Version May 2024
INTRODUCTION — This topic will review hypersensitivity (allergic) reactions to macrolides, aminoglycosides, tetracyclines, clindamycin, and metronidazole. Hypersensitivity reactions to other antibiotic classes, namely beta-lactams, sulfonamides, fluoroquinolones, and vancomycin, are discussed separately.
●(See "Penicillin allergy: Immediate reactions".)
●(See "Cephalosporin hypersensitivity: Clinical manifestations and diagnosis".)
●(See "Sulfonamide allergy in HIV-uninfected patients".)
●(See "Hypersensitivity reactions to fluoroquinolones".)
●(See "Vancomycin hypersensitivity".)
OVERVIEW — The antimicrobial groups discussed in this review cause hypersensitivity reactions relatively infrequently compared with penicillins, cephalosporins, sulfonamides, and fluoroquinolones [1,2].
Types of hypersensitivity reactions — Hypersensitivity reactions, or allergic reactions, are immunologic reactions to a drug. There are many types of hypersensitivity reactions, which are broadly divided into immediate and delayed reactions, based upon the time between the first administered dose and the appearance of signs or symptoms [3]:
●Immediate reactions are defined as reactions that begin within one hour of the first administered dose. In reality, symptoms and signs may appear up to one to two hours later if the drug was taken orally or with food or other medications that slow absorption. The most common signs and symptoms of immediate reactions are urticaria (picture 1 and picture 2), pruritus, flushing, angioedema of the face, extremities, or laryngeal tissues (leading to throat tightness with stridor or rarely, asphyxiation), wheezing, nausea, abdominal cramping or diarrhea, and/or hypotension or shock. Immediate reactions can be caused by the formation of immunoglobulin E (IgE) to the causative drug, which can then activate mast cells and basophils in the presence of the drug. Some drugs can cause immediate reactions by directly or indirectly activating mast cells and basophils, without the presence of drug-specific IgE. Immediate-type skin testing is used to evaluate immediate reactions. (See 'Allergy evaluation' below.)
●Delayed reactions begin later than one hour (and sometimes days) after the first dose. Many different reaction types are classified as delayed. The most common are maculopapular or morbilliform exanthems (picture 3 and picture 4). There is a lack of consensus about how best to evaluate patients with past maculopapular exanthems. Some allergy experts perform intradermal skin testing that is interpreted 24 to 72 hours after placement, with erythema and induration representing a positive reaction. Others only perform graded challenges to diagnose such reactions, which is the most common approach in the United States.
There are several types of delayed hypersensitivity reactions that are uncommon but potentially life-threatening for which no testing is informative. Furthermore, testing can be dangerous because re-exposure can cause a recurrence of the reaction. Such reactions include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DiHS).
The intent of discriminating between immediate and delayed drug reactions is to distinguish immediate reactions from other types, since immediate reactions can escalate to potentially life-threatening anaphylaxis if the patient is re-exposed to the causative drug, even in very small amounts.
The classification and pathogenesis of drug hypersensitivity reactions are reviewed in greater detail separately. (See "Drug hypersensitivity: Classification and clinical features" and "Drug allergy: Pathogenesis".)
Clinical history — Evaluation of a patient with a past drug reaction always begins with a careful clinical history and an assessment of the type of hypersensitivity reaction the patient most likely experienced. Important questions for the patient with drug allergy are reviewed separately. (See "An approach to the patient with drug allergy", section on 'Clinical history'.)
A thorough history of the reaction is essential and usually constitutes the most useful element of the evaluation. Many patients labeled as allergic to a drug actually experienced nonallergic adverse reactions. Common examples include gastrointestinal side effects with macrolides and tetracyclines or photosensitivity with tetracyclines. In some cases, such patients should continue to avoid the causative drug, but they are not candidates for further allergy evaluation.
Referral — Referral to an allergy expert with experience in drug-allergic reactions is appropriate in any of the following situations:
●The patient has reactions to numerous antibiotics, and treatment options are becoming limited.
●The patient experienced a life-threatening reaction to a drug and requires advice about how best to prevent re-exposure and whether related antibiotics can be safely administered.
