Previous changes

October 2024 — minor update. The preferred antibiotic choices for children aged 1 month or over have been clarified. 

July 2024 — minor update. Minor typographical error corrected in the prescribing section. Updated information on exclusion periods for cases and recommendations concerning the window of eligibility for antibiotics to align with the UKHSA national guidance on public health management of pertussis, June 2024. 

May 2024 — minor update. Added information regarding the tests available and the sources of each test for pertussis. Information added stating that concomitant treatment with clarithromycin and ivabradine is now contra-indicated and caution is now advised when co-administering clarithromycin with edoxaban, in line with the manufacturer's updated SPC. Additional detail has been added about the interaction between clarithromycin and tacrolimus.

March 2024 — minor update. A minor typographical error has been corrected.

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

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).

January 2023 — reviewed. A literature search was conducted in December 2022 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. No major changes to recommendations have been made.

April 2022 — minor update. The section on drug interactions of azithromycin has been updated to include a possible interaction with hydroxychloroquine and chloroquine, in line with a revised manufacturer's Summary of Product Characteristics (SPC). 

February 2022 — minor update. Links to key therapeutic topic guidance have been removed as the service has been retired.

August 2021 — minor update. The section on adverse effects of co-trimoxazole has been updated to include a rare problem of severe respiratory toxicity with the potential to progress to adult respiratory distress syndrome (ARDS), in line with a revised SPC.

January 2021 — minor update. The sections on contraindications and drug interactions for erythromycin have been updated in line with a drug safety update issued by the Medicines and Healthcare products Regulatory Agency (MHRA). 

June 2018 — minor update. The section on drug interactions of azithromycin has been updated to include a possible drug interaction with azithromycin and colchicine, in line with a revised SPC.

March to April 2017 — reviewed. A literature search was conducted in March 2017 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials (RCTs) published since the last revision of this topic. The topic has undergone minor restructuring. No major changes to recommendations have been made.

July 2015 — reviewed. A literature search was conducted in July 2015 to identify evidence-based guidelines, UK policy, systematic reviews, and RCTs published since the last revision of this topic. The topic has undergone minor restructuring. No major changes to recommendations have been made.

February 2013 — minor update. The 2013 quality, innovation, productivity and prevention (QIPP) options for local implementation have been added to this topic.

November 2012 — minor update. Text and prescriptions have been revised to include updated guidance from the Health Protection Agency (HPA).

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

September 2011 — minor update. More recent prevalence data from the HPA has been added. 

July 2011 — minor update. More exact paracetamol dosing for children has been introduced by the 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. 

March 2011 — minor update to make the topic consistent with guidance produced by the HPA. 

September to December 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

• UKHSA (2023) Pertussis outbreaks in nurseries and educational settings. UK Health Security Agency. www.gov.uk [Full-text]
• UKHSA (2024) Pertussis: guidelines for public health management. UK Health Security Agency. www.gov.uk [Full-text]
• UKHSA (2024) Guidance on the management of casesof pertussis in England during the re-emergence of pertussis in 2024. UK Health Security Agency. www.gov.uk [Full-text]

HTAs (Health Technology Assessments)

No new HTAs since 1 December 2022.

Economic appraisals

No new economic appraisals relevant to England since 1 December 2022.

Systematic reviews and meta-analyses

No new systematic reviews or meta-analysis which reach the CKS threshold for inclusion since 1 December 2022.

Primary evidence

• UKHSA (2023) Pertussis: laboratory confirmed cases reported in England 2022. UK Health Security Agency www.gov.uk [Free Full-text]

New policies

• UKHSA (2024) Guidance on the management of cases of pertussis in England during the re-emergence of pertussis. Guidance in the management of cases of pertussis

New safety alerts

No new safety alerts since 1 December 2022.

Changes in product availability

No changes in product availability since 1 December 2022.

Basis for recommendation

The clinical features of whooping cough are based on the Centers for Disease Control and Prevention (CDC) guideline Pertussis (Whooping Cough) [CDC, 2022], the Public Health England (PHE) guideline Immunisation against infectious disease (The Green Book) Chapter 24: Pertussis [PHE, 2016], and on expert opinion in the textbook Principles and practice of infectious diseases [Waters, 2010] and review articles [Braman, 2006; Gregory, 2006; Harnden, 2009; BMJ Best Practice, 2022].

