Recommendations on minimizing/ preventing fatalities due to medication errors and severe hypersensitivity reactions when administering antibiotics

Background

Medication errors can occur when deciding which medicine and dosage regimen to use (e.g. inappropriate, overprescribing); writing the prescription (prescription errors); dispensing the formulation (wrong drug, wrong formulation, wrong label); administering the medicine (wrong dose, wrong route, wrong frequency, wrong duration); and monitoring therapy (failing to alter therapy when required, erroneous alteration). These errors could lead to adverse events and adverse drug reactions.

Anaphylaxis is a severe type of adverse drug reaction which could result in high morbidity and mortality. Among all the causes, medications are the most common cause for anaphylaxis worldwide. Antibiotics are the main culprit for drug induced anaphylaxis. Further, drugs as the elicitor of anaphylaxis has the highest mortality associated with it.

Anaphylaxis is a life threatening sever immune mediated hypersensitivity reaction and occurs due to biding of specific IgE to receptors on mast cells which lead to release of histamines, proteases and other inflammatory mediators from activated mast cells. Immune mediated anaphylaxis has a memory response; hence the culprit drug and the cross reactive agents should be avoided. However, some severe reactions can also occur due to direct mast cell activation and degranulation without the involvement of IgE antibodies which are described as “non-immunologic anaphylaxis” or “anaphylactoid” reactions. These non-immune mediated reactions are dose and rate dependent and usually occur due to rapid intravenous administration of higher doses of antibiotics.

SLCM intends to give recommendations in order to minimize fatalities due to medication errors and severe adverse reactions including anaphylaxis in view of the recent events of several cases of antibiotic associated anaphylaxis reported in the country and to ensure patient safety when administering antibiotics.

1. Rational prescribing and minimize use of antibiotics

Minimize exposure to antibiotics by rational prescribing is the best way to prevent fatalities from all adverse effects including allergic reactions in addition to prevention of development of bacterial resistance. Therefore, restrict antibiotic use, particularly beta-lactams, only for essential indications.

1.1. Basic principles of rational use of empirical antibiotics 

• Do not prescribe antibiotics for viral or self-limiting bacterial infections.
• Interpret basic laboratory results (high CRP, procalcitonin, white cell count) cautiously with the clinical presentation of the patients.
• Start antibiotics only for a suspected bacterial infection after obtaining relevant specimens for microscopy, culture and antibiotic sensitivity or other appropriate microbiology investigations for aetiological diagnosis. When a specific diagnosis is not possible follow the syndromic approach.
• In patients, diagnosed with sepsis or septic shock, (diagnosed by using a recommended score such as systemic inflammatory response syndrome criterion, National Early Warning Score(NEWS-2), or Modified Early Warning Score (MEWS)), start broad spectrum antibiotics early (within 1 hour) after collecting at least 2 blood cultures (start smart then focus).
• Empirical antibiotics should only be started in critically ill or systemically unwell patients with an infectious disease in instances where we cannot wait for the culture and sensitivity results. Use evidenced based guidelines to choose the narrowest possible antibiotic when a bacterial infection is suspected and only when there is likely to be a clear clinical benefit (National guideline for empiric and prophylactic use of antimicrobials, 2016 (under review). Antibiotic Guidelines 2016
• Review the patients with culture results and other relevant investigations and the empirical antibiotics should be switched to targeted antibiotics as early as possible.
• Avoid prescription of multiple antibiotics unless in special circumstances such as severe immunosuppression or specified by guidelines.
• Evidence for use of prophylactic antimicrobials are only available for limited clinical situations and avoid unnecessary use of antibiotics.
• Enhance timely and adequate source control for surgical infections and avoid using antimicrobials as the sole management option in such situations.
• Whenever possible, inform the patient and/or responsible caregiver about the reason for antimicrobial treatment and potential side effects and ensure that the patient understands the dosage and duration of treatment.

1.2. Appropriate use of intravenous antibiotics

There is substantial evidence that intravenous (IV) administration of antibiotics results in higher risk of immunologically and non-immunologically mediated allergic reactions in addition to the complication due to vascular access. Therefore, the intravenous antibiotics should only be used if indicated.

1.2.1. Indications for intravenous administration of antibiotics

• Sepsis or deteriorating clinical condition due to bacterial infection irrespective of site
• Fever and neutropenia / immunosuppression
• When effective oral antibiotic options are not available
• Deep seated infections where antibiotic penetration is poor
• Infection where initial IV therapy is mandatory
  • Endocarditis, CNS infection, S. aureus bacteraemia, Vascular graft infection
• Infection requiring antibiotics but oral route compromised - Nil by mouth, reduced gastrointestinal absorption, mechanical swallowing disorder, severe vomiting etc.

1.2.2. Discipline in intravenous administration of antibiotics

Administering intravenous (IV) antibiotics requires proper technique and adherence to aseptic procedures to prevent introduction of infection and to minimise adverse reactions including allergies.

