Previous changes

February 2024 — minor update. Infantile hypertrophic pyloric stenosis added as a possible adverse effect of azithromycin after use in neonates. 

June 2023 — reviewed. A literature search was conducted in May 2023 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of this topic. No major changes to the recommendations have been made. Additional information about differential diagnosis and persisting non-specific symptoms have been included. 

November 2022 — minor update. Information that doxycycline prescribing for children aged 9-12 is an off-label indication added to the prescribing section of this topic.

October 2022 — minor update. Information that tick-borne encephalitis was detected in a small number of ticks in Thetford Forest and an area on the border between Hampshire and Dorset in 2019 has been added to this topic.

April 2022 — minor update. Drug interactions with azithromycin to include hydroxychloroquine and chloroquine added in line with the manufacturer's summary of product characteristics.

August 2019 — minor update. Prescribing information for amoxicillin in children under 9 years weighing over 33 kg has been added. 

July 2018 — reviewed. A literature search was conducted in July 2018 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of this topic. The recommendations have been updated in line with the latest guidelines. 

December 2014 to February 2015 — reviewed. A literature search was conducted in December 2014 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of this topic. The recommendations in this topic have not changed since the last revision.

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 2011 — minor update. Text changed in line with the British Infection Association's position statement The epidemiology, prevention, investigation and treatment of Lyme borreliosis in UK patients. 

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

February 2010 — minor update to the sections on When to suspect Lyme disease. 

September 2009 to January 2010 — this is a new CKS topic. The evidence-base has been reviewed in detail, and recommendations are clearly justified and transparently linked to the supporting evidence.

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 May 2023.

HTAs (Health Technology Assessments)

No new HTAs since 1 May 2023.

Economic appraisals

No new economic appraisals relevant to England since 1 May 2023.

Systematic reviews and meta-analyses

No new systematic reviews and meta-analyses since 1 May 2023.

Primary evidence

No new primary evidence which reaches the CKS threshold for inclusion published since 1 May 2023.

New policies

No new national policies or guidelines since 1 May 2023.

New safety alerts

No new safety alerts since 1 May 2023.

Changes in product availability

No changes in product availability since 1 May 2023.

Erythema migrans

• Primary (or solitary) erythema migrans has the following features:
  • Appearance 
    • A spreading erythema with a well-defined edge.
    • Usually round or oval in shape, but may be triangular or linear.
    • Red, purple or bluish-red in colour.
    • Usually flat, but may be palpable, and there may be a central punctum, spot, vesicle or pustule is present at the centre.
    • As the rash expands, there may be clearing behind the leading edge, giving the classical annular or bulls-eye appearance. This is much less common in erythema migrans acquired in the USA, where it is more likely to be uniform in colour. Central clearing is more common when the cause is B. afzelii which is one of the common pathogens in Europe.
    • See the NICE resource for images of erythema migrans. Further images are available on the DermNet NZ site or that of the Primary Care Dermatology Society.
  • Size
    • Usually expands over days to weeks.
    • Diameter is usually larger than 5 cm (typically around 15 cm), and can be as large as 70 cm.
  • Location
    • At the site of a tick bite. 
    • Often on the legs, at flexor creases (knees, axillae, and groins), around the waistband, under the breasts, near to straps (which impede the forward progress of ticks), or (particularly in children) at the hairline or the upper parts of the body.
  • Timing
    • It usually becomes visible from 1–2 weeks (but can appear from 1 day to 36 days) after a tick bite and lasts for several weeks untreated.
  • Associated symptoms
    • The rash is not usually itchy hot, or painful.
    • In Europe, around a third of people with erythema migrans experience flu-like symptoms, including fever, headache, tiredness, nausea, vomiting, arthralgia (joint pain), and myalgia (muscle pain). Flu-like symptoms are more common in the US.
    • Rarely, neurological features may also be present, but these usually occur later in the disease.
  • Be aware that a rash which is not erythema migrans can develop as a reaction to a tick bite, but it:
    • Usually develops and recedes within 48 hours from the time of the tick bite.
    • Is more likely than erythema migrans to be hot, itchy or painful.
    • May be caused by an inflammatory reaction or infection with a common skin pathogen.
• Secondary (or disseminated) erythema migrans may occur following haematogenous dissemination of infection, resulting in multiple lesions, usually smaller than 5 cm in diameter.
• Erythema migrans may be confused with a number of other skin conditions — see Differential diagnosis (erythema migrans).