Laboratory tests for whooping cough

• Laboratory confirmation of clinically suspected cases of whooping cough can be made by culture, polymerase chain reaction (PCR), serological testing, or oral fluid testing (OFT).
• The local health protection team will advise on appropriate tests for confirmation and surveillance, this will depend on the person's age, duration of symptoms, and local laboratory facilities. The following tests are available:
  • Culture and isolation of Bordetella pertussis (from nasopharyngeal aspirate [NPA] or nasopharyngeal swab [NPS]/pernasal swab [PNS]) is suitable for people of all age groups with a cough duration of less than 21 days. Available from NHS laboratories, confirmed isolates are sent to  the Respiratory and Vaccine Preventable Bacteria Reference Unit (RVPBRU).
  • PCR, a molecular technique used to detect DNA sequences of B. pertussis, is suitable for people of all age groups with a cough duration of less than 21 days. PCR is usually more sensitive than culture as the organism does not need to be viable; however, PCR is less likely to be positive in people with a symptom duration of 21 days or more. Available from regional UKHSA laboratories.  Positive samples are sent to RVPBRU. 
  • Serology may be considered for anyone aged over 1 year old with more than 14 days history of cough and at least one year after the most recent dose of pertussis vaccine (including any dose administered in pregnancy). It is not typically recommended in infants as antibody response in children of this age group may not be typical of that seen in older children and adults. It may be suitable in people with a cough duration of 21 days or more, when culture and PCR are unlikely to yield positive results. Available from RVPBRU.
  • OFT is suitable for people aged between 2–16 years (that is, aged 2 to under 17 years) with a history of more than 14 days of cough and at least one year after the most recent dose of whooping cough vaccine. They are tested for anti-pertussis toxin immunoglobulin G (IgG). The OF kits are sent to the patient at notification by the health protection team and samples tested and reported by the RVPBRU.
• Whooping cough is confirmed by the presence of clinical features plus one of the following:
  • B. pertussis isolated from a respiratory sample, typically an NPA or NPS/PNS (or throat swab).
  • B. pertussis PCR positive in a respiratory clinical specimen.
  • IgG titre greater than 70 International Units per millilitre (IU/ml) from a serum specimen, or greater than 70 arbitrary units (aU) from an oral fluid specimen (in the absence of vaccination within the past year).

[PHE, 2018b; PHE, 2018a; UKHSA, 2026]

Basis for recommendation

These recommendations are based on the Centers for Disease Control and Prevention (CDC) publication Pertussis (Whooping Cough) [CDC, 2022], the UK HSA National pertussis guidance - Advice on the public health management of pertussis [UKHSA, 2026], and the PHE Pertussis brief for healthcare professionals [PHE, 2018b].

Basis for recommendation

Information on the differential diagnosis of whooping cough is based on expert opinion in review articles [Frydenberg, 2004; Tiwari, 2005; Braman, 2006; Shields, 2008; BMJ Best Practice, 2022].

How should I manage a person with whooping cough?

• Arrange hospital admission for people with significant breathing difficulties (for example, apnoea episodes, severe paroxysms, or cyanosis) or significant complications (for example, seizures or pneumonia).
  • Have a low threshold for admitting children aged 6 months or younger, as they are at increased risk of severe illness and death.
  • Inform the hospital of the need for appropriate isolation before the person is admitted.
• If admission is not necessary and the onset of the cough is within the previous 21 days, prescribe antibiotic treatment.
  • Prescribe a macrolide first line: 
    • For infants aged under 1 month, clarithromycin is preferred. Azithromycin may be used, although there are limited data in this age group.
    • For children aged 1 month or over, prescribe azithromycin or clarithromycin.
    • For non-pregnant adults, prescribe azithromycin or clarithromycin.
    • For pregnant women, prescribe erythromycin. The second-line option is azithromycin, and the third-line option is clarithromycin, as alternatives where necessary. 
  • If macrolides are contraindicated or not tolerated, prescribe co-trimoxazole.
    • Do not prescribe co-trimoxazole to pregnant women or infants younger than 6 weeks old.
  • For information on dosing regimens, contraindications, cautions, adverse effects, and drug interactions of these antibiotics, see the section on Prescribing information.
• Advise the person and/or their family/carers:
  
  • On self-care measures including rest, adequate fluid intake, and the use of paracetamol or ibuprofen for symptomatic relief. For more information, see the CKS topics on Analgesia - mild-to-moderate pain and NSAIDs - prescribing issues.
  • That even with antibiotic treatment, whooping cough is likely to cause a protracted non-infectious cough that may take several weeks to completely resolve.
    • Symptoms are likely to be less severe and resolve more quickly if the person has been immunized or has had whooping cough before.
  • That they should seek medical advice if they develop complications.
  • That exclusion from nursery, school, or work is required for suspected, confirmed, or epidemiologically-linked cases as follows:
    • Children should stay off nursery, school, or work until they have completed 48 hours of appropriate antibiotic treatment, or for 21 days from the onset of coughing if not treated.
    • Staff working in nurseries and childcare settings providing close personal care to infants should be excluded until they have completed 48 hours of appropriate antibiotic treatment, or for 21 days following the onset of cough, if untreated.
    • Staff in other nursery and childcare settings, school and other educational settings should be excluded until they have completed 48 hours of appropriate antibiotic treatment, or for 21 days from the onset of coughing, if untreated.
    • Healthcare workers providing close personal care to infants in a priority group, or to pregnant women, should be excluded until they have completed 48 hours of appropriate antibiotic treatment, or for 21 days from the onset of coughing, if untreated.
      • In addition, healthcare workers should inform their occupational health department and infection prevention control team as soon as possible, and should do so even if beyond 21 days from the onset of coughing as vulnerable contacts may still be within their incubation period.
    • People who work in other settings should stay off nursery, school, or work and avoid contact with infants under one year who are unvaccinated, partially vaccinated, or pregnant women until 48 hours of appropriate antibiotic treatment, or for 21 days after the onset of coughing if not treated.

• Arrange for the person to have any outstanding vaccinations after they have recovered from the acute illness. 
  
