2003 and issued in October 2003.

March 2001 — reviewed. Validated in July 2001 and issued in October 2001.

June 1999 — reviewed.

April 1998 — reviewed.

January 1997 — new topic.

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

• Sirota, S. B., Doxey, M. C., Dominguez, R. M. V., et al. (2024). Global, regional, and national burden of upper respiratory infections and otitis media, 1990–2021: a systematic analysis from the Global Burden of Disease Study 2021. The Lancet Infectious Diseases. [Abstract]

Primary evidence

• Shaikh, N., Conway, S.J., Kovacevic, J., et al. (2024) Development and Validation of an Automated Classifier to Diagnose Acute Otitis Media in Children. JAMA Pediatrics. https://jamanetwork.com/journals/jamapediatrics [Abstract]

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 January 2024.

Basis for recommendation

These recommendations are based on a US clinical guideline The diagnosis and management of acute otitis media [Lieberthal, 2013], a Canadian position statement Management of acute otitis media in children six months of age and older [Le Saux, 2016], expert opinion published in a systematic review Does this child have acute otitis media? [Rothman, 2003], and narrative review articles [Powers, 2007; Atkinson, 2015; Rosa-Olivares, 2015; Finnikin, 2016; Schilder, 2016; Gaddey, 2019; BMJ Best Practice, 2023].

Accurate diagnosis and antimicrobial stewardship

• A Canadian position statement on the diagnosis and management of AOM [Le Saux, 2016] emphasises the importance of accurate diagnosis for determining which children with AOM will most likely experience a faster recovery with antibiotics. Such an approach was considered likely to help minimise antibiotic use and thereby decrease the risk of antibiotic resistance and adverse effects.
• There is no gold standard set of criteria for the diagnosis of AOM [Lieberthal, 2013; BMJ Best Practice, 2023].
• Of the spectrum of signs that occur as the disease develops, moderate to severe bulging of the tympanic membrane is the most helpful in making the diagnosis. The combination of a cloudy, bulging tympanic membrane with impaired mobility is the best predictor of AOM [Lieberthal, 2013].
• Although non-specific, symptoms of an upper respiratory infection that may be ongoing or resolving are common among people with AOM. Other common features include otalgia, irritability, sleep disturbance and fever [Gaddey, 2019; BMJ Best Practice, 2023].

Red flags

• Symptoms such as altered conscious level, vomiting, photophobia, and persistent headache may indicate an intracranial complication (for example, meningitis, or temporal lobe or extradural/subdural abscess) [Atkinson, 2015].

Basis for recommendation

These recommendations are based on expert opinion from narrative review articles [Finnikin, 2016; Schilder, 2016; Gaddey, 2019; BMJ Best Practice, 2023].

How should I manage people at initial presentation?