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Lyme disease [NICE, 2018]. The advice to make a clinical diagnosis of Lyme disease without further investigation in the presence of erythema migrans is also provided in other international guidelines and expert review articles [Shapiro, 2014; Eldin, 2019; Kullberg, 2020; BMJ Best Practice, 2021; Lantos, 2021].

Further information on other dermatological manifestations comes from expert review articles [Stanek, 2018; Kullberg, 2020; Marques, 2021; Radolf, 2021].

Erythema migrans

The information in this section is based on descriptions in expert review articles [Shapiro, 2014; DermNet NZ, 2015; Kullberg, 2020; BMJ Best Practice, 2021; Marques, 2021; Radolf, 2021; PCDS, 2022] as well as the National Institute for Health and Care Excellence (NICE) guideline Lyme disease [NICE, 2018].

The NICE guideline states that the erythema migrans rash may take up to 3 months to develop but the majority of the literature and expert opinion above gives the upper range no longer than 36 days.

How should I manage a person with suspected Lyme disease?

• Discuss the diagnosis and management of Lyme disease in children and young people aged under 18 years with a specialist, unless they have a single erythema migrans lesion and no other symptoms.
• For all other people with erythema migrans who have no evidence of focal symptoms (for example, neurological, cardiac, or joint involvement), start treatment with oral antibiotics.
• If Lyme disease is suspected in people without erythema migrans, offer an enzyme-linked immunosorbent assay (ELISA) test for Lyme disease.
  • If there is a high clinical suspicion of Lyme disease, consider starting treatment with antibiotics while waiting for the results.
  • See the NICE visual summary Lyme disease: laboratory investigations and diagnosis.
• If the ELISA test (in people without erythema migrans) is:
  • Positive or equivocal — perform an immunoblot test for Lyme disease.
    • Consider starting treatment with antibiotics while waiting for the results if there is a high clinical suspicion of Lyme disease.
  • Negative and the person still has symptoms — review their history and symptoms, and consider an alternative diagnosis.
    • If Lyme disease is still suspected in people tested within 4 weeks from symptom onset, repeat the ELISA 4–6 weeks after the first ELISA test.
    • If Lyme disease is still suspected in people who have had symptoms for 12 weeks or more, perform an immunoblot test.
• If the immunoblot test is:
  • Positive — diagnose Lyme disease. Start treatment with oral antibiotics.
  • Negative, but symptoms persist — consider a discussion with or referral to a specialist (regardless of the ELISA result) to review whether further tests are required or to consider alternative diagnoses.
  • Negative, and symptoms have resolved — no treatment is required.
• Be cautious about diagnosing Lyme disease in people without a supportive history or positive serological testing because of the risk of:
  • Missing an alternative diagnosis.
  • Providing inappropriate treatment.
• Refer people with focal symptoms to the appropriate specialist, or consider a discussion with a specialist, but do not delay treatment.

How to arrange tests for Lyme disease

• Healthcare professionals wishing to discuss a case, or find out about local provision for testing for Lyme disease should contact their local consultant in microbiology or infectious diseases. 
• In the UK, NHS testing for Lyme disease is arranged through local service providers and the Rare and Imported Pathogens Laboratory (RIPL). The form for a Lyme disease test request, sample testing advice and contact details are all available online through information published by the UK Health Security Agency (UKSA).
  • RIPL can be contacted by phone (01980 612348) or email (lyme.ripl@phe.gov.uk). 

What should I prescribe for people with Lyme disease?