  • The whooping cough vaccination programme for pregnant women offers vaccination to pregnant women, normally at the time of the congenital anomaly scan (around 20 weeks) but women can receive it from as early as week 16. To help provide optimal protection the vaccine should be given before 32 weeks. However, women who miss out can still have the vaccine later in the pregnancy. If a pregnant woman is diagnosed with whooping cough before 16 weeks gestation, she should wait until she reaches 16 weeks of pregnancy (and ideally following the detailed ultrasound scan) to have the vaccine. For more information, see the CKS topic on Antenatal care - uncomplicated pregnancy.
  • It is important that unvaccinated and partially immunised cases up to 10 years of age complete their course of primary immunisation and booster vaccine once they have recovered from their acute illness, following the UKHSA guidance document. Currently, routine immunisation against pertussis is not recommended for those aged ten years and over, except for pregnant women.
  • The whooping cough vaccine is given as part of the 6-in-1 vaccine offered to children aged 8, 12, and 16 weeks and as part of the 4-in-1 pre-school booster offered to children at the age of 3 years and 4 months old. For more information, see the CKS topic on Immunizations - childhood. 
• Manage the person's close contacts.

How should I manage close contacts of a person with suspected or confirmed whooping cough?

• Offer antibiotic prophylaxis to close contacts of the ‘index case’ when coughing in the 'index case’ started within the previous 21 days:
  • Close contacts are defined as family members or people living in the same household (close ‘household contacts’) and contacts in institutional settings with an overnight stay in the same room (for example, an inpatient bay) during the infectious period.
    • Other types of contact, for example, contact at work or school, would generally not be considered to represent a close contact group where a public health intervention is likely to be effective. 
    • For healthcare workers, special considerations apply concerning close contact. For these individuals, significant exposure is defined as follows:
      • Contact with a pertussis case in their own household.
      • Unprotected, direct, face-to-face contact in their place of work for more than one hour (cumulatively) with a pertussis case who is within 21 days of cough onset. 
      • Direct contact with respiratory secretions from a pertussis case within 21 days of cough onset (for example, when performing an aerosol-generating procedure without appropriate personal protective equipment). 
• Prescribe a macrolide antibiotic first line.
  
  • For infants aged under 1 month, clarithromycin is preferred. Azithromycin may be used, although there are limited data in this age group.
  • For non-pregnant adults and children aged over 1 year, prescribe azithromycin or clarithromycin.
  • For pregnant women, prescribe erythromycin.
  • If macrolides are contraindicated or not tolerated, prescribe co-trimoxazole. Do not prescribe co-trimoxazole to pregnant women and infants younger than 6 weeks of age.
  • For information on dosing regimens, contraindications, cautions, adverse effects, and drug interactions of these antibiotics, see the section on Prescribing information.
• Advise the person and/or their family/carers that exclusion from nursery, school, or work for asymptomatic contacts is not required.
• Offer immunization to all people who have been offered antibiotic prophylaxis.
  • Unimmunized and partly immunized contacts up to 10 years of age should complete the schedule of the Childhood Immunization Programme with the appropriate vaccination. For more information, see the CKS topic on Immunizations - childhood. 
  • Post-exposure vaccination in pregnancy is vital to protect young infants at greatest risk of severe disease. Any pregnant contacts who have reached their 20th week of pregnancy but have not yet received a pertussis-containing vaccine should be vaccinated. 
  • Contacts who are healthcare workers and provide close, personal care to vulnerable infants, or to pregnant women, should have a booster of a pertussis-containing vaccine if they have not received a dose in the previous 5 years. 

What is the recommended dosage of oral clarithromycin?

• Prescribe clarithromycin for 7 days. The recommended dosage is: 
  
  • Neonates (less than 1 month): 7.5 mg/kg twice a day.
  • Children aged 1 month to under 11 years:
    • Body weight under 8 kg: 7.5 mg/kg twice a day.
    • Body weight 8–11 kg: 62.5 mg twice a day.
    • Body weight 12–19 kg: 125 mg twice a day.
    • Body weight 20–29 kg: 187.5 mg twice a day.
    • Body weight 30–40 kg: 250 mg twice a day.
  • Children aged 12 years and over and adults: 500 mg twice a day.

[PHE, 2018a]

What are the contraindications and cautions for clarithromycin?

• Do not prescribe clarithromycin to people with:
  
  • A history of QT prolongation or ventricular cardiac arrhythmia, including Torsades de pointes.
  • Conditions that predispose to QT interval prolongation, such as electrolyte disturbances (hypokalaemia or hypomagnesaemia) or the use of some medications that prolong the QT interval.
  • Severe hepatic impairment in combination with renal impairment.
• Prescribe clarithromycin with caution to people with:
  • Hepatic impairment (or concurrently receiving potentially hepatotoxic drugs) — clarithromycin is mainly excreted by the liver.
  • Moderate to severe renal impairment.
    • For immediate-release preparations: if creatinine clearance (CrCl) is less than 30 mL/minute, prescribe half the normal dose and use for a maximum duration of 14 days.
    • For modified-release preparations: if CrCl is 30–60 mL/minute, prescribe half the normal dose. Avoid if CrCl is less than 30 mL/minute.
  • Myasthenia gravis — macrolides may aggravate weakness symptoms.
  • Other risk factors for QT prolongation, such as:
    • Coronary artery disease, severe cardiac insufficiency, conduction disturbances, or clinically relevant bradycardia.
    • The use of some medications associated with QT prolongation. 

[ABPI, 2021b; BNF, 2022]

What are some possible adverse effects of oral clarithromycin?