●The patient experienced a serious reaction in the context of receiving multiple drugs (eg, perioperative anaphylaxis), and the cause of the reaction is not clear.
●The patient has a high likelihood of needing future treatment with a certain drug due to the nature of his/her underlying medical problems.
Allergy evaluation — The clinical history is the most important component of a drug allergy evaluation. Other tools that are widely used include immediate-type skin testing and graded challenge. These procedures should be performed by allergy specialists because they require experience to interpret correctly, and although they are considered safe interventions, there is a risk of inducing another allergic reaction. Skin testing and challenges should be performed in a setting prepared to treat possible severe reactions, including anaphylaxis. In addition, any procedure that involves the deliberate exposure of a patient to a substance to which he/she may be allergic should be undertaken by someone with specific training in these techniques.
Immediate-type skin testing — Skin testing (prick-puncture and intradermal) is helpful in the evaluation of immediate reactions to some drugs. Briefly, prick-puncture skin testing should be performed first, along with positive and negative controls. If prick-puncture tests are negative, they are followed by intradermal skin testing. Skin test results are recorded 15 minutes after placement in the skin. Skin testing techniques and patient preparation are described in detail elsewhere. (See "Overview of skin testing for IgE-mediated allergic disease", section on 'Prick/puncture method' and "Overview of skin testing for IgE-mediated allergic disease", section on 'Intradermal method'.)
Unlike skin testing for penicillin allergy, skin testing for allergy to the drugs discussed in this review is not standardized or validated, and allergy experts may have different approaches.
Graded challenge — Graded challenge procedures may be required in the evaluation of antibiotic hypersensitivity. Challenges are mentioned briefly here. Indications, contraindications, and protocols are discussed in detail separately. (See "An approach to the patient with drug allergy", section on 'Graded challenge and drug provocation'.)
Graded challenge is used to exclude allergy to the medication in question and is most appropriate for a patient who is unlikely to be allergic to that drug.
Graded challenge does not modify the allergic response to the drug or prevent recurrent reactions. Therefore:
●Patients who tolerate a drug upon graded challenge prove that they are not allergic to it.
●A challenge procedure in a patient with a possible IgE-mediated drug allergy could potentially induce anaphylaxis and should be performed by an allergy expert in a setting prepared to identify and manage possible reactions.
Challenges with the drug in question should not be performed in patients whose past reactions involved exfoliation, blistering, or sloughing of the mucous membranes or skin (eg, erythema multiforme, SJS/TEN) or inflammation of internal organs (DRESS/DiHS), since even small amounts of the suspect drug can reactivate these reactions.
MACROLIDES — Commonly used macrolide antibiotics include erythromycin, clarithromycin, and azithromycin. Nonallergic adverse effects, such as QT interval prolongation and gastrointestinal symptoms, are reviewed separately. (See "Azithromycin and clarithromycin", section on 'Adverse reactions'.)
Types of reactions — Allergic reactions due to macrolides are less common than reactions to beta-lactam antibiotics, sulfonamide antibiotics, and fluoroquinolones [4,5]. Most patients reporting macrolide reactions prove not to have a serious allergy. If patients from the largest published series are combined (in which most or all subjects, skin test-positive and skin test-negative, undergo graded challenge), the cumulative rate of reactions upon challenge with the culprit drug in patients with history of convincing macrolide allergy was 5 percent (13 of 255 subjects), and most reactions were mild [6-9].
The following studies address specific types of reactions:
●Immunoglobulin E (IgE)-mediated reactions to macrolides are rare and largely confined to anecdotal case reports [10-14].
●The vast majority of skin reactions are maculopapular exanthems:
•In an analysis of over 40 clinical trials of children treated with azithromycin for various bacterial infections, 29 of 2655 (1.1 percent) developed skin eruptions [15]. Of note, this study was not designed to include control patients treated with placebo, and 1 percent is a common rate of skin eruption to placebo in other drug studies.
•A retrospective analysis of a general practice database of 150,000 mostly adult patients over an 18-month period revealed an incidence of macrolide-related cutaneous reactions of 1.1 percent [5]. Again, there was no placebo group for comparison.