• Admit for immediate specialist assessment:
  • People with a severe systemic infection.
  • Adults and children with red flag symptoms suggesting complications of acute otitis media (AOM), such as meningitis, mastoiditis, intracranial abscess, sinus thrombosis, or facial nerve paralysis.
  • Children younger than 3 months of age with a temperature of 38°C or more. See the CKS topic on Feverish children - risk assessment and management for more information. 
• Consider admitting:
  • Children younger than 3 months of age. 
  • Children 3–6 months of age with a temperature of 39°C or more.
• For all people with AOM:
  • Advise that the usual course of acute otitis media is about 3 days, but can be up to 1 week. 
  • Advise regular doses of paracetamol or ibuprofen for pain, using a dosing schedule appropriate for the age and weight of a child. For more information, see the CKS topics on Analgesia - mild-to-moderate pain and NSAIDs - prescribing issues.
  • Explain that there is no evidence to support the use of decongestants or antihistamines for the management of symptoms.
  • Advise that AOM does not require any restrictions from usual daily activities, but swimming should be avoided if there is evidence of tympanic membrane perforation, and ear pain may worsen with air travel.
    • Children may return to school or daycare once they are afebrile and the otalgia has resolved.
• For people who do not require admission to hospital but are systemically unwell, have symptoms and signs of a more serious illness or condition, or have a high risk of complications:
  • Offer an immediate antibiotic prescription. 
  • Advise them to seek medical advice if symptoms worsen rapidly or significantly, or if they become systemically very unwell.
• For people who may be more likely to benefit from antibiotics (those with otorrhoea or those aged less than 2 years with bilateral infection), take account of evidence that acute complications such as mastoiditis are rare with or without antibiotics and the potential adverse effects of antibiotics, and consider:
  • No antibiotic prescription — with advice about an antibiotic not being needed and seeking medical help if symptoms worsen rapidly or significantly, do not improve after 3 days, or the person becomes systemically very unwell, or
  • A back-up antibiotic prescription — with advice about an antibiotic not being needed immediately; using the back-up prescription if symptoms do not start to improve within 3 days or worsen significantly or rapidly at any time; and seeking medical help if symptoms worsen rapidly or significantly, or the person becomes systemically very unwell, or 
  • An immediate antibiotic prescription — with advice to seek medical advice if symptoms worsen rapidly or significantly or the person becomes systemically very unwell.
  • Analgesic and anaesthetic ear drops — where immediate antibiotics are not prescribed, prescribe ear drops containing an analgesic and anaesthetic for children or young people under the age of 18 where there is no ear drum perforation or otorrhoea.
    • See the section on Prescribing information for detailed information on how to prescribe ear drops.
• For other people who may be less likely to benefit from antibiotics, take into account that antibiotics make little difference to symptoms or the development of common complications (which are rare with or without antibiotics), and the potential adverse effects of antibiotics, and consider: 
  • No antibiotic prescription — with advice about an antibiotic not being needed and seeking medical help if symptoms worsen rapidly or significantly, do not improve after 3 days, or the person becomes systemically very unwell, or 
  • A back-up antibiotic prescription — with advice about an antibiotic not being needed immediately; using the back-up prescription if symptoms do not start to improve within 3 days or worsen significantly or rapidly at any time; and seeking medical help if symptoms worsen rapidly or significantly, or the person becomes systemically very unwell. 
  • Analgesic and anaesthetic ear drops — where immediate antibiotics are not prescribed, prescribe ear drops containing an analgesic and anaesthetic for children or young people under the age of 18 where there is no ear drum perforation or otorrhoea.
    • See the section on Prescribing information for detailed information on how to prescribe ear drops.
• If an antibiotic is required: 
  • Prescribe a 5–7 day course of amoxicillin.
  • For people who are allergic to, or intolerant of, penicillin, prescribe a 5–7 day course of clarithromycin or erythromycin (erythromycin is preferred in pregnant women).
  • The second choice oral antibiotic is to prescribe a 5-7 day course of co-amoxiclav where there are worsening symptoms on the first choice antibiotic taken for at least 2-3 days. Where a person has a penicillin allergy or is intolerant, seek specialist advice from the local microbiology department. 
    • See the section on Prescribing information for detailed information on how to prescribe antibiotics.
• Review treatment if symptoms do not improve within 7 days or at any time if symptoms worsen, taking account of: 
  • Alternative diagnoses, such as otitis media with effusion (glue ear). For more information, see the CKS topic on Otitis media with effusion. 
  • Any symptoms or signs suggesting a more serious illness or condition. For more information, see the sections on Complications and Differential diagnosis. 
  • Previous antibiotic use which may lead to resistant organisms.
• Routine follow up is not required in the absence of persistent symptoms of AOM.
  • For people with persisting symptoms despite antibiotic treatment, see the Scenario: Persistent acute otitis media - treatment failure.
  • For people with recurrent symptoms (three or more separate episodes in the previous 6 months, or four or more episodes in the previous 12 months with at least one episode in the past 6 months), see the Scenario: Recurrent acute otitis media.

How should I manage persistent symptoms and treatment failure?

• If an episode of acute otitis media (AOM) fails to improve or worsens, reassess the person and exclude other causes of middle ear inflammation and pain.
  • If there is hearing loss in the absence of pain or fever, see the CKS topic on Otitis media with effusion.
  • If there is discharge from the ear canal persisting for 2 weeks, see the CKS topic on Otitis media - chronic suppurative.
  • Consider referring adults with persistent acute otitis media to an ear, nose, and throat specialist, especially if symptoms last more than 6 weeks or are associated with persistent hearing loss.  
• Admit for immediate specialist assessment:
  • People with a severe systemic infection.
  • Adults and children with red flag symptoms suggestive of acute complications of acute otitis media (AOM), such as meningitis, mastoiditis, intracranial abscess, sinus thrombosis, or facial nerve paralysis.
  • Children younger than 3 months of age with a temperature of 38°C or more. See the CKS topic on Feverish children - risk assessment and management for more information.
• Consider admitting:
  • Children younger than 3 months of age. 
  • Children 3–6 months of age with a temperature of 39°C or more.
• For all people with AOM:
  • Advise regular doses of paracetamol or ibuprofen for pain, using a dosing schedule appropriate for the age and weight of a child. For more information, see the CKS topics on Analgesia - mild-to-moderate pain and NSAIDs - prescribing issues.
  • Explain that there is no evidence to support the use of decongestants or antihistamines for the management of symptoms.
• If admission or referral is not necessary and the person has not taken an antibiotic: 
  • Prescribe a 5–7 day course of amoxicillin.
  • For people who are allergic to, or intolerant of, penicillin, prescribe a 5–7 day course of clarithromycin or erythromycin (erythromycin is preferred in pregnant women).
    • See the section on Prescribing information for detailed information on how to prescribe these antibiotics.
• If admission or referral is not necessary and symptoms are worsening despite taking a first-line antibiotic for at least 2–3 days, offer a second–line antibiotic: 
  • Prescribe a 5–7 day course of co-amoxiclav. 
  • For people who are allergic to, or intolerant of, penicillin, seek specialist advice from the local microbiology department.
• If symptoms persist despite two courses of antibiotics, seek specialist advice from a local microbiologist or an Ear, Nose and Throat specialist if the diagnosis is uncertain. 

How should I manage a person with recurrent acute otitis media?