• For people diagnosed with Lyme disease (or with a high suspicion of Lyme disease awaiting test results), prescribe oral antibiotics:
  • Adults and children aged 12 years or older: 
    • Doxycycline 100 mg twice daily (or 200 mg once daily) for 21 days.
    • Amoxicillin 1000 mg three times daily for 21 days (if doxycycline is not suitable).
    • Azithromycin 500 mg daily for 17 days (if doxycycline and amoxicillin are not suitable).
  • Children aged 9–12 years:
    • Doxycycline — 5 mg/kg in two divided doses on day one, followed by 2.5 mg/kg daily in one or two divided doses for a total of 21 days, for children under 45 kg. For severe infections, up to 5 mg/kg daily for 21 days. 
    • Amoxicillin — 30 mg/kg three times daily for 21 days, for children 33 kg and under (if doxycycline is not suitable).
    • Azithromycin — 10 mg/kg daily for 17 days, for children 50 kg and under (if doxycycline and amoxicillin are not suitable). 
  • Children aged under 9 years: 
    • Amoxicillin — 30 mg/kg three times daily for 21 days, for children 33 kg and under. Children over 33 kg, 1000 mg three times daily for 21 days.
    • Azithromycin — 10 mg/kg daily for 17 days, for children 50 kg and under (if amoxicillin is unsuitable).
  • Note: Use of doxycycline and azithromycin for treating Lyme disease is considered off-label and outside the scope of their licence, but is recommended by national and international guidelines as first line treatment. Use of doxycycline in children between the ages of 9 and 11 is similarly off-label but supported by guidelines for use in Lyme disease.
  • Note: The antibiotic regime above applies to people being treated in primary care for Lyme disease without focal symptoms, but with erythema migrans and/or non-focal symptoms. Different regimes may be applied for treatment by specialists for the treatment of Lyme disease with focal neurological, cardiac, dermatological or rheumatological features.
  • Note: a Jarisch-Herxheimer reaction may develop (in up to 15% of people) in the first 24 hours of treatment with any antibiotic for Lyme disease. This is a systemic reaction thought to be caused by the release of cytokines when antibiotics kill large numbers of bacteria.
    • Symptoms include a worsening of fever, chills, muscle pains and headache. It may be mistaken for an allergic reaction and the person may stop their antibiotics. 
    • The reaction can start between 1–12 hours after antibiotics are started, but can also occur later and can last for a few hours or 1–2 days.
    • The reaction is self-limiting and usually resolves within 24–48 hours. 
    • Provided the symptoms are not severe and there is no evidence of an allergic reaction (such as urticaria), the person can be advised to continue the antibiotic.
• Manage symptoms (for example, headache, muscle pain) as required.

How should I manage people with ongoing symptoms of Lyme disease?

• If treatment for Lyme disease has:
  • Started and symptoms worsen despite treatment for Lyme disease — assess for an allergic reaction to the antibiotic.
    • A Jarisch-Herxheimer reaction may cause an exacerbation of symptoms but does not usually warrant stopping treatment.
  • Finished and symptoms have not improved, or have worsened — review the person's history and symptoms to explore:
    • Possible alternative causes of the symptoms.
    • If re-infection may have occurred — if the person's history suggests reinfection, offer antibiotic treatment.
    • If treatment may have failed.
    • Details of any previous treatment, including whether the course of antibiotics was completed without interruption.
    • If symptoms may be related to organ damage caused by Lyme disease, for example, nerve palsy.
• Consider a second course of antibiotics for people with ongoing symptoms if treatment may have failed — use an alternative antibiotic to the initial course.
• If symptoms persist despite two completed courses of antibiotics:
  • Do not routinely offer further antibiotics.
  • Consider discussion with a national reference laboratory, or discussion, or referral to a specialist.
• Explain to people with ongoing symptoms that:
  • Continuing symptoms may not mean they still have an active infection.
  • Symptoms of Lyme disease may take months or years to resolve even after treatment.
  • Some symptoms may be a consequence of permanent damage from infection.
  • There is no test to assess for active infection and an alternative diagnosis may explain their symptoms.
• Longer-term ongoing symptoms - be alert to the possibility of symptoms related to Lyme disease that may need assessment, management and support, such as:
  • Chronic pain. See the CKS topic Chronic pain.
  • Depression and anxiety. See the prodigy topics Depression and Generalized anxiety disorder.
  • Fatigue. See the CKS topic Tiredness/fatigue in adults. 
  • Sleep disturbance. See the CKS topic Insomnia. 

What information and advice should I give people with Lyme disease?