• The most common adverse effects of macrolides are gastrointestinal symptoms, such as nausea, vomiting, abdominal discomfort, decreased appetite, diarrhoea, pancreatitis, altered taste, and gastrointestinal discomfort.
• Other common or very common adverse effects of macrolides include dizziness, headache, insomnia, paraesthesia, skin reactions, vasodilation, and vision disorders.
• Consider pseudomembranous colitis (an acute, exudative colitis caused by an overgrowth of Clostridium difficile bacteria) if a person develops severe diarrhoea during or after treatment with clarithromycin. See the CKS topic on Diarrhoea - antibiotic associated for more information.
• Less common adverse effects include:
  
  • Uncommon
    • For clarithromycin — burping, dry mouth, epistaxis, muscle complaints, oral disorders, thrombocytosis, and tremors.
    • For all macrolides — angioedema, anxiety, arrhythmias, candida infection, chest pain, drowsiness, eosinophilia, hearing impairment, hepatic disorders, leucopenia, neutropenia, palpitations, QT interval prolongation, severe cutaneous adverse reactions (SCARs), tinnitus, and vertigo.
  • Rare or very rare 
    • For all macrolides — myasthenia gravis and nephritis tubulointerstitial.
  • Frequency not known
    • For clarithromycin — abnormal dreams, agranulocytosis, depersonalization, depression, mania, myopathy, psychotic disorder, renal failure, tooth discolouration, and urine discolouration.
    • For all macrolides — altered smell, hallucination, hypotension, seizure, thrombocytopenia, and tongue discolouration.

[ABPI, 2021b; BNF, 2022]

What are some possible drug interactions with oral clarithromycin?

Possible drug interactions of clarithromycin include:

• Calcium channel blockers (CCBs) — clarithromycin is predicted to increase exposure to CCBs, such as verapamil, felodipine, nifedipine, amlodipine, and diltiazem. Concurrent use may increase the risk of adverse effects.
  • Monitor for adverse effects of the CCB (such as hypotension, headache, and oedema), and reduce the dose of the CCB as necessary.
• Ciclosporin — clarithromycin can increase ciclosporin levels.
  • If concurrent administration is necessary, monitor ciclosporin levels and adjust the dose accordingly.
• Digoxin — digoxin is a substrate for the efflux transporter P-glycoprotein (P-gp), and clarithromycin is known to inhibit P-gp. Concurrent administration may lead to increased digoxin concentrations.
  • Monitor serum digoxin levels during concurrent treatment with clarithromycin.
• Drugs metabolized by cytochrome P450 3A4 (CYP3A4) — clarithromycin is a strong CYP3A4 inhibitor. Concurrent use with drugs metabolized by CYP3A4 may result in elevations in plasma concentrations of the concurrent drug, leading to increased or prolonged therapeutic and/or adverse effects of the concurrent drug.
  • Concurrent use with the following drugs is contraindicated:
    • Colchicine. There have been post-marketing reports of colchicine toxicity with concurrent use of clarithromycin, especially in elderly people (some with renal insufficiency). Deaths associated with colchicine toxicity have been reported.
    • Midazolam.
    • Ticagrelor.
    • Ranolazine.
  • Use clarithromycin with caution in people receiving other CYP3A enzyme substrates, such as carbamazepine, quinidine, rifabutin, sildenafil, and sirolimus. Consider dosage adjustments and, when possible, closely monitor serum concentrations of the concurrent drug.
    • Tarolimus — large increases in tacrolimus concentrations and renal toxicity have been reported with clarithromycin. Both clarithromycin and tacrolimus have been associated with QT prolongation or torsade de pointes but an effect is not established. Monitor the concentrations and effects (e.g. on renal function) of tacrolimus more frequently if clarithromycin is started or stopped, adjusting the tacrolimus dose as necessary.
• Drugs that prolong QT intervals — clarithromycin can also prolong QT intervals.
  • Concurrent use with the following drugs is contraindicated:
    • Pimozide. 
    • Terfenadine.
    • Astemizole.
    • Cisapride.
  • Concurrent use with other drugs that prolong the QT interval (such as haloperidol, sotalol, lithium, amiodarone, domperidone, citalopram, risperidone, and chlorpromazine) is not recommended.
• Drugs that cause hypokalaemia — hypokalaemia is a risk factor for QT prolongation.
  • Avoid concurrent treatment with drugs that increase the risk of hypokalaemia, such as diuretics, corticosteroids, and short-acting beta-2 agonists.
• Ergotamine or dihydroergotamine — co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity, characterized by vasospasm and ischaemia of the central nervous system, extremities and other tissues.
  • Concurrent use is contraindicated. 
• Edoxaban — manufacturer advises caution with concurrent treatment with edoxaban, particularly in those with a high risk of bleeding.
• Ivabradine — concomitant treatment is contra-indicated, owing to CYP3A4 inhibition by clarithromycin which can cause elevated levels of ivabradine.
• Hydroxychloroquine — clarithromycin may increase the risk of serious cardiovascular adverse effects when given with hydroxychloroquine.
  • The Medicines and Healthcare products Regulatory Agency (MHRA) advises caution.
• Oral hypoglycemic drugs/insulin — concurrent use with clarithromycin can result in significant hypoglycemia.
  • Monitor blood glucose levels more regularly, and adjust the antidiabetic drug (and/or insulin) dose accordingly.
• Oral anticoagulants (such as direct-acting oral anticoagulants [DOACs] and warfarin) — there is a risk of serious haemorrhage and significant elevations in international normalized ratio (INR) and prothrombin time when co-administered with clarithromycin.
  • DOACs — monitor for signs and symptoms of bleeding or anaemia, especially, in elderly people and those with renal impairment.
  • Warfarin — monitor INR and prothrombin times closely during concurrent treatment with clarithromycin.
• Ototoxic drugs (such as aminoglycosides) — clarithromycin may cause hearing impairment, especially at high doses.
  