• Refer urgently (within 2 weeks) using a suspected cancer pathway referral to an ear, nose, and throat (ENT) specialist if nasopharyngeal cancer (rare) is suspected, especially in the presence of any one of the following:
  • Persistent symptoms and signs of otitis media with effusion in between episodes (for example conductive hearing loss) due to obstruction of the eustachian tube orifice. 
  • Persistent cervical lymphadenopathy (usually in the upper levels of the neck).
  • Epistaxis and nasal obstruction.
• Consider referral to an ENT specialist for all people with recurrent AOM, especially if:
  • The person has a craniofacial abnormality (Down's syndrome or a cleft palate). 
  • Recurrent episodes are unexplained, very distressing, or associated with complications.
  • An adult is affected. 
• If referral is not necessary:
  • Manage acute episodes in the same way as for initial presentation.
  • In people with grommets (tympanostomy or ventilation tubes) who present with acute discharge:
    • Consider taking an ear swab for culture and sensitivity.
    • Treat as for initial presentation or seek advice from an ENT specialist.
  • Provide advice on measures to prevent recurrence of AOM, including:
    • In children — avoiding exposure to passive smoking, use of dummies, and flat, supine feeding, encouraging breastfeeding where appropriate. 
    • In children — ensuring they have had a complete course of pneumococcal vaccinations as part of the routine childhood immunization schedule and that any gastro-oesophageal reflux disease (GORD) is managed appropriately. For more information, see the CKS topics on Immunizations - childhood and GORD in children.
    • In adults — avoiding smoking and/or passive smoking.
• Do not initiate long-term prophylactic antibiotics in primary care — prophylactic antibiotics for the prevention of AOM are likely to be of limited benefit and may increase the selection of resistant bacteria.

Dosing regime

• The treatment duration for acute otitis media is 5–7 days.
• In children, prescribe: 
  • Child 1–11 months: 125 mg three times a day.
  • Child 1–4 years: 250 mg three times a day.
  • Child 5–17 years: 500 mg three times a day.
• The dose should be reduced in children (weighing 40 kg or less) with renal impairment:
  • If the glomerular filtration rate (GFR) is 10–30 mL/minute, prescribe 15 mg/kg twice daily (maximum 500 mg twice daily).
  • If the GFR is less than 10 mL/minute, prescribe 15 mg/kg, but only once daily (maximum 500 mg).
• In adults, prescribe 500 mg three times a day.
• The dose should be reduced in adults (and children weighing more than 40 kg) with renal impairment. If the GFR is less than 30 mL/minute an increase in the dosage interval and a reduction in the total daily dose is recommended: 
  • If GFR is 10–30 mL/minute, prescribe a maximum 500 mg twice a day.
  • If GFR is less than 10 mL/minute, prescribe a maximum 500 mg once a day.     

[NICE, 2022; EMC, 2023a; BNF, 2024]

Contraindications and cautions

• Do not prescribe amoxicillin to people with
  • A true penicillin hypersensitivity. Allergic reactions to penicillins occur in 1–10% of exposed individuals. Anaphylactic reactions occur in fewer than 0.05% of treated patients.
    • Gastrointestinal adverse effects alone (such as nausea, vomiting, or diarrhoea) do not constitute an allergy to penicillin.
  • Hypersensitivity to cephalosporins, carbapenems, or monobactams — there is some evidence of partial cross-allergenicity.
• Prescribe amoxicillin with caution in people with:
  • Renal impairment — it may be necessary to reduce the dose of amoxicillin. See the section on Dosing regime for more information.
  • Glandular fever (infective mononucleosis) — these people are especially susceptible to amoxicillin-induced skin rashes.
  • Acute or chronic lymphocytic leukaemia — these people are susceptible to amoxicillin-induced skin rashes.

[EMC, 2023a; BNF, 2024]

Adverse effects

• The most common adverse effects of penicillins include diarrhoea, nausea, and skin rash.
  • Severe diarrhoea during or after treatment with antibiotics may be a sign of pseudomembranous colitis. For more information, see the CKS topic on Diarrhoea - antibiotic associated.
  • In addition to rash, other skin symptoms include urticaria and pruritus. Very rarely, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis, and acute generalised exanthematous pustulosis have been reported.
• Anaphylaxis (immediate or delayed) is a serious but rare adverse effect of amoxicillin. For more information, see the CKS topic on Angio-oedema and anaphylaxis.
• Other very rare adverse effects include:
  • Hepatitis and cholestatic jaundice.
  • Hyperkinesia, dizziness, and convulsions.
  • Interstitial nephritis.
  • Leucopenia, thrombocytopenia, and haemolytic anaemia.

[EMC, 2023a; BNF, 2024]

Drug interactions

• Allopurinol — be aware that concomitant use of allopurinol and amoxicillin may increase the incidence of skin rashes. Concomitant use need not be avoided for this reason.
• Anticoagulants (for example warfarin) — monitor the prothrombin time or international normalized ratio (INR) more closely with the addition or withdrawal of a penicillin. Adjustment of the anticoagulant dose may be necessary.
  • Prolongation of INR has been reported in people taking penicillins and warfarin concurrently.
• Methotrexate — monitor methotrexate levels more closely. One recommendation is to carry out twice weekly platelet and white cell counts for 2 weeks initially, with the measurement of methotrexate levels if toxicity is suspected.
  • Penicillins may reduce the excretion of methotrexate, potentially increasing toxicity. The interaction is not usually serious and risk factors are unknown (even people on low doses of methotrexate have been affected).
• Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of penicillins.
  • However, advise women on the importance of correct contraceptive practice if they experience vomiting or diarrhoea. For further information, see the section on vomiting or diarrhoea in the CKS topics on Contraception - combined hormonal methods and Contraception - progestogen-only methods.
• Probenecid — may cause increased and prolonged blood levels of amoxicillin. The manufacturer recommends avoiding concurrent use.
• Tetracyclines — the bactericidal effects of amoxicillin may be affected by concurrent tetracycline use.