• Explain how to minimise the risk of being bitten by a tick.
• Explain to people diagnosed with Lyme disease that:
  • It is a bacterial infection treated with antibiotics. 
  • Most people recover completely.
  • Prompt antibiotic treatment reduces the risk of further symptoms developing and increases the chance of complete recovery.
  • It may take time to get better, but their symptoms should continue to improve in the months after antibiotic treatment.
  • They may need additional treatment for symptom relief.
• Tell people who are starting antibiotics for Lyme disease that some people may have a Jarisch-Herxheimer reaction to treatment. Explain that:
  • This causes a worsening of symptoms early in treatment.
  • It can happen when large numbers of bacteria in the body are killed.
  • It does not happen to everyone treated for Lyme disease.
  • They should contact their doctor and keep taking their antibiotics if their symptoms worsen.
• Advise people with Lyme disease to talk to their doctor if their symptoms have not improved or if symptoms return after completing treatment.
• Explain to people with Lyme disease that infection does not give them lifelong immunity and that it is possible for them to be re-infected and develop Lyme disease again.

What advice should I give someone to help prevent tick bites?

• To minimize the risk of being bitten by an infected tick, give people advice about: 
  • Where ticks are commonly found (such as grassy and wooded areas, including urban gardens and parks).
    • Keep to paths and away from long grass or overgrown vegetation, as ticks crawl up long grass in their search for a feed.
    • Regularly check clothing and exposed skin for ticks and brush off immediately.
  • Covering exposed skin and using insect repellents that protect against ticks.
    • Consider using an insect repellent containing N,N-diethyl-m-toluamide (DEET).
    • Wear appropriate clothing (long sleeved shirt and long trousers tucked into socks) in tick-infested areas. Light coloured fabrics are useful, as it is easier to see ticks against a light background.
  • How to check themselves and their children for ticks on the skin:
    • Inspect skin frequently and remove any attached ticks as soon as possible after noticing them.
    • At the end of the day, check again for ticks, especially in skin folds.
    • Make sure that children's head and neck areas, including scalps, are properly checked.
    • Check that ticks are not brought home on clothes.
    • Check that pets do not bring ticks into the home on their fur.
  • The importance of prompt, correct tick removal and how to do this.
  • Sources of information on Lyme disease, such as the UK Health Security Agency (UKHSA) leaflet Enjoy the outdoors but 'be tick aware', and organisations providing information and support, such as charities, like Lyme Disease Action (www.lymediseaseaction.org.uk).

What advice should I give to a person bitten by a tick?

• If a tick is still attached to the skin, remove it as soon as possible using the following method:
  • Grasp the tick as close to the point of attachment to the skin as possible using fine-tipped tweezers or a tick removal device.
  • Pull upwards slowly and firmly, away from the skin, without twisting — there is a possibility that fragments of the mouthparts may be left in the skin, which can cause a local infection. 
  • After removal:
    • Clean the skin with water and antibacterial soap, and wash hands.
    • Keep an eye on the bite area for several weeks for changes.
• If the person has a history of a recent tick bite but is otherwise well:
  • Antibiotic prophylaxis following a tick bite is not routinely recommended.
  • Advise the person to seek immediate medical advice if they develop any symptoms of Lyme disease or other tick-borne diseases (such as a rash or flu-like illness).
• The UK Health Security Agency leaflet Enjoy the outdoors but be 'tick aware', provides information on tick bite risks and prevention.

Contraindications and cautions

• Do not prescribe doxycycline to:
  • Pregnant or breastfeeding women and children under 12 years of age as it is deposited in the teeth and bones of unborn or developing children.
  • People with known hypersensitivity to any of the tetracyclines.
  • Acute porphyria.
• Prescribe doxycycline with caution in people with:
  • Impaired hepatic or renal function.
  • Myasthenia gravis — tetracyclines may increase muscle weakness in people with myasthenia gravis.
  • Systemic lupus erythematous — tetracyclines may exacerbate systemic lupus erythematosus.
• Advise people likely to be exposed to direct sunlight or ultraviolent light that an exaggerated sunburn reaction can occur due to photosensitivity whilst taking doxycycline.
• Note: The use of doxycycline for treating Lyme disease is off-label but is endorsed by guidelines from the National Institute for Health and Care Excellence (NICE). Use of doxycycline in children between the ages of 8 and 11 is generally advised only in acute or severe infections due to the risk of deposition in growing bones and teeth. NICE notes the use in this age group is off-label but recommends it first-line for Lyme disease with erythema migrans and/or non-focal symptoms.