  • Concurrent use with other ototoxic drugs should be done with caution.
• Statins — there is an increased risk of myopathy (due to CYP3A4 inhibition) in people taking clarithromycin and some statins: 
  • Simvastatin — clarithromycin markedly increases simvastatin exposure. Several cases of rhabdomyolysis have been reported.
    • Concurrent use is contraindicated.
    • Temporarily withhold simvastatin if clarithromycin treatment is necessary.
  • Atorvastatin — clarithromycin slightly to moderately increases the exposure to atorvastatin. Cases of rhabdomyolysis have been reported with concurrent use.
    • Avoid concurrent use if possible. If concurrent use cannot be avoided, do not exceed 20 mg atorvastatin daily [MHRA, 2014].
    • Advise the person to report any signs of rhabdomyolysis (such as muscle pain, tenderness, or weakness).
  • Other statins — clinically significant drug interactions resulting from cytochrome P450-mediated metabolism are not expected for rosuvastatin and pravastatin as they are not metabolized to a clinically significant extent by the cytochrome P450 system. Fluvastatin is not dependent on CYP3A metabolism; therefore, interaction with clarithromycin is unlikely. Nevertheless, advise the person to report any muscle pain, tenderness, or weakness.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of clarithromycin. However, advise women on the importance of correct contraceptive practice if they experience vomiting or diarrhoea.

 [MHRA, 2020; BNF, 2022; EMC, 2024]

What is the recommended dosage of oral erythromycin?

Erythromycin is recommended for pregnant women. See the section on Management for more information.

• The recommended dosage is 500 mg 4 times a day for 7 days.

[ABPI, 2022a; BNF, 2022]

What are the contraindications and cautions for erythromycin?

• 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 or the use of medications that prolong the QT interval.
• Prescribe erythromycin with caution to people with:
  
  • Impaired hepatic function (or concurrently receiving potentially hepatotoxic drugs) — erythromycin is principally excreted by the liver. 
  • Moderate to severe renal impairment — prescribe a maximum dose of 1.5 g a day in people with severe renal impairment, due to the risk of ototoxicity.
  • Myasthenia gravis — macrolide antibiotics may aggravate weakness symptoms.

[ABPI, 2022a; BNF, 2022]

What are some possible adverse effects of oral erythromycin?

• The most common adverse effects of macrolides are gastrointestinal symptoms, such as nausea, vomiting, abdominal discomfort, decreased appetite, diarrhoea, pancreatitis, altered taste, and gastrointestinal discomfort.
• Other common or very common adverse effects of macrolides include dizziness, headache, insomnia, paraesthesia, skin reactions, vasodilation, and vision disorders.
• Consider pseudomembranous colitis (an acute, exudative colitis caused by an overgrowth of Clostridium difficile bacteria) if a person develops severe diarrhoea during or after treatment with erythromycin. See the CKS topic on Diarrhoea - antibiotic associated for more information.
• Less common adverse effects include:
  • Uncommon
    • For all macrolides — angioedema, anxiety, arrhythmias, candida infection, chest pain, drowsiness, eosinophilia, hepatic disorders, leucopenia, neutropenia, palpitations, QT interval prolongation, severe cutaneous adverse reactions (SCARs), tinnitus, and vertigo.
  • Rare or very rare 
    • For all macrolides — myasthenia gravis and nephritis tubulointerstitial.
  • Frequency not known
    • For erythromycin — cerebral impairment and reversible hearing loss (mainly at high doses and in people with renal insufficiency).
    • For all macrolides — altered smell, hallucination, hypotension, seizure, thrombocytopenia, and tongue discolouration.

[ABPI, 2022a; BNF, 2022]

What are some possible drug interactions with oral erythromycin?

Possible drug interactions of erythromycin include:

• Calcium channel blockers (CCBs) — erythromycin is predicted to increase exposure to CCBs, such as verapamil, felodipine, nifedipine, amlodipine, and diltiazem. Concurrent use may increase the risk of adverse effects.
  • Monitor for adverse effects of the CCB (such as hypotension, headache, and oedema), and reduce the dose of the CCB as necessary.
• Cimetidine — cimetidine can almost double the serum levels of erythromycin. A single case report describes reversible deafness attributed to this interaction.
  • Monitor concurrent use for erythromycin adverse effects.
  • Stop erythromycin if deafness occurs.
• Corticosteroids — levels of corticosteroids may be increased. Monitor for corticosteroid adverse effects (such as moon face, weight gain, hyperglycaemia), and adjust the corticosteroid dose or stop the macrolide as appropriate. 
• Drugs metabolized by cytochrome P450 3A4 (CYP3A4) — erythromycin is a moderate CYP3A4 inhibitor. Concurrent use with drugs metabolized by CYP3A4 may result in elevations in plasma concentrations of the concurrent drug, leading to increased or prolonged therapeutic and/or adverse effects of the concurrent drug.
  • Use erythromycin with caution in people receiving treatment with cytochrome P450 enzyme substrates, such as colchicine, carbamazepine, ciclosporin, digoxin, ergotamine, midazolam, rifabutin, and tacrolimus.
  • Consider dose adjustments and, when possible, closely monitor serum concentrations of the concurrent drug.
  • Concurrent use with colchicine is contraindicated in people with renal or hepatic impairment [Preston, 2023].
• Drugs that prolong QT intervals — erythromycin can also prolong QT intervals.
  • Concurrent use with the following drugs is contraindicated:
    • Pimozide. 
    • Terfenadine.
    • Astemizole.
    • Cisapride.
    • Mizolastine.
    • Amisulpride.
    • Domperidone.
  • Concurrent use with other drugs that prolong the QT interval (such as haloperidol, sotalol, lithium, amiodarone, citalopram, risperidone, and chlorpromazine) is not recommended.
• Drugs that increase the risk of hypokalaemia — hypokalaemia is a risk factor for QT prolongation.
  • Avoid concurrent treatment with drugs that increase the risk of hypokalaemia, such as diuretics, corticosteroids, theophylline, and short-acting beta-2 agonists.
• Ergotamine and dihydroergotamine — co-administration of erythromycin with ergotamine or dihydroergotamine may increase plasma concentration of ergotamine, resulting in toxicity. 
  • Concurrent use is contraindicated. 
• Hydroxychloroquine — erythromycin may increase the risk of serious cardiovascular adverse effects when given with hydroxychloroquine.
  • The Medicines and Healthcare products Regulatory Agency (MHRA) advises caution.
• Lomitapide — concurrent use with erythromycin increases transaminase levels and is contraindicated.
• Oral anticoagulants — erythromycin increases the anticoagulant effect of warfarin and may increase the anticoagulant effect of direct oral anticoagulants (DOACs), such as apixaban and dabigatran.
  • Warfarin — monitor international normalized ratio (INR) and prothrombin time when co-administered with erythromcyin.
  • DOACs — monitor for signs and symptoms of bleeding or anaemia.
• Statins — there is an increased risk of myopathy (due to CYP3A4 inhibition) in people taking erythromycin and some statins: 
  • Simvastatin — erythromycin markedly increases simvastatin exposure. Several cases of rhabdomyolysis have been reported.
    • Concurrent use is contraindicated.
    • Temporarily withhold simvastatin if erythromycin treatment is necessary.
  • Atorvastatin — erythromycin slightly increases atorvastatin exposure. Cases of rhabdomyolysis have been reported with concurrent use.
    • Avoid concurrent use if possible. If concurrent use cannot be avoided, do not exceed 20 mg atorvastatin daily [MHRA, 2014].
    • Advise the person to report any signs of rhabdomyolysis (such as muscle pain, tenderness, or weakness).
  • Other statins — clinically significant drug interactions resulting from cytochrome P450-mediated metabolism are not expected for rosuvastatin and pravastatin as they are not metabolized to a clinically significant extent by the cytochrome P450 system. Fluvastatin is not dependent on CYP3A metabolism; therefore, interaction with erythromycin is unlikely. Nevertheless, advise the person to report any muscle pain, tenderness, or weakness.
• Zopiclone — erythromycin has been reported to decrease the clearance of zopiclone leading to an increased effect.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of erythromcyin. However, advise women on the importance of correct contraceptive practice if they experience vomiting or diarrhoea.

[MHRA, 2020; ABPI, 2021b; BNF, 2022]

What is the recommended dosage of oral azithromycin?

• Prescribe azithromycin for 3 days. The recommended dosage is: 
  
  • Neonates (less than 1 month): 10 mg/kg once a day.
  • Children aged 1–6 months: 10 mg/kg once a day.
  • Children aged over 6 months: 10 mg/kg (maximum 500 mg) once a day. 
  • Adults: 500 mg once a day.

[PHE, 2018a]

What are the contraindications and cautions for azithromycin?

• Prescribe azithromycin with caution in people with:
  • Risk factors for QT interval prolongation, such as:
    • Uncorrected electrolyte imbalance (for example hypokalaemia or hypomagnesaemia).
    • Cardiac disease (for example heart failure, myocardial infarction, symptomatic arrhythmias, or bradycardia).
    • Congenital long QT syndrome.
    • Concurrent use of medications that are known to prolong the QT interval (such as tricyclic antidepressants and antipsychotics).
  • Hepatic impairment — consider avoiding in severe impairment.
  • Renal impairment — use with caution if estimated glomerular filtration rate (eGFR) is less than 10 mL/minute/1.73 m².
  • Myasthenia gravis —  macrolide antibiotics may aggravate weakness symptoms.

[ABPI, 2022c; BNF, 2022]

What are some possible adverse effects of oral azithromycin?