[CoSRH, 2022; EMC, 2023a; BNF, 2024; Preston, 2024]

Pregnancy and breastfeeding

Pregnancy

• Amoxicillin is not known to be harmful in pregnancy [BNF, 2024]. 
  • Penicillins are the antibiotics of choice in pregnancy [Schaefer, 2015]. The UK Teratology Information Service (UKTIS) states that the majority of a large amount of data shows no increased risk of congenital malformation, spontaneous abortion (miscarriage), intrauterine death, low birth weight, preterm delivery, or neonatal complications when penicillins are taken at therapeutic doses during pregnancy [UKTIS, 2019].  

Breastfeeding

• Trace amounts of amoxicillin are found in breastmilk, but it is appropriate to use in women who are breastfeeding [BNF, 2024].  
  • Co-amoxiclav use in breastfeeding may cause diarrhoea or fungal infection of mucous membranes in the infant [SPS, 2020a].
  • Penicillins (and cephalosporins) are the antibiotics of choice in women who are breastfeeding [Schaefer, 2015].

Dosing regime

• The treatment duration for AOM is 5–7 days.
• In children, prescribe:
  • Child 1 month to 11 years:
    • Body weight under 8 kg: 7.5 mg/kg twice daily.
    • Body weight 8–11 kg: 62.5 mg twice daily.
    • Body weight 12–19 kg: 125 mg twice daily.
    • Body weight 20–29 kg: 187.5 mg twice daily.
    • Body weight 30–40 kg: 250 mg twice daily.
  • Child 12–17 years: 250 mg twice daily, increased if necessary in severe infections to 500 mg twice daily.
• In children with renal impairment, if estimated glomerular filtration rate (eGFR) is less than 30 mL/minute/1.73m²:
  • Prescribe half the normal dose of clarithromycin.
  • Avoid Klaricid XL® or clarithromycin M/R preparations.
• In adults, prescribe 250 mg twice daily, increased in severe infections to 500 mg twice daily.
• In adults with renal impairment, if the eGFR is less than 30 mL/minute/1.73m²:
  • Prescribe half the normal dose of clarithromycin.
  • Avoid Klaricid XL^® or clarithromycin M/R preparations.
• In adults and children with renal impairment, if eGFR is between 30 and 60 mL/minute/1.73m²:
  • Prescribe the normal dose of immediate release preparations of clarithromycin.
  • Prescribe half the normal dose of Klaricid XL^® or clarithromycin M/R preparations.

[NICE, 2022; EMC, 2023b; BNF, 2024]

Contraindications and cautions

• Do not prescribe clarithromycin to people:
  • Taking drugs that prolong the QT interval (for example, terfenadine, and pimozide) — macrolides can also prolong the QT interval, which is a risk factor for Torsades de pointes.
  • With a history of QT prolongation or ventricular cardiac arrhythmia, including Torsades de pointes arrhythmias.
  • With severe hepatic failure in combination with renal impairment.
  • With hypokalaemia.
  • With known hypersensitivity to clarithromycin or other macrolide antibiotics.
  • Using HMG-CoA reductase inhibitors (statins) that are extensively metabolised by CYP3A4 (such as simvastatin) — increased risk of myopathy, including rhabdomyolysis.
  • Using colchicine — risk of colchicine toxicity, particularly in the elderly or those with renal insufficiency.
• Prescribe clarithromycin with caution in people with:
  • Moderate to severe renal impairment.
  • Impaired hepatic function — clarithromycin is principally excreted by the liver. 
  • Conditions which predispose to QT interval prolongation such as electrolyte disturbances (for example, hypomagnesemia).
  • Myasthenia gravis — macrolide antibiotics may aggravate the symptoms.
  • Coronary artery disease, severe cardiac insufficiency, or bradycardia (less than 50 beats per minute) — increased risk of QT prolongation.
  • Concomitant medication use including triazolobenzodiazepines (triazolam or midazolam), hypoglycaemic agents (such as sulfonylureas) and/or insulin, and oral anticoagulants — clarithromycin can increase the bioavailability of these medications and result in extended pharmacological effects.