  [NICE, 2018; EMC, 2021; BNF, 2023]

Adverse effects

• Blood disorders — haemolytic anaemia, thrombocytopenia, neutropenia, eosinophilia (frequency unknown).
• Gastrointestinal — nausea, vomiting (common), dyspepsia (uncommon), abdominal discomfort, diarrhoea, tooth discolouration and enamel hypoplasia in children (frequency unknown).
  • Rarely: dysphagia, oesophagitis, oesophageal irritation, pseudomembranous colitis. For more information, see the CKS topic on Diarrhoea - antibiotic associated.
• Hepatic disorders – hepatotoxicity, hepatitis, jaundice, hepatic failure (frequency unknown).
• Renal disorders — blood urea increased.
• Skin — photosensitivity, rash (common).
  • Rarely: toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiforme, exfoliative dermatitis, and fixed eruption.
• Other rare adverse effects include:
  • Anaphylaxis.
  • Arthralgia, myalgia.
  • Bulging fontanelles in infants.
  • Flushing.
  • Severe headache and/or visual disturbances — may be an early symptom of benign intracranial hypertension, a rare but serious adverse effect. If this occurs the drug should be stopped immediately.
  • Tinnitus.
• A Jarisch-Herxheimer reaction — this has been observed in about 15% of people with Lyme disease. It is a systemic reaction thought to be caused by the release of cytokines when antibiotics kill large numbers of bacteria. Symptoms include a worsening of fever, chills, muscle pains and headache. It may be mistaken for an allergic reaction and the person may stop their antibiotics. The reaction can start between 1–12 hours after antibiotics are started, but can also occur later and can last for a few hours or 1–2 days. The reaction is self-limiting and usually resolves within 24 to 48 hours. Provided the symptoms are not severe and there is no evidence of an allergic reaction (such as urticaria), the person can be advised to continue the antibiotic.

[Dubrey et al, 2014; NICE, 2018; Torbahn, 2018; BNF, 2023; EMC, 2024]

Drug interactions

• Antacids (containing aluminium, bismuth, calcium, or magnesium) and other medications containing iron or zinc — these reduce the absorption of tetracyclines if taken concurrently.
  • Avoid taking antacids and other medications containing iron or zinc, 2 hours before or after taking tetracyclines.
• Ciclosporin — doxycycline may increase plasma concentration of ciclosporin. Monitor if given together.
• CYP3A enzyme inducers (phenobarbital, carbamazepine or phenytoin) — these may reduce the serum half-life of doxycycline. Monitor and adjust the dose if necessary.
• Lithium — levels may be increased by doxycycline. Consider increasing the frequency of lithium monitoring.
• Methotrexate — both can increase the risk of hepatotoxicity.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of doxycycline.
  • 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. 
• Penicillin — doxycycline may interfere with the bactericidal action of penicillin. Avoid giving together.
• Retinoids — there is a possible increased risk of benign intracranial pressure if tetracyclines are used concurrently with retinoids (such as isotretinoin).
  • Avoid the concurrent use of tetracyclines and retinoids.
• Rifampicin — doxycycline levels are markedly reduced, which may lead to treatment failure. Monitor the effects and increase doxycycline dose if necessary.
• Warfarin — the concurrent use of warfarin with tetracyclines may increase the anticoagulant effect. However, there is little evidence to suggest clinical relevance.
  • Consider monitoring the person's international normalized ratio (INR) regularly and within 3 days of starting the tetracycline. Adjust the warfarin dose accordingly.

   [NICE, 2018; EMC, 2021; CoSRH, 2022; BNF, 2023]

Pregnancy and breastfeeding

Pregnancy

• Doxycycline is contraindicated in women who are pregnant.

Breastfeeding

• Doxycycline is contraindicated in women who are breastfeeding.
  • However, 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. Absorption by 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. Long-term use is not advisable.