•Several large-scale pediatric trials have compared treatment of otitis media with azithromycin versus amoxicillin-clavulanate [16-21]. The safety data in these studies reported rates of cutaneous eruptions 0.3 to 1.7 percent for azithromycin and 2.0 to 5.2 percent for amoxicillin-clavulanate.
Cross-reactivity — There are substantial differences in structure among macrolides with different sized lactone rings, and one would not expect extensive cross-reactivity [22]. However, the allergic determinants of macrolide molecules have not been identified.
Data regarding allergic cross-reactivity among macrolides are limited to case reports and small series. In these, the majority of patients who reacted to one macrolide (mostly with delayed reactions) tolerated other macrolides, suggesting little allergic cross-reactivity [23-26]. However, most patients were only challenged with a macrolide different from the one that caused the initial reaction. Although understandable, this approach is not sufficient to prove lack of cross-reactivity, because many patients will also tolerate the culprit drug if it is given again. To conclusively study cross-reactivity, challenges to both drugs should be performed in close temporal association, which is not typically done, but there are rare reports of patients demonstrating convincing allergic reactions to multiple different macrolides [14,27].
Evaluation — History is an essential first step in evaluating patients who report an allergy to macrolides. If the patient's history suggests an immunologic reaction, referral to an allergy expert may be appropriate, although this is usually not warranted in patients who report past allergic reactions only to macrolides, because there are multiple alternative groups of antibiotics. Possible exceptions to this include patients predisposed to sinopulmonary infections because macrolides are very useful for these infections. (See 'Referral' above.)
Our approach — We suggest performing skin testing in patients whose past reactions had features of immediate reactions, such as pruritic rashes, urticaria, or angioedema. Others have argued that it is not sufficiently helpful and instead advocate performing challenge directly [9,28].
●In the author's clinic, azithromycin is the only macrolide used for skin testing. We use the highest nonirritating concentration of azithromycin, which is 0.01 mg/mL (a 1:10,000 dilution of the commercially available 100 mg/mL intravenous [IV] formulation) [29].
●Clarithromycin is not commercially available in the United States in an IV formulation, and no data are available about using oral formulations of clarithromycin for skin testing. In countries where IV clarithromycin is available, studies have used concentrations ranging from 0.5 mg/mL to approximately 0.05 mg/mL (corresponding to a 1:100 to a 1:1000 dilution of the commercial formulation), which were reported as nonirritating in previously unexposed subjects [8,30]. Of note, the study which used 0.05 mg/mL found 0.167 mg/mL to be irritating in some patients, so we suggest using the more dilute concentration.
●We do not test with erythromycin, since it is used less commonly.
Although the positive predictive value (PPV) of macrolide skin testing was low in the studies discussed below, we advise patients with positive skin test results to avoid the drugs in question, in part because there are usually equivalent alternative antibiotics. If they require treatment with a specific macrolide and there are no acceptable antibiotic alternatives, we administer it using a desensitization protocol, which has been described in the published literature [27]. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)
In patients with negative macrolide skin testing, the first administration of the macrolide should be via graded challenge, since skin testing does not detect all patients at risk for recurrent reactions. The author's approach to macrolide challenges is described below, and a general discussion of challenges is found separately. (See "An approach to the patient with drug allergy", section on 'Graded challenge and drug provocation'.)
Studies of skin testing — The utility of immediate-type skin testing for IgE-mediated allergy to macrolides has significant limitations, as illustrated in the following studies [6-9,29,31]:
●In a series of 73 consecutive children with cutaneous reactions to clarithromycin, reactions consisted of urticaria (62 percent), angioedema (18 percent), and maculopapular rash (19 percent) [8]. There were no cases of anaphylaxis. Twenty children had immediate reactions, 49 had delayed reactions, and 4 had reactions of undetermined timing. All the children were skin tested (prick-puncture and intradermal, read at 20 minutes and 48 hours) using 0.5 mg/mL of IV clarithromycin, which was found to be the highest nonirritating concentration in 18 control subjects. All patients (except 9 who refused) underwent blinded five-day oral challenges, regardless of the skin test results. Of the 64 challenged subjects, 9 (14 percent) had positive intradermal skin tests at 20 minutes. No patient was positive on prick-puncture tests or 48-hour intradermal tests.