• The most common adverse effects of macrolides are gastrointestinal symptoms, such as nausea, vomiting, abdominal discomfort, decreased appetite, diarrhoea, pancreatitis, altered taste, and gastrointestinal discomfort.
• Other common or very common adverse effects of macrolides include dizziness, headache, insomnia, paraesthesia, skin reactions, vasodilation, and vision disorders.
• Consider pseudomembranous colitis (an acute, exudative colitis caused by an overgrowth of Clostridium difficile bacteria) if a person develops severe diarrhoea during or after treatment with azithromycin. See the CKS topic on Diarrhoea - antibiotic associated for more information.
• Less common adverse effects include:
  • Uncommon
    • For azithromycin — numbness, oedema, and photosensitivity reaction.
    • For all macrolides — angioedema, anxiety, arrhythmias, candida infection, chest pain, drowsiness, eosinophilia, hepatic disorders, leucopenia, neutropenia, palpitations, QT interval prolongation, severe cutaneous adverse reactions (SCARs), tinnitus, and vertigo.
  • Rare or very rare 
    • For all macrolides — myasthenia gravis and nephritis tubulointerstitial.
  • Frequency not known
    • For azithromycin — acute kidney injury, aggression, akathisia, haemolytic anaemia, and syncope.
    • For all macrolides — altered smell, hallucination, hypotension, seizure, thrombocytopenia, and tongue discolouration.
• Infantile hypertrophic pyloric stenosis (IHPS) has been reported after use in neonates (up to 42 days of life).

What are some possible drug interactions with oral azithromycin?

Possible drug interactions of azithromycin include:

• Chloroquine and hydroxychloroquine  — may increase the risk of serious cardiovascular adverse effects when given with azithromycin. 
  • The Medicines and Healthcare products Regulatory Agency (MHRA) advises caution.
• Colchicine — azithromycin is predicted to increase exposure to colchicine.
  • Avoid concurrent treatment, or adjust the colchicine dose.
• Digoxin — azithromycin increases the concentration of digoxin.
  • Monitor digoxin concentrations.   
• Oral anticoagulant drugs — azithromycin is predicted to increase the exposure to direct oral anticoagulants (DOACs), such as apixaban, edoxaban, and dabigatran. Studies have not demonstrated a consistent interaction between azithromycin and warfarin, but case reports suggest some people may develop increased international normalized ratios (INRs). 
  • For DOACs, monitor for signs and symptoms of bleeding, particularly in those with renal impairment. Stop the DOAC if bleeding occurs. 
  • For warfarin, monitor INR and adjust the dose as necessary.
• Rifabutin — has been reported to cause neutropenia when given with azithromycin. 
  
  • Advise the person to report any signs or symptoms of neutropenia (fever, sore throat, swollen glands, mouth ulcers, infections).
  • Adjust the rifabutin dose if necessary.
• Ticagrelor — azithromycin is predicted to increase the exposure to ticagrelor.
  • Use with caution or avoid.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of azithromycin. However, advise women on the importance of correct contraceptive practice if they experience vomiting or diarrhoea.

[ABPI, 2022c; BNF, 2022]

What is the recommended dosage of co-trimoxazole?

• Prescribe co-trimoxazole for 7 days. The recommended dosage is:
  • Infants 6 weeks to 5 months: 120 mg twice a day.
  • Infants and children 6 months to 5 years: 240 mg twice a day.
  • Children 6–11 years: 480 mg twice a day.
  • Children 12 years and over and adults: 960 mg twice a day.

[PHE, 2018a; BNF, 2022]

What are the contraindications and cautions for co-trimoxazole?

• Do not prescribe co-trimoxazole to people with:
  
  • Severe hepatic impairment. 
  • Severe renal impairment (creatinine clearance [CrCl] less than 15 mL/minute), unless plasma levels of co-trimoxazole can be monitored regularly.
    • If plasma levels of co-trimoxazole can be monitored regularly, prescribe half the normal dose.
  • Severe haematological disorders, such as blood dyscrasias (except under careful supervision).
  • A history of drug-induced immune thrombocytopenia with the use of trimethoprim and/or sulphonamides.
  • Acute porphyria — both trimethoprim and sulfonamides (although not specifically sulfamethoxazole) have been associated with clinical exacerbation of porphyria.
• Prescribe co-trimoxazole with caution to:
  • Elderly people — increased risk of serious adverse effects, particularly when complicating conditions exist; for example, renal impairment, hepatic impairment, and/or concurrent use of other drugs.
  • People with:
    • Moderate renal impairment — prescribe half the normal dose if CrCl is 15–30 mL/minute.
    • Severe hepatic parenchymal damage — there may be changes in the absorption and biotransformation of trimethoprim and sulfamethoxazole.
    • Glucose-6-phosphate dehydrogenase deficiency — risk of haemolytic anaemia.
    • Severe allergy and asthma.
    • A predisposition to folate deficiency.
    • A predisposition to hyperkalaemia or hyponatraemia — close monitoring is warranted. 
    • Metabolic acidosis.
• During treatment with co-trimoxazole, an adequate urinary output should be maintained. 
  • Evidence of crystalluria in vivo is rare, although sulfonamide crystals have been noted in cooled urine from people treated with co-trimoxazole. The risk may be increased in people who are malnourished.

[ABPI, 2022d; BNF, 2022]

What are some possible adverse effects of co-trimoxazole?