  [NICE, 2018; SPS, 2020a; EMC, 2021; BNF, 2023]

Contraindications and cautions

• Do not prescribe amoxicillin in people with a true penicillin hypersensitivity.
  • 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 people.
  • 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.
• Prescribe amoxicillin with caution to people with:
  • Hypersensitivity to cephalosporins.
  • Renal impairment — reduce the dose of amoxicillin in severe renal impairment.
  • Glandular fever (infective mononucleosis) — these people are especially susceptible to amoxicillin-induced skin rashes.

[BNF, 2023; EMC, 2023b]

Adverse effects

• Gastrointestinal — nausea and diarrhoea (common), vomiting (uncommon).
  • Very rarely: antibiotic-associated colitis.
• Skin — skin rash (common), urticaria and pruritus (uncommon).
  • Very rarely: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis and acute generalised exanthematous pustulosis.
• Other very rare adverse effects include:
  • Hepatitis, cholestatic jaundice.
  • Mucocutaneous candidiasis.
  • Hyperkinesia, dizziness, convulsions.
  • Interstitial nephritis.
  • Leucopenia, thrombocytopenia, haemolytic anaemia.
  • Severe allergic reactions.
• A Jarisch-Herxheimer reaction — this has been observed in about 15% of people with Lyme disease. It is a systemic reaction thought to be caused by the release of cytokines when antibiotics kill large numbers of bacteria. Symptoms include a worsening of fever, chills, muscle pains and headache. It may be mistaken for an allergic reaction and the person may stop their antibiotics. The reaction can start between 1–12 hours after antibiotics are started, but can also occur later and can last for a few hours or 1–2 days. The reaction is self-limiting and usually resolves within 24–48 hours. Provided the symptoms are not severe and there is no evidence of an allergic reaction (such as urticaria), the person can be advised to continue the antibiotic.

[Dubrey et al, 2014; NICE, 2018; Torbahn, 2018; BNF, 2023; EMC, 2023b]

Drug interactions

• Allopurinol — increased risk of rash when allopurinol is given with amoxicillin. 
• Methotrexate — amoxicillin may reduce methotrexate clearance, causing an increased risk of toxicity.
  • Monitor methotrexate levels more closely. 
• Oral anticoagulants (warfarin, phenindione) — INR may be increased. Monitor the international normalized ratio (INR) closely during concomitant use. Dosage adjustments may be necessary.  
• Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of amoxicillin.
  • 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 — may cause increased and prolonged blood levels of amoxicillin. The manufacturer recommends avoiding concurrent use.
• Tetracyclines — the antibacterial effects of amoxicillin may be antagonised.

[CoSRH, 2022; BNF, 2023; EMC, 2023b]

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. 
  • Penicillins (and cephalosporins) are the antibiotics of choice in women who are breastfeeding.
  • Although unlikely, the infant could develop gastrointestinal disturbances and oral candida infection, particularly if used for prolonged periods or high doses, and there is a theoretical risk of hypersensitivity.

[SPS, 2020b; BNF, 2023; EMC, 2023b]

Contraindications and cautions

• Do not prescribe azithromycin in people:
  • With severe hepatic impairment.
  • With hypersensitivity to azithromycin, erythromycin or any macrolide or ketolide antibiotic.
  • With hypersensitivity to lactose (tablets only, manufacturers' information for capsules and film-coated tablets do not have this warning).
• Prescribe azithromycin with caution in people:
  • Who may be predisposed to prolongation of the QT interval. For example, people with:
    • Congenital or documented acquired QT prolongation.
    • Currently receiving treatment with other active substances known to prolong the QT interval such as antiarrhythmics of classes IA and III.
    • With electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesaemia.
    • With clinically relevant bradycardia, cardiac arrhythmia, or severe cardiac insufficiency, including Torsades de pointes.
  • With mild to moderate hepatic impairment.
  • With severe renal impairment.
  • With myasthenia gravis — macrolides may aggravate symptoms.
• Note: the use of azithromycin for Lyme disease is considered outside the scope of its licence but is supported by NICE guidelines.