[FDA, 2018; EMC, 2023b; BNF, 2024; Preston, 2024]

Adverse effects

• Nausea, vomiting, abdominal discomfort, and diarrhoea are the most common adverse effects of macrolides, but they are mild and less frequent with clarithromycin than with erythromycin.
  • Consider pseudomembranous colitis if a person develops severe diarrhoea during or after treatment with clarithromycin. For more information, see the CKS topic on Diarrhoea - antibiotic associated.
• Anaphylaxis is rarely associated with clarithromycin. For more information, see the CKS topic on Angio-oedema and anaphylaxis.
• Hepatotoxicity (including cholestatic jaundice) and rash have rarely been reported following treatment with erythromycin or clarithromycin.
• Reversible hearing loss (sometimes with tinnitus) can occur after large doses of erythromycin or clarithromycin.
• Cardiac disorders such as  QT interval prolongation, arrhythmias and palpitations.
• Other uncommon adverse effects include angioedema, anxiety, candida infection, constipation, drowsiness, eosinophilia, leucopenia, neutropenia, tinnitus and vertigo.
• Other adverse effects reported rarely or very rarely include pancreatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

[EMC, 2023b; BNF, 2024]

Drug interactions

• Calcium channel blockers (CCBs) — there is an increased risk of hypotension if CCBs, such as verapamil, amlodipine, and diltiazem are taken concomitantly with clarithromycin, as they are metabolised by CYP3A4. This may also lead to increased levels of clarithromycin.
• Ciclosporin — clarithromycin can increase ciclosporin levels. If co-administration of these drugs is necessary, ciclosporin levels should be monitored and the dose adjusted accordingly.
• Colchicine — colchicine toxicity has been reported with concomitant use of clarithromycin so the combination is contraindicated.
• CYP3A enzyme inducers (rifampicin, carbamazepine, phenobarbital) — these may induce the metabolism of clarithromycin, resulting in sub-therapeutic levels.
  • It may be necessary to monitor the levels of these drugs, as CYP3A is inhibited by clarithromycin leading to higher plasma levels of the inducer.
• Digoxin — clarithromycin increases digoxin levels. Monitor and reduce the digoxin dose if required.
• Edoxaban — manufacturer advises caution with concurrent treatment with edoxaban, particularly in those with a high risk of bleeding.
• Ergot alkaloids — concomitant administration is contraindicated, due to the risk of acute ergot toxicity.
• Ivabradine — concomitant treatment is contraindicated, owing to CYP3A4 inhibition by clarithromycin which can cause elevated levels of ivabradine.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of clarithromycin.
  • However, women should be advised that if diarrhoea, vomiting or breakthrough bleeding occur there is a possibility of contraceptive failure. For further information, see the sections on vomiting or diarrhoea in the CKS topics on Contraception - combined hormonal methods and Contraception - progestogen-only methods. 
• Oral hypoglycaemic drugs (sulfonylureas) and insulin — the concomitant use of clarithromycin and oral hypoglycaemic drugs and/or insulin can result in significant hypoglycaemia. Monitor glucose levels.
• Statins (atorvastatin, simvastatin) — these are extensively metabolised by CYP3A4. Concomitant administration with clarithromycin increases the plasma levels.
  • Simvastatin — do not prescribe clarithromycin to a person taking simvastatin. If treatment with clarithromycin cannot be avoided, stop treatment with simvastatin temporarily.
  • Atorvastatin — avoid concurrent use with clarithromycin. If concurrent use cannot be avoided, prescribe the lowest dose of atorvastatin.
  • Other statins not dependent on cytochrome P450 3A4 metabolism (fluvastatin, pravastatin and rosuvastatin) — these drugs should be used with caution in combination with erythromycin and the person should be advised to report any muscle pain, tenderness, weakness or dark coloured urine (signs of myopathy). 
• Warfarin — clarithromycin increases the anticoagulant effect of warfarin. Monitor the international normalized ratio (INR), and adjust the warfarin dose accordingly.
• Drugs that prolong the QT interval (such as amiodarone, domperidone, or sotalol) — all macrolides can prolong the QT interval, and concomitant use of drugs that prolong the QT interval is contraindicated.

[BNF, 2024; Preston, 2024; EMC, 2024a]

Pregnancy and breastfeeding

Pregnancy

• The safety of clarithromycin in pregnancy has not been established. Avoid (especially in the first trimester), unless the benefit outweighs the risks [EMC, 2023b; UKTIS, 2020].
  • Erythromycin is considered the macrolide of choice in pregnancy because it has the most documented experience, and is considered to be a safe and effective antibiotic during pregnancy [UKTIS, 2020]. For more information, please refer to the prescribing information for Erythromycin.

Breastfeeding

• Clarithromycin is present in breastmilk in low amounts, and these levels are considered unlikely to affect a breastfed infant [LactMed, 2022a].
• Although experts have recommended that macrolides should be considered a suitable choice of antibiotic during breastfeeding [Schaefer, 2015], the manufacturer advises that use should be avoided by breastfeeding women unless the potential benefits outweigh the risks [BNF, 2024].
  • Epidemiological studies have shown an increased risk of hypertrophic pyloric stenosis in infants breastfed by maternal macrolide users, especially infants exposed in the first 2 weeks after birth [SPS, 2020b].
  • Infants should be monitored for gastrointestinal disturbances and oral candida infection, although these effects are unlikely to occur [SPS, 2020b].