Overall, 4 of 64 patients (6 percent) reacted on challenge: two immediate (urticaria) and two delayed (day 3 and 4) reactions (maculopapular rashes). Three out of 9 skin test-positive patients and 1 of 55 skin test-negative patients reacted on challenge. Thus, based on these small numbers, skin testing had a PPV of 33 percent, negative predictive value (NPV) of 98 percent, sensitivity of 75 percent, and specificity of 90 percent. The authors did not report the skin test and challenge results according to the type of reaction (immediate versus delayed) the patients had originally.
●The same investigators studied 58 additional children with history of clarithromycin allergy (21 immediate reactors and 37 delayed reactors) and 19 with azithromycin allergy (6 immediate reactors and 13 delayed reactors) [31]. All the patients underwent skin testing, using 0.5 mg/mL IV clarithromycin and 0.1 mg/mL IV azithromycin. Unlike the previous study, only skin test-negative patients were challenged with five days of the culprit macrolide. In the clarithromycin group, 7 of 58 (12 percent) had positive skin tests (2 of 21 immediate reactors, 5 of 37 delayed reactors). Among the skin test-negative subjects, 2 of 51 had positive challenges (0 of 19 immediate reactors, 2 of 32 delayed reactors). In the azithromycin group, 9 of 19 (47 percent) had positive skin tests (4 of 6 immediate reactors, 5 of 13 delayed reactors). None of the 10 skin test-negative patients reacted to challenge. Therefore, a higher proportion of children were diagnosed with azithromycin allergy, but the conclusion is uncertain, since the azithromycin skin test concentration used is known to be irritating, and none of the skin test-positive patients were challenged.
●In a similar series of 45 pediatric patients referred for clarithromycin allergy (urticaria, angioedema, and maculopapular rashes), 9 (20 percent) had immediate reactions, and 36 had delayed reactions [28]. Twenty of the patients were skin tested (up to 0.05 mg/mL intradermally), and all the patients underwent graded challenge with clarithromycin (one day for immediate reactors, five days for delayed reactors). Nine patients had positive skin tests, but none of them reacted on challenge. Two of 11 patients with negative skin tests developed urticaria on challenge. None of the 25 patients who were challenged without prior skin tested reacted. Hence, overall, only 2 of 45 (4 percent) of the patients were confirmed to be allergic, and skin testing performance was poor (PPV 0 percent, NPV 82 percent, sensitivity 0 percent, and specificity 50 percent).
●Another series consisted of 107 consecutive patients evaluated over a five-year period for suspected macrolide allergy [6]. Eleven percent of reactions were immediate, 66 percent were delayed, and 23 percent were of unknown type. Five percent of the patients reported anaphylaxis, 53 percent reported urticaria and/or angioedema, 24 percent reported maculopapular rashes, and the rest were unknown. Skin testing (prick-puncture and intradermal) was carried out in only 33 patients using macrolide concentrations of 10 mg/mL (there is no mention of a control group). The other 74 patients were not skin tested. All the patients (regardless of skin test results) underwent single-blinded challenges with the culprit macrolide, and 8 of 107 (7.5 percent) reacted, one-half of whom had positive skin tests. In the challenge-negative group, 7 of 25 had positive skin tests. The eight reactions to challenge consisted of four maculopapular rashes, three urticarial reactions, and one case of anaphylaxis, although all were easily treated. Although the study's usefulness was limited by the low percentage of patients skin tested, the PPV of skin testing was 36 percent, NPV was 82 percent, sensitivity was 50 percent, and specificity was 72 percent.
Graded challenge — Graded challenge can be performed with or without prior skin testing, as discussed previously. It is useful for patients with either immediate or delayed past reactions. We prefer to challenge with azithromycin (rather than other macrolides) because it is available in both parenteral and oral formulations to treat future infections. Also, azithromycin has a more favorable gastrointestinal side effect profile compared with other macrolides. Patients with recent severe anaphylaxis should undergo rapid desensitization rather than graded challenge. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)
A representative macrolide graded challenge starts with 1/100th of the full dose and includes two to four steps until the full dose is reached. The degree of caution exercised may be adjusted based upon the severity of the historical reaction and the time elapsed since the reaction.