[NICE, 2018; EMC, 2022; BNF, 2023; EMC, 2023a]

Adverse effects

• Gastrointestinal — diarrhoea, abdominal pain, nausea, flatulence, vomiting (common or very common).
  • Rarely: pancreatitis, pseudomembranous colitis (for more information, see the CKS topic on Diarrhoea - antibiotic associated).
• Nervous system — headache (common), dizziness, somnolence, dysgeusia, paraesthesia.
  • Rarely: convulsions, hyperactivity, syncope, myasthenia gravis.
• Psychiatric — nervousness, insomnia (uncommon).
  • Rarely or very rarely:  agitation, aggression, anxiety, delirium, hallucination.
• Skin and subcutaneous tissue — rash, pruritus, urticaria, dermatitis (uncommon).
  • Rarely, or very rarely: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.
• Other adverse effects reported less commonly, include: 
  • Anaphylaxis.
  • Arrhythmias.
  • Arthralgia.
  • Candidiasis.
  • Deafness.
  • Vision disorders
  • Hepatitis, cholestatic jaundice.
  • Pancreatitis. 
  • QT interval prolongation.
• Jarisch-Herxheimer reaction — this has been observed in about 15% of people with Lyme disease. It is a systemic reaction thought to be caused by the release of cytokines when antibiotics kill large numbers of bacteria. Symptoms include a worsening of fever, chills, muscle pains and headache. It may be mistaken for an allergic reaction and the person may stop their antibiotics. The reaction can start between 1–12 hours after antibiotics are started, but can also occur later and can last for a few hours or 1–2 days. The reaction is self-limiting and usually resolves within 24–48 hours. Provided the symptoms are not severe and there is no evidence of an allergic reaction (such as urticaria), the person can be advised to continue the antibiotic.
• Infantile hypertrophic pyloric stenosis (IHPS) has been reported after use in neonates (up to 42 days of life).

[Dubrey et al, 2014; NICE, 2018; Torbahn, 2018; EMC, 2022; BNF, 2023]

Drug interactions

• Antacids — plasma concentrations of azithromycin may be reduced. Simultaneous administration should be avoided and an interval of about two hours is recommended.
• Chloroquine and hydroxychloroquine — the manufacturer advises that clinicians carefully consider balance of benefits and risks of co-administration due to increased risk of cardiovascular events and mortality.
• Ciclosporin — azithromycin can affect clearance of ciclosporin. If co-administration of these drugs is necessary, ciclosporin levels should be monitored and the dose adjusted accordingly.
• Colchicine — azithromycin slightly increases the levels of colchicine. Monitor for signs of colchicine toxicity (for example, nausea, vomiting, diarrhoea, myopathy, and pancytopenia).
• Digoxin — macrolides increase digoxin levels. However, the risk of toxicity may be lower with azithromycin than with clarithromycin. Monitor and reduce the digoxin dose if required.
• Edoxaban — levels may be increased by azithromycin. Dose adjustment of edoxaban may be required.
• Ergot derivatives — there is a theoretical possibility of ergot toxicity if taken concomitantly with azithromycin. The manufacturer of azithromycin recommends avoiding.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of azithromycin.
  • 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.
• Rifabutin — azithromycin increases the risk of neutropenia when given with rifabutin. Monitor closely.
• Statins — there is a possible increased risk of myopathy.
  • Advise the person to report any muscle pain, tenderness, or weakness.
• Warfarin — occasionally and unpredictably, the effects of warfarin may be markedly increased by macrolides.
  • Monitor the international normalized ratio (INR), and adjust the warfarin dose accordingly.
• Drugs that prolong the QT interval (such as amiodarone, or sotalol) — all macrolides can prolong the QT interval, and concomitant use of drugs that prolong the QT interval is not recommended.
  • Use an alternative antibiotic and/or seek advice from a microbiologist.

[EMC, 2022; CoSRH, 2022; BNF, 2023]

Pregnancy and breastfeeding

Pregnancy

• There is limited data available on the use of azithromycin in women who are pregnant. Avoid use unless a suitable alternative is not available.

Breastfeeding

• Present in breastmilk — avoid use unless a suitable alternative is not available.
• If used in women who are breastfeeding, the manufacturer recommends a decision is taken whether to discontinue breastfeeding, taking into account the benefit of breastfeeding for the child, and the benefit of treatment for the mother.

 [EMC, 2022; BNF, 2023]