Dosing regime

• The treatment duration for acute otitis media is 5–7 days.
• Prescribe: 
  • Child 1–11 months: 0.25 mL/kg of 125/31 suspension three times a day.
  • Child 1–5 years: 5 mL of 125/31 suspension three times a day or 0.25 mL/kg of 125/31 suspension three times a day.
  • Child 6–11 years: 5 mL of 250/62 suspension three times a day or 0.15 mL/kg of 250/62 suspension three times a day.
  • Child 12–17 years: 250/125 mg or 500/125 mg three times a day.
• In children with renal impairment:
  • If the estimated glomerular filtration rate (eGFR) is 10–30 mL/minute/1.73 m², prescribe the normal dose every 12 hours.
  • If the eGFR is less than 10 mL/minute/1.73 m², use the normal dose recommended for mild to moderate infections every 12 hours.
• In adults, prescribe one 250/125 strength tablet three times a day; increased in severe infections to one 500/125 strength tablet three times a day.
• In adults with renal impairment:
  • If the eGFR is 10–30 mL/minute/1.73 m², prescribe one 250/125 strength tablet every 12 hours or one 500/125 strength tablet every 12 hours.
  • If the eGFR is less than 10 mL/minute/1.73 m², prescribe one 250/125 strength tablet every 24 hours or one 500/125 strength tablet every 24 hours.

[NICE, 2022; BNF, 2024]

Contraindications and cautions

• Do not prescribe co-amoxiclav in people with:
  • A true penicillin allergy — allergic reactions to penicillins occur in 1–10% of exposed individuals; anaphylactic reactions occur in fewer than 0.05% of treated patients.
    • Gastrointestinal adverse effects alone (for example, nausea, vomiting, or diarrhoea) do not constitute an allergy to penicillin. See the CKS topic on Angio-oedema and anaphylaxis for more information.
  • A hypersensitivity to cephalosporins, carbapenems, or monobactams — as there is some evidence of partial cross-allergenicity. 
  • A history of co-amoxiclav-associated or penicillin-associated jaundice or hepatic dysfunction.
• Prescribe co-amoxiclav with caution in people with:
  • Hepatic impairment – monitor closely.
  • Chronic kidney disease (CKD) — reduce the dose if the estimated glomerular filtration rate (eGFR) is 30 mL/minute/1.73 m² or less.
  • Acute lymphocytic leukaemia, chronic lymphocytic leukaemia, cytomegalovirus infection, or glandular fever — increased risk of erythematous rashes.

[EMC, 2023c; BNF, 2024]

Adverse effects

• Gastrointestinal — diarrhoea (very common), nausea and vomiting (common), and drug-induced enterocolitis syndrome (unknown frequency).
  • Very rarely: antibiotic-associated colitis.
• Nervous system — headache, dizziness (uncommon), and aseptic meningitis (unknown frequency).
• Skin — skin rash, urticaria, pruritus (uncommon), and drug reaction with eosinophilia and systemic symptoms (DRESS) (unknown frequency).
  • Very rarely: erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis, and acute generalized exanthematous pustulosis.
• Cardiac disorders — QT interval prolongation, arrhythmias, and palpitations.
• Other uncommon adverse effects include angioedema, anxiety, Candida infection, constipation, drowsiness, eosinophilia, leucopenia, neutropenia, tinnitus, and vertigo.
• Other rare or very rare adverse effects include:
  • Hepatitis and cholestatic jaundice.
  • Reversible hearing loss (sometimes with tinnitus) can occur after large doses of erythromycin.
  • Hyperactivity and convulsions.
  • Hypersensitivity reactions (serious and occasionally fatal).  
  • Interstitial nephritis.
  • Linear IgA disease (renal deposition of IgA).  
  • Leucopenia, thrombocytopenia, and haemolytic anaemia.
  • Kounis syndrome (an allergic reaction which can cause myocardial infarction). 
• Symmetrical Drug-related Intertriginous and Flexural Exanthema (SDRIFE) are adverse effects of unknown frequency.

[EMC, 2023c; BNF, 2024; EMC, 2024b]

Drug interactions

• Allopurinol — concomitant use of allopurinol and amoxicillin may increase the incidence of skin rashes.
• Methotrexate — co-amoxiclav may reduce methotrexate clearance, causing an increased risk of toxicity.
  • Monitor methotrexate levels more closely. One recommendation is to carry out twice weekly platelet and white cell counts for 2 weeks initially, with the measurement of methotrexate levels if toxicity is suspected. 
• Mycophenolate mofitil — reduction in the level of active metabolite may occur when given with co-amoxiclav.
• Oral anticoagulants (warfarin and phenindione) — prolongation of international normalised ratio has been reported in people taking penicillins and warfarin concurrently.
  • Monitor the prothrombin time or international normalized ratio (INR) more closely with the addition or withdrawal of a penicillin. Adjustment of the anticoagulant dose may be necessary.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of co-amoxiclav.
  • However, women should be advised about the importance of correct contraceptive practice if they experience vomiting or diarrhoea. For further information, see the sections on vomiting or diarrhoea in the CKS topics on Contraception - combined hormonal methods and Contraception - progestogen-only methods.
• Probenecid — concomitant administration may result in increased levels of amoxicillin, but not clavulanic acid.

[CoSRH, 2022; EMC, 2023c; BNF, 2024; Preston, 2024]

Pregnancy and breastfeeding

Pregnancy

• Co-amoxiclav is not known to be harmful in pregnancy [BNF, 2024], but the manufacturer advises avoidance unless considered essential [EMC, 2023c].
  