●For patients with immediate past reactions, such as a pruritic rash five years ago, an oral challenge with 2.5 mg, 25 mg, and 250 mg azithromycin, given hourly under observation would be suitable.
●For patients with delayed past reactions, the author's approach to challenge is to administer 25 mg azithromycin, observe for one hour, and then administer 250 mg, and observe for an additional hour. The reason for giving the initial dose under observation is the author's experience that, unless the patient knows that the drug can be safely ingested, there may be continued reluctance to use it in the future. A delayed reaction may occur during the 24 hours following the initial dose, and patients should be instructed to inform the clinician if this occurs.
It is important to understand the limitations of challenge procedures for delayed maculopapular exanthema. Some of these reactions only recur after several days of therapy, and there is no practical way to elicit such reactions without administering a full therapeutic course. This should be explained to patients.
After completion of the challenge procedure, patients who do not need the antibiotic at that time can simply take it normally in the future. Patients who need macrolide therapy at that time can continue the treatment for a full course.
If a patient develops a mild exanthema during future courses of therapy, it may be reasonable to attempt to continue the drug and add antihistamine therapy, provided that the reaction lacks any worrisome features. This approach has not been formally studied and is only appropriate when the benefit of continued treatment clearly outweighs the risk of further reaction. Such situations require clinical judgement.
AMINOGLYCOSIDES — Aminoglycosides have been in widespread clinical use since the 1940s and are generally well-tolerated. The main nonallergic adverse effects are nephrotoxicity and ototoxicity, as reviewed elsewhere. (See "Aminoglycosides", section on 'Toxicity'.)
Types of reactions — Aminoglycosides uncommonly cause allergic reactions, with the notable exception of allergic contact dermatitis (a type IV immunologic reaction) to topical aminoglycosides. Allergic contact dermatitis due to topical neomycin is common, and neomycin is included in the T.R.U.E. TEST panel and other commercial patch test products [32,33]. Gentamicin in eye and ear drops is implicated in contact dermatitis less often [34]. (See "Patch testing".)
Immunoglobulin E (IgE)-mediated reactions to aminoglycosides are rare, with only a few reported cases of anaphylaxis [35-42].
Allergic cross-reactivity among aminoglycosides in all types of allergic reactions appears to be extensive, based primarily on patch test data for contact dermatitis and on anecdotal reports of patients developing reactions of other types from multiple aminoglycosides [37,43-45]. Therefore, patients allergic to one aminoglycoside should avoid the entire class.
The evaluation of patients with possible allergy to aminoglycosides is warranted only if there is an imminent need for treatment with this class of antibiotics. This clinical scenario is most often encountered in patients with cystic fibrosis.
Skin testing for immediate reactions — In two patients with immediate reactions, IgE-mediated allergy was confirmed by positive prick-puncture skin testing with gentamicin [35,37,41,42]. If skin testing is pursued, the highest nonirritating concentration of aminoglycoside should be used [29]. We suggest the following concentrations for both prick-puncture and intradermal testing:
●Gentamicin – 0.4 mg/mL (1:100 dilution of the commercially available 40 mg/mL intravenous [IV] solution).
●Tobramycin – 4 mg/mL (1:10 dilution of commercially available 40 mg/mL IV solution).
●Streptomycin – 0.1 to 1 mg/mL initially [39], potentially increasing (if negative) to concentrations as high as 20 mg/mL [46]. Of note, there is a case report of anaphylaxis to prick-puncture testing with 1 mg/mL, and irritant properties of higher concentrations have not been studied [40,46].
Patients with IgE-mediated allergy to aminoglycosides who require the drug for severe infections and for whom there are no suitable alternatives may undergo rapid desensitization. This has been successfully accomplished with IV tobramycin and with inhaled tobramycin [45,47]. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)
Patch testing for contact dermatitis — Patch testing is valuable in patients with contact dermatitis-type reactions, and since neomycin is one of the most common contact allergens, it is included in the commercially available T.R.U.E. TEST panel [33]. Patch testing is performed by some allergists and by dermatologists. (See "Patch testing".)