Following are the important aspects to be considered in administering IV antibiotics:

• Medication compatibility: Confirm the compatibility of the prescribed medication with other prescriptions/medications or fluids that may be administered concurrently. Some medications can interact or precipitate when they are mixed, leading to adverse effects or reduced effectiveness. DO NOT MIX antibiotics with any other medication. Always infuse IV antibiotics separately and leave a gap between injections/infusions.
• Dosages: Calculate and verify the medication dosages accurately, according to the indication and the site of infection and the adjustments may be needed according to current/latest renal and liver functions. Both under and over dosage can cause serious harmful effects. Pay attention to units of measurement, concentration, and infusion rates to prevent dosage errors.
• Patient identification: Use at least two patient identifiers (e.g., name, date of birth) to confirm the patient’s identity before administering any medication. This ensures that the medication is being given to the correct patient.
• Expiration date: Ensure that the antibiotics and the diluents are not expired. Expired products may lose their effectiveness or have increased risks of contamination.
• Reconstitution of the antibiotic: Reconstituting antibiotics correctly is crucial to ensure the effectiveness and safe administration. Intravenous (IV) drugs are supplied by pharmaceutical manufacturers to the hospitals in a variety of forms like,
  • Lyophilised powders requiring aqueous diluents for reconstitution
  • Lyophilised powders requiring aqueous diluents without preservatives for reconstitution
  • Lyophilised powders supplied with special diluents for reconstitution
  • Aqueous solutions ready to administer
  • Non aqueous solutions ready to administer

If reconstitution is needed, it has to be done according to the manufacturers’ guidelines with the recommended diluent at the bedside of the patient not as batches in the nursing stations. Keeping reconstituted antibiotics and left-over diluents over extended times should be avoided. Most IV antibiotics cannot be stored once reconstituted. Avoid administration of the antibiotic if there is a colour change or haziness observed after reconstitution.

• Infusion rates: Administer IV medications according to the prescribed rate by the manufacturer to ensure expected outcome and minimise adverse effects. Use infusion pumps when necessary to maintain precise control over the infusion rate.
  • Most IV antibiotics are given as slow boluses over 3-5 minutes with or without reconstitution. This may vary with different brands of the same antibiotic.
  • Certain antibiotics are required to be further diluted with a larger volume of recommended/compatible solution/s after reconstitution, which should be infused slowly over a long-fixed time durations (E.g. vancomycin, piperacillin-tazobactam, amphotericin B). Refer to the manufacturer's instructions or consult with a pharmacist or related healthcare professional for specific guidance.
  • Certain formulations are required to be started with a defined slower rate for a few minutes before giving in the normal rates of infusions (such as loading doses).
• Inform and monitor the patients: Educate the patient when an antibiotic is given and the possible immediate adverse effects. Closely monitor the patient for any signs of adverse reactions, such as allergic reactions, respiratory distress, or changes in vital signs for first 30 minutes after a slow bolus and during full time for infusions. Do not let the patient to get down from the bed after administration of an intravenous antibiotic.
• Emergency medication and equipment: Make sure that all the necessary medications (e.g. Adrenalin), equipment (e.g. O2 mask, nebulizer, and intubation equipment) and O2 are available readily to manage anaphylaxis. Anaphylaxis management protocols and algorithms should be available/ displayed in each ward/ unit.
• Identification and management of an immediate hypersensitivity reaction: All medical officers and nursing officers should be able to recognise symptoms and signs of a severe allergic reaction. In case of an immediate reaction with systemic symptoms (severe generalised urticaria/ mucosal swellings, nausea, abdominal cramps, diarrhoea, chest or throat tightness, shortness of breath, wheezing, light headedness, loss of consciousness, low BP, rapid clammy pulse, low SpO2), call for help and stop infusion/ administration of the antibiotic immediately. Manage anaphylaxis immediately with IM Adrenalin 0.5mg (1:1000) and according to the guideline.

2. Proper labelling and de-labelling of patients with antibiotic allergies and appropriate management of patients with a history of beta-lactam antibiotic allergy

Appropriate labelling of patients following a reaction to an antibiotic is important in order to prevent future episodes that may even be fatal. However, all adverse events experienced by a patient following use of antibiotics are not due to an allergic reaction/ type 1 hypersensitivity reaction. Inaccurate allergy labels may lead to the use of antibiotics with a broader spectrum, lower efficacy or increased side-effects. In addition, alternative antibiotics may lead to the development of hospital acquired infections, high cost of care and development of resistant organisms. Therefore, accurate labelling and de-labelling of antibiotic allergy is an important consideration in antibiotic stewardship

2.1. Proper labelling and de-labelling of antibiotic allergy

Following is a guide to follow for accurate labelling and de-labelling of antibiotic allergy