  • Penicillins are the antibiotics of choice in pregnancy [Schaefer, 2015]. The UK Teratology Information Service (UKTIS) states that co-amoxiclav use in pregnancy has not been linked with an increased risk of congenital malformation, spontaneous abortion (miscarriage), intrauterine death, low birth weight, preterm delivery, or neonatal complications when penicillins are taken at therapeutic doses during pregnancy [UKTIS, 2019]. 

Breastfeeding

• Although adverse infant reactions, including restlessness, diarrhoea and rash, have been described following the use of co-amoxiclav in women who are breastfeeding, these events are thought to be uncommon. Use during breastfeeding is therefore considered acceptable [LactMed, 2018]. 
  • Trace amounts of amoxicillin are found in breast milk, but it is appropriate to use in women who are breastfeeding [BNF, 2024].  
  • Use of penicillins in breastfeeding may cause diarrhoea or fungal infection of mucous membranes in the infant [SPS, 2020a].
  • Penicillins (and cephalosporins) are the antibiotics of choice in women who are breastfeeding [Schaefer, 2015].

Dosing regime

• The treatment duration for acute otitis media (AOM) is 5–7 days.
• Prescribe for children:
  • 1 month to 1 year: 125 mg four times a day or 250 mg twice a day.
  • 2 years to 7 years: 250 mg four times a day or 500 mg twice a day.
  • 8 years to 17 years: 250–500 mg four times a day or 500-1000 mg twice a day.
• In children with severe renal impairment, the dose of erythromycin should be reduced.
• In adults, prescribe 250–500 mg four times a day.
• In adults with severe renal impairment, prescribe a maximum daily dose of 1.5 g of erythromycin.

[NICE, 2022; EMC, 2023d; BNF, 2024; BNFC, 2024]

Contraindications and cautions

• Do not prescribe erythromycin to people:
  • With porphyria.
  • A history of QT interval prolongation or ventricular cardiac arrhythmia.
  • Conditions that predispose to QT interval prolongation such as electrolyte disturbances and people taking drugs that prolong the QT interval.
  • With known hypersensitivity to erythromycin or other macrolide antibiotics.
  • Using simvastatin, tolterodine, mizolastine, amisulpride, astemizole, terfenadine, domperidone, cisapride, pimozide, ergotamine, or lomitapide.
• Prescribe erythromycin with caution in people with:
  • Renal impairment.
  • Impaired hepatic function (or people concomitantly receiving potentially hepatotoxic drugs) — erythromycin is principally excreted by the liver. 
  • Myasthenia gravis — macrolide antibiotics may aggravate the symptoms of people with myasthenia gravis.

[MHRA, 2020; EMC, 2023d; BNF, 2024; Preston, 2024]

Adverse effects

• Nausea, vomiting, abdominal discomfort, and diarrhoea are the most common adverse effects of macrolides.
  • Consider pseudomembranous colitis if a person develops diarrhoea during or after treatment with erythromycin. For more information, see the CKS topic on Diarrhoea - antibiotic associated. 
• Anaphylaxis is rarely associated with erythromycin. For more information, see the CKS topic on Angio-oedema and anaphylaxis. 
• Hepatotoxicity (including cholestatic jaundice) and rash have rarely been reported following treatment with erythromycin or clarithromycin.
• Reversible hearing loss (sometimes with tinnitus) can occur after large doses of erythromycin or clarithromycin.
• Cardiac disorders such as  QT interval prolongation, arrhythmias, and palpitations.
• Other uncommon adverse effects include angioedema, anxiety, Candida infection, constipation, drowsiness, eosinophilia, leucopenia, neutropenia, tinnitus, and vertigo.
• Other adverse effects reported rarely or very rarely include pancreatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

[EMC, 2023d; BNF, 2024]