TETRACYCLINES — The tetracycline group of antibiotics includes tetracycline, minocycline, doxycycline, demeclocycline, and tigecycline. Newer agents include eravacycline, sarecycline, and omadacycline. Nonallergic adverse effects, such as photosensitivity, are reviewed separately. (See "Tetracyclines", section on 'Adverse reactions'.)
Immunoglobulin E (IgE)-mediated reactions due to the tetracyclines are rare, with only a few published case reports and small series [48-52]. In a report of ten patients, investigators performed intradermal skin testing when prick-puncture testing was negative, whereas only prick-puncture testing had been reported in earlier studies [52]. The non-irritating intradermal concentrations of doxycycline, minocycline, and tigecycline (in non-allergic controls) were found to be 0.001 mg/mL, 0.002 mg/mL, and 0.1 mg/mL, respectively. Five subjects with negative skin testing tolerated graded challenge, but the positive predictive value was not determined, since all subjects with positive skin tests were either successfully desensitized or avoided the drug.
Minocycline — Minocycline appears to be a relatively common cause of severe non-IgE-mediated reactions and is implicated far more often than other tetracyclines [53]. This may be because minocycline is metabolized to reactive intermediates, whereas doxycycline and tetracycline are not [53].
Reactions attributed to minocycline include the following [53-59]:
●Drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DiHS) – In a seven-year prospective study evaluating the incidence of DRESS/DiHS, minocycline was the third most common cause, after carbamazepine and allopurinol [60-63]. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)
●Serum sickness-like reactions [53,55]. (See "Serum sickness and serum sickness-like reactions".)
●Stevens-Johnson syndrome (SJS) [59]. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
●Eosinophilic pneumonia [58]. (See "Overview of pulmonary eosinophilia", section on 'Medications and toxins'.)
●Drug-induced lupus – Minocycline is the only tetracycline associated with drug-induced lupus [53,55,64]. This observation might be due to the fact that minocycline is prescribed much more commonly for long-term use, especially for treatment of acne, whereas doxycycline and tetracycline are more likely prescribed for acute infections with short duration of therapy. It is also possible that minocycline metabolism produces more reactive intermediates capable of possibly binding to major histocompatibility complex (MHC) class II molecules leading to autoimmune reactions. It is important for clinicians to be aware that there may be a long interval between the start of therapy and onset of symptoms. The average time to onset of minocycline-induced lupus is two years after initiation of therapy, and it may be delayed as long as six years [53]. In contrast, the other non-IgE-mediated allergic reactions mentioned above typically appear within one month of initiation of therapy [53]. Minocycline-induced lupus afflicts the same population (predominantly females) as idiopathic lupus. There are no data to support or refute the safety of minocycline or other drugs associated with drug-induced lupus in patients with idiopathic lupus. However, standard practice is to avoid the tetracyclines in patients with lupus. Drug-induced lupus is reviewed in more detail elsewhere. (See "Drug-induced lupus".)
Cross-reactivity — The extent of allergic cross-reactivity among tetracyclines has not been studied. Given that non-IgE-mediated allergic reactions to minocycline are often severe and the natural history of these reactions is unknown, it seems prudent to advise patients with history of severe hypersensitivity reactions to minocycline (or another tetracycline) to avoid all tetracyclines unless there is a compelling reason for use of these drugs. However, there are anecdotal reports of patients with minocycline-induced hypersensitivity reactions who later tolerated other tetracyclines [58].
CLINDAMYCIN — Allergic reactions to clindamycin are uncommon. Clindamycin is a frequent cause of gastrointestinal side effects and also one of the more common causes of Clostridioides difficile colitis, and patients may report these side effects as allergies, although they are not immunologic reactions. Nonallergic adverse effects of clindamycin are discussed elsewhere. (See "Clindamycin: An overview", section on 'Toxicity'.)