• The most common adverse effects of co-trimoxazole are nausea, diarrhoea, headache, hyperkalaemia, rash, fungal overgrowth, and skin reactions.
• Consider pseudomembranous colitis (an acute, exudative colitis caused by an overgrowth of Clostridium difficile bacteria) if a person develops severe diarrhoea during or after treatment with co-trimoxazole. See the CKS topic on Diarrhoea - antibiotic associated for more information.
• Blood disorders (including leucopenia, thrombocytopenia, anaemia, and eosinophilia) are rare, but serious, adverse effects.
  • Discontinue treatment with co-trimoxazole immediately if blood disorders develop.
• Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been rarely reported.
  • Advise people taking co-trimoxazole to monitor closely for skin reactions. The highest risk for occurrence of SJS, TEN, or DRESS is within the first weeks of treatment.
  • If symptoms or signs of SJS, TEN, or DRESS (for example progressive skin rash often with blisters or mucosal lesions) occur, discontinue treatment with co-trimoxazole.
  • If a person develops SJS or TEN with the use of co-trimoxazole, co-trimoxazole must not be re-started at any time.
• Other adverse effects include:
  • Uncommon, rare, and very rare
    
    • Immune system disorders, such as anaphylactic reactions, allergic myocarditis, systemic lupus erythematosus, and severe hypersensitivity reactions.
    • Metabolism and nutrition disorders, such as hypoglycaemia, hyponatraemia, decreased appetite, and metabolic acidosis.
    • Psychiatric disorders, such as depression, hallucination, and psychotic disorder.
    • Nervous system disorders, such as ataxia, dizziness, peripheral neuropathy, and seizure.
    • Ear and eye disorders, such as vertigo, tinnitus, and uveitis.
    • Respiratory disorders, such as cough, dyspnoea, and lung infiltration.
    • Gastrointestinal disorders, such as glossitis, stomatitis, pancreatitis, and vomiting.
    • Hepatobiliary disorders, such as cholestatic jaundice and increased transaminases,
    • Musculoskeletal and connective tissue disorders, such as arthralgia and myalgia.
    • Renal and urinary disorders, such as renal impairment, tubulointerstitial nephritis, and renal tubular acidosis.
  • Frequency not known
    • Acute febrile neutrophilic dermatosis (Sweet's syndrome).

[ABPI, 2022d; BNF, 2022]

What are some possible drug interactions with co-trimoxazole?

Possible drug interactions of sulfamethoxazole and/or trimethoprim include:

• Amiodarone — co-trimoxazole is predicted to increase the risk of QT prolongation and ventricular arrhythmias with amiodarone, but clinical evidence for this is sparse.
  • Increasing age, female sex, cardiac disease, and some metabolic disturbances (notably hypokalaemia) predispose to QT prolongation; in their presence, consider ECG monitoring.
• Azathioprine — there is some evidence that the risk of haematological toxicity may be increased in people taking azathioprine if they are treated with co-trimoxazole, particularly if given for extended periods. However, other evidence suggests that the drugs may be used together safely. 
  • Monitor full blood count when azathioprine is used. If any abnormalities arise, consider this interaction as a possible cause.
• Ciclosporin — sulfamethoxazole, either alone or with trimethoprim, may increase serum creatinine concentrations in people with a kidney transplant who are taking ciclosporin. Interstitial nephritis, granulocytopenia, and thrombocytopenia have been reported in a few people.
  • If concurrent treatment is indicated, increase monitoring of ciclosporin concentrations.
• Clozapine — sulfamethoxazole and trimethoprim may increase the risk of neutropenia when given with clozapine.
  • Avoid concurrent treatment.
• Drugs that increase the risk of hyperkalaemia —concurrent use with co-trimoxazole may result in clinically relevant hyperkalaemia.
  • Exercise caution in people taking other drugs that can cause hyperkalaemia, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and spironolactone. 
  • Monitor potassium concentrations. Avoid, where possible, in elderly people with or without chronic renal impairment. 
• Digoxin — concurrent use of trimethoprim with digoxin has been shown to increase plasma digoxin levels, particularly in older people.
  • If symptoms of digoxin toxicity are present (for example, nausea, anorexia, or disturbance of colour vision), check serum digoxin levels and reduce the dose if necessary.
• Methotrexate — co-trimoxazole may increase free plasma levels of methotrexate. In addition, methotrexate and trimethoprim are both anti-folate drugs.
  • Avoid concurrent use with co-trimoxazole. If co-trimoxazole treatment is necessary, consider prescribing a folate supplement.
• Phenytoin — co-trimoxazole prolongs the half-life of phenytoin, and co-administration could result in increased serum phenytoin levels.
  • If symptoms of phenytoin toxicity are present (confusion, blurred vision, nystagmus, ataxia, or drowsiness), monitor serum phenytoin levels and reduce the dose if necessary.
• Repaglinide — hypoglycaemia has been reported following the use of co-trimoxazole and repaglinide.
  • If concurrent use is indicated, monitor closely and adjust the dose of repaglinide if necessary.
• Sulfonylureas — cases of acute hypoglycaemia have been reported following concurrent use of gliclazide and co-trimoxazole. Cases have also been reported following concurrent use with other sulfonylureas.
  • Increase blood glucose monitoring, and adjust the dose of the sulfonylurea if necessary.
• Warfarin — co-trimoxazole has been shown to potentiate the anticoagulant activity of warfarin via stereo-selective inhibition of its metabolism. Sulfamethoxazole may displace warfarin from plasma-albumin protein-binding sites in vitro.
  
  • Monitor the international normalised ratio (INR), and adjust the warfarin dose as necessary.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of co-trimoxazole. However, advise women on the importance of correct contraceptive practice if they experience vomiting or diarrhoea.

[ABPI, 2022d; BNF, 2022]