Drug interactions

• Carbamazepine — erythromycin markedly increases the concentration of carbamazepine. Monitor carbamazepine levels and adjust the dose.
  • Advise the person to report symptoms of carbamazepine toxicity (such as nausea, vomiting, ataxia, or drowsiness).
• Corticosteroids — levels of corticosteroids may be increased. Monitor for corticosteroid adverse effects (such as moon face, weight gain, and hyperglycaemia), and adjust the corticosteroid dose or stop the macrolide as appropriate. 
• Drugs that prolong the QT interval — particular care should be taken with these medications. The concurrent use of two or more drugs that prolong the QT interval should be avoided because of the risk of torsade de pointes arrhythmias. Seek advice from a microbiologist regarding a suitable alternative antibiotic.
• Drugs that cause hypokalaemia (such as diuretics, corticosteroids, and short-acting beta₂-agonists). Hypokalaemia is a risk factor for QT prolongation — seek advice from a microbiologist regarding a suitable alternative antibiotic.
• Lomitapide — concurrent use with erythromycin increases transaminase levels and is contraindicated.
• Statins (atorvastatin and simvastatin) — these are extensively metabolised by CYP3A4. Concomitant administration with erythromycin increases the plasma levels.
  • Simvastatin — do not prescribe clarithromycin to a person taking simvastatin. If treatment with erythromycin cannot be avoided, stop treatment with simvastatin temporarily.
  • Atorvastatin — avoid concurrent use with erythromycin. If concurrent use cannot be avoided, prescribe the lowest dose of atorvastatin.
  • Other statins not dependent on cytochrome P450 3A4 metabolism (fluvastatin, pravastatin, and rosuvastatin) — these drugs should be used with caution in combination with erythromycin and the person should be advised to report any muscle pain, tenderness, weakness, or dark coloured urine (signs of myopathy). 
• Theophylline — check theophylline levels 48 hours after starting erythromycin, and adjust the dose of theophylline accordingly.
  • Erythromycin increases plasma concentrations of theophylline, and theophylline may also reduce serum concentrations of erythromycin. 
• Rivaroxaban — erythromycin may increase levels of rivaroxaban, increasing the risk of bleeding. 
• Warfarin — the anticoagulant effect of warfarin may be increased by erythromycin. Monitor the international normalized ratio (INR), and adjust the warfarin dose accordingly.
• Calcium channel blockers (CCBs) — due to an increased risk of adverse effects such as hypotension, caution is advised with the concurrent use of erythromycin and CCBs. Monitor and reduce the dose of CCB if adverse effects occur.
• Contraceptives — additional contraceptive precautions are not required during or after a course of clarithromycin or erythromycin.
  • However, advise women on the importance of correct contraceptive practice if they experience vomiting or diarrhoea. For further information, see the section on vomiting or diarrhoea in the CKS topics on Contraception - combined hormonal methods and Contraception - progestogen-only methods. 

[MHRA, 2020; CoSRH, 2022; EMC, 2023d; BNF, 2024; Preston, 2024]

Pregnancy and breastfeeding

Pregnancy

• The British National Formulary (BNF) states that specialist sources recommend that erythromycin should only used in pregnancy if the potential benefits outweigh the risks [BNF, 2024].
• Most studies do not suggest erythromycin use is associated with malformations or other adverse effects on the fetus, but there is an inconclusive association with cardiovascular defects [UKTIS, 2020; EMC, 2023d].
  • The manufacturer reports that animal studies have shown no hazard, and erythromycin has been reported to cross the placental barrier in humans but fetal plasma levels are generally low [EMC, 2023d].
• Erythromycin is the macrolide of choice because it has more documented experience and is considered to be a safe and effective antibiotic during pregnancy [UKTIS, 2020].

Breastfeeding

• Erythromycin is present in breast milk in low amounts, and these levels are considered unlikely to affect a breastfed infant [LactMed, 2022b].
• Macrolides are a suitable choice during breastfeeding [Schaefer, 2015], and the BNF advises that erythromycin is not known to be harmful when used by breastfeeding women [BNF, 2024].
  • Epidemiological studies have shown an increased risk of hypertrophic pyloric stenosis in infants breastfed by maternal macrolide users, especially infants exposed in the first 2 weeks after birth — the risk may be greater with erythromycin [SPS, 2020b].
  • Infants should be monitored for gastrointestinal disturbances and oral candida infection, although these effects are unlikely to occur [SPS, 2020b].

Dosing regime

The treatment for children and young people under 18 with acute otitis media is to prescribe:

• Phenazone 40 mg/g with lidocaine 10 mg/g. Apply 4 drops two or three times a day for up to 7 days, available as Otigo®. 

[EMC, 2020; BNF, 2024]

Contraindications and cautions

• Phenazone and lidocaine ear drops should not be prescribed to children or young people who have:
  • Hypersensitivity to the active substances or any of the excipients, sodium thiosulfate, ethanol, and glycerol.
  • Infectious or traumatic perforation of the tympanic membrane (including myringotomy) — intra-auricular administration may lead to contact with middle ear structures and ototoxicity.
• Phenazone and lidocaine ear drops should be prescribed with caution to children and young people who:
  • Are susceptible to methemoglobinemia, including infants under 3 months of age.
  • Have haemoglobinopathies.
  • Have Glucose-6-phosphate dehydrogenase (G6PD) deficiency.

[EMC, 2020; BNF, 2024]

Adverse effects

• Ear and labyrinth disorders — Rarely local allergic reactions (itching and maculopapular rash), auditory canal or tympanic membrane hyperaemia can occur.

[EMC, 2020; BNF, 2024]

Drug interactions

• Potential drug interactions with phenazone with lidocaine:
  • Since systemic absorption can occur with topical application of lidocaine and NSAIDs, the possibility of interactions with these medications should be borne in mind. There have been no studies conducted on potential drug interactions. 

[EMC, 2020; BNF, 2024]

Pregnancy and breastfeeding

• The BNF advises that these drops should be used with caution in pregnancy and in women who are breastfeeding. They advise that systemic absorption is unlikely with an intact tympanic membrane.
• The manufacturer's summary of product characteristics advises that if the recommended dosage (4 drops two or three times daily) and therapy duration (should not exceed 7 days) are observed, the product can be administered during pregnancy and breastfeeding, if necessary.
• It is not known if phenazone and lidocaine pass into breast milk or/and cross the placenta.

[EMC, 2020; BNF, 2024]