• A comprehensive evaluation of the reaction should be done.
  • If the reaction occurs in the hospital setting or if the patient presents with an allergic reaction while on treatment, the medical officer/ house office should document the names of antibiotics and the names of other drugs if used simultaneously, type of reaction including features of anaphylaxis if present, timing of the reaction in relation to the drug administration, whether the reaction occurred with the first dose or subsequent doses (dose number) and document how the reaction was managed in the ward.
  • If the patient conveys a history of a previous reaction to antibiotics as a historical event, all efforts should be taken to document whether the reaction was likely a type 1 hypersensitivity reaction and details of the reaction as mentioned above. In addition, subsequent use of antibiotics and the antibiotics that the patient had tolerated should be documented.
• All patients who had a confirmed or presumptive diagnosis of drug allergy should be issued a diagnosis card indicating the name/s of the culprit drug and other cross reactive drugs.
• Patients should be educated on how to recognize a type 1 hypersensitivity reaction and should be advised to carry antihistamines, adrenaline if indicated along with clear instructions on what to do if a subsequent reaction develops outside of the hospital.
• All patients with a diagnosis of drug allergy should be advised to show their diagnosis card prior to any treatment including local applications and vaccination.
• Where the history is unclear or a confirmation of the allergy is required, patient should be referred to an allergist early. Delay in presentation may lead to inability to confirm by testing as patients may lose IgE with time. Confirmation is done by accurate history, skin prick test followed by intradermal test and oral challenge where necessary.
• Pre-testing is not beneficial in a patient without a history of drug allergy. Irrational skin tests without the use of control tests may lead to irritant skin reactions and inaccurate labelling. Similarly, intradermal testing with inappropriate concentrations can cause false labelling due to irritation and if done without preceding skin tests, they may lead to development of severe reactions including anaphylaxis during test. In addition, such testing may give a false sense of security which may lead to the poor management of a subsequent reaction. Therefore, incorrect and irrational skin or intradermal testing should not be done for labelling or de-labelling of allergy.

2.2. Appropriate management of patients with a history of beta-lactam antibiotic allergy

• All patients who had a confirmed or presumptive diagnosis of beta-lactam allergy should be managed with an alternative antibiotic regimen considering the cross reactivity of antibiotics in the same class.
• The appropriate antibiotic options can be decided by evaluating the history and categorizing the patients into 3 risk groups; low risk (pruritus without rash, a remote of >10 years), moderate risk (mild urticaria or mild reactions with features of IgE-mediated allergy but not anaphylaxis) and high risk (anaphylaxis, recurrent beta-lactam reactions, severe urticaria/ angioedema).
• In patients with moderate to high risk, a non-betalactam antibiotic should be considered. However, if a beta-lactam antibiotic is absolutely indicated, an Immunologist should be consulted.
• In patients with a lower risk, a non-cross reactive beta-lactam can be considered. Consult an Immunologist/ Microbiologist when deciding on a non-cross reactive antibiotic. A graded challenge can be attempted with the culprit antibiotic for de-labelling after consultation with an Immunologist.
• The antibiotics that the patient could tolerate should be recorded in all patient records for future reference.

3. Training and Education

Continuous education and training programmes should be conducted to medical and nursing offices on medication errors and patient safety.

3.1. Short term measures

• Organize island wide training workshops in all hospitals for doctors and nurses on rational prescribing of antibiotics, adverse reactions including allergy, patient safety, IV drug reconstitution and administration and identification, management, and prevention of anaphylaxis by collaboration with college of Intensivists/Anesthetist/ Critical-care Medicine/ Microbiologists etc.
• Develop policy document for the country on identification and management of antibiotic hypersensitivity reactions.
• Develop guidelines for identification and management of anaphylaxis should be prepared for each hospital and the management algorithms should be displayed visibly in all treatment areas.
• Organize public awareness on antibiotic allergy, early identification, and prevention of future episodes through mass media (College of anesthetists / intensivists/ critical care medicine/ microbiologists)

3.2. Intermediate and long-term measures

• Organize educational programmes on patient safety, adverse reactions and safety goals to all medical officers.
• Training workshops on ‘Identification and management of anaphylaxis’ to be included in the induction programs conducted by hospitals for all intern house officers and nurses before commencement of their duties. Simulation activities can be arranged if facilities are available.
• Conduct continuous staff education and training programs for doctors on types of hypersensitivity reactions to antibiotics (anaphylaxis, mild to moderate reactions, immediate and delayed reactions, immunological and non-immunological reactions), cross reacting antibiotics and the types of antibiotics which need to be avoided and given with caution.
• Antibiotic allergy, identification and management of anaphylaxis should be included in the undergraduate and post graduate medical training programs of all clinical specialties as a mandatory component.
• ‘Antibiotic reconstitution and correct administration’ and ‘Early identification and management of anaphylaxis’ to be included as a mandatory component in nurses undergraduate training program and should be included in their practical assessment.

4. Timely reporting of incidents of severe allergic reactions to relevant authorities

• Fill in relevant forms in a timely manner with all the details of the reaction
• Reporting to Head of Institution for further investigation if needed

5. Ensuring quality of antibiotics

• Emphasizing the importance of registration of good quality antibiotics (FDA, EUA registered) to make sure that the antibiotics do not contain impurities during manufacturing process
• Ensure that the antibiotics which are available in private sector pharmacies are all registered under NMRA

Date: 18.08.2023

Resource persons:

1. Mahen Kothalawala
2. Nadisha Badanasinghe
3. Dhanushka Dasanayake
4. Madhumanee Abeywardhene
5. Dhananja Namalie
6. Dilini Nakkawita
7. Wasana Kudagammana