Types of reactions — Maculopapular eruptions are reported more than any other type of hypersensitivity. In a retrospective review of inpatient pharmacy and medical records, allergic-type reactions were reported in 0.4 percent (14 of 3896) courses of clindamycin, seven of which were confounded by concurrent administration of other medications, including other antibiotics [65]. Almost all of the reactions were maculopapular eruptions. There were no anaphylactic reactions and no severe non-IgE-mediated reactions.
Based on available literature, anaphylactic reactions to clindamycin are rare [66,67]. Severe non-IgE-mediated reactions, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DiHS) have been reported [68-70].
Evaluation — As with other antibiotics, evaluation of clindamycin allergy should start with a complete history and review of medical records if possible.
Maculopapular eruptions — If the reaction history is compatible with a possible maculopapular eruption, a graded challenge with clindamycin can be performed. A sample protocol for graded challenge with a drug that may have caused a maculopapular eruption in the past is found separately. (See "An approach to the patient with drug allergy", section on 'For delayed reactions'.)
Graded challenge with clindamycin is typically pursued only if patients are likely to require treatment with this antibiotic. This situation is unusual, since the types of bacteria and infections amenable to treatment with clindamycin are relatively narrow compared with other antibiotic classes. Successful desensitization has been described in rare patients who are confirmed to be allergic (eg, such as during graded challenge) and require treatment with clindamycin [71].
For patients with reactions to clindamycin as well as multiple other antibiotics, evaluation of allergies to the other antibiotics should usually be pursued first. This is because other antibiotics (such as penicillins, cephalosporins, and fluoroquinolones) have broader bacterial coverage (and are therefore more clinically useful), allergies to other antibiotics have a better defined natural history, and testing and challenge procedures are more established for other antibiotics.
Neither skin testing nor patch testing appears to be useful for the evaluation of maculopapular eruptions to clindamycin, as demonstrated in the following studies [72-74]:
●In a series of 33 consecutive patients who developed maculopapular rashes while taking clindamycin, evaluation occurred within one year of the reaction in all cases [72]. One-half of patients reported onset of symptoms on days 1 to 6 of the treatment course, the other one-half on day 6 or later. Twenty-seven of the reactions were graded as mild or moderate, and the rest were severe. All subjects underwent prick-puncture skin testing (which was read at 20 minutes and 72 hours) and patch testing, although intradermal skin testing was not performed. Prick-puncture and patch testing were found to be nonirritating in control subjects. Prick-puncture skin testing was negative at 20 minutes in all patients. Five patients had both positive prick-puncture skin tests at 72 hours and positive patch tests, and they were not challenged with clindamycin. Of the remaining 28 patients, 26 underwent graded oral challenges (2 refused) and 6 were positive (3 maculopapular rashes, 2 symmetrical intertriginous exanthems, and 1 fixed drug eruption).
●In a review of 31 patients with delayed-onset reactions temporally associated with clindamycin, all patients underwent prick and intradermal skin testing with readings at 20 minutes and 48 to 72 hours [74]. None of the patients had positive skin tests at the 20-minute reading, whereas two patients were positive at 48 hours. All patients were challenged with a single dose of 150 mg of oral clindamycin. Ten of 31 (32 percent) experienced reactions. Eight occurred two to six hours after challenge and two occurred one to two days after challenge. The reactions consisted of eight pruritic maculopapular rashes, one urticaria, one angioedema, and no severe reactions. Of the two patients with positive-delayed skin tests, one reacted on challenge (maculopapular rash on day 2), and the other patient did not react. Thus, skin testing was not useful for the identification of clindamycin-allergic patients.
METRONIDAZOLE — Metronidazole is an imidazole with structural similarities to clotrimazole, ketoconazole, miconazole, and albendazole. Nonallergic adverse effects are reviewed separately. (See "Metronidazole: An overview", section on 'Toxicity'.)
Hypersensitivity reactions due to metronidazole are rare, with only a small number of case reports in the published literature [75-84]. However, an array of different reaction types (both immediate and delayed) have been reported, including various generalized exanthems, fixed drug eruption [80-82,85], serum sickness-like reaction [83], Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) [84], and anaphylaxis [75].
Based primarily on patch test data (and some challenges), there appears to be a moderate degree of allergic cross-reactivity between metronidazole and other imidazoles [86-88]. Therefore, patients allergic to metronidazole should avoid other imidazoles, such as clotrimazole, ketoconazole, miconazole, and albendazole.
Skin testing — A small number of studies have described skin testing with metronidazole [75,76]. Prick-puncture testing was positive in one case of anaphylaxis [75], although other larger studies suggest that the sensitivity is low. In the largest series, 14 patients with a history of recent (<1 year) cutaneous reactions to Rhodogil (metronidazole plus spiramycin) underwent prick-puncture and intradermal skin testing (20-minute, 48-hour, and 96-hour readings) and oral challenges [76]. Eleven patients were skin test-negative, but three of these reacted to a single-dose challenge of metronidazole, developing pruritic rashes and facial angioedema at 45 minutes, 1 hour, and 7 hours. The remaining 10 patients were skin test-negative and passed challenges with metronidazole and spiramycin. The one patient who was prick test-positive was not challenged.
Thus, in patients in whom the suspicion of an immediate reaction is high based upon the clinical history, we suggest avoidance of all imidazoles in the future. If the patient requires a specific drug and there are no suitable alternatives, a desensitization procedure can be performed [78,89,90]. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)
In patients whose history is not suggestive of a true hypersensitivity reaction or the reaction history is distant and mild, we suggest graded challenge to confirm lack of reactivity.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Drug allergy and hypersensitivity".)
SUMMARY AND RECOMMENDATIONS
●Macrolides, aminoglycosides, tetracyclines, clindamycin, and metronidazole infrequently cause hypersensitivity reactions, compared with penicillins, sulfonamides, and other classes of antimicrobials. (See 'Overview' above.)
●Evaluation of a patient with a past drug reaction always begins with a careful clinical history to determine what type of adverse reaction the patient likely experienced. Hypersensitivity (allergic) reactions are adverse reactions that are mediated by the immune system. Referral to an expert in drug allergy is indicated in specific circumstances. (See 'Referral' above.)
●The pathogenesis of hypersensitivity reactions to the antibiotics discussed in this review is not well-characterized, and none of the diagnostic tests used to evaluate patients with these reactions is standardized or validated. Thus, skin testing with the antibiotics discussed in this topic is much less informative than that performed to evaluate penicillin allergy. In some cases, the evaluation consists of a careful history and graded challenge. (See 'Allergy evaluation' above.)
●Macrolides cause delayed-onset maculopapular exanthems in about 1 percent of treated patients, which is close to the rate in placebo-treated patients in many drug studies. Anaphylaxis and serious non-immunoglobulin E (IgE)-mediated reactions are rare. Skin testing is controversial, and graded challenge is often required for conclusive diagnosis, although there are usually alternate classes of antibiotics that can be substituted for macrolides. Patients who have reacted to one macrolide in the past may tolerate other macrolides. (See 'Macrolides' above.)
●Aminoglycosides are well-tolerated as a group, with the exception of topical neomycin, which is a relatively common cause of allergic contact dermatitis and is included on many commercial patch testing panels. Rare cases of anaphylaxis have been confirmed with immediate-type skin testing. Cross-reactivity appears to be extensive, and patients are usually advised to avoid all aminoglycosides if they have had a significant reaction to one. (See 'Aminoglycosides' above.)
●Among tetracycline drugs, minocycline causes more hypersensitivity reactions than all others. Minocycline has been implicated in an array of serious non-IgE-mediated reactions, such as drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DiHS), drug-induced lupus, and toxic epidermal necrolysis (TEN). Among the other drugs, rare cases of anaphylaxis have been confirmed with immediate-type skin testing. Cross-reactivity is not well-studied, so patients with past reactions are usually advised to avoid the entire group if possible. (See 'Tetracyclines' above.)
●The most common reaction to clindamycin is maculopapular exanthem. Neither skin testing nor patch testing appears to be useful for the evaluation of this reaction. (See 'Clindamycin' above.)
●Metronidazole has been anecdotally implicated in several types of rare hypersensitivity reactions, including anaphylaxis, fixed drug eruption, serum sickness-like reaction, and Stevens-Johnson syndrome (SJS)/TEN. (See 'Metronidazole' above.)
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