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Penicillin allergy: Delayed hypersensitivity reactions

Penicillin allergy: Delayed hypersensitivity reactions
Literature review current through: Jan 2024.
This topic last updated: Mar 16, 2021.

INTRODUCTION — Penicillins are the medications to which allergy is most commonly reported. Penicillin allergy in all of its forms is self-reported by about 5 to 10 percent of patients [1-3]. Many of these patients have delayed forms of hypersensitivity, which typically begin more than six hours after the last administered dose and often after days of treatment. The epidemiology, risk factors, diagnosis, and management of the most common types of delayed reactions to penicillins will be discussed here.

DEFINITIONS — A drug allergy (or hypersensitivity) reaction is defined as a specific immunologic reaction to a drug. The classification and pathogenesis of drug allergies are discussed in detail separately. (See "Drug hypersensitivity: Classification and clinical features" and "Drug allergy: Pathogenesis".)

The World Allergy Organization (WAO) has recommended categorizing immunologic drug reactions based on the timing of the appearance of symptoms [4]. This system defines two general types of reactions: immediate and delayed.

Immediate reactions – Immediate reactions classically begin within one hour of the initial dose in a course or within one hour of the last administered dose. Symptoms may appear slightly later if the drug was administered orally or taken with food so that absorption is slowed. Nevertheless, the period of one hour identifies many of these reactions. When allergic sensitization first develops, the initial symptoms may appear during the latter days of treatment (ie, not following the first dose of the course) but usually within one hour of the last administered dose and then escalate rapidly. Immediate reactions to penicillins are often immunoglobulin E (IgE)-mediated, and signs and symptoms reflect widespread activation of mast cells (table 1). (See "Penicillin allergy: Immediate reactions".)

Delayed (nonimmediate) reactions – Delayed (nonimmediate) reactions usually appear after more than one dose of drug and typically after days of treatment. For example, delayed cutaneous maculopapular eruptions to amoxicillin classically start on day 7 to 10 of treatment and may even begin 1 to 3 days after cessation of treatment. The symptoms typically begin several hours after the last administered dose, although the timing relative to the last administered dose is variable. However, symptoms should not begin within one hour of the initial dose of a medication. There are different mechanisms underlying various forms of delayed reactions, but they are not IgE-mediated.

Although this classification is helpful in many cases, patients often do not recall the timing with which symptoms began, and not all drug reactions can be temporally classified.

TAKING A USEFUL DRUG ALLERGY HISTORY — Penicillins include the following:

The natural penicillins – Penicillin V (oral), penicillin G (parenteral), benzathine penicillin (intramuscular), and procaine penicillin (intramuscular)

The antistaphylococcal penicillins – Dicloxacillin, nafcillin, oxacillin, cloxacillin, and flucloxacillin (used in Europe and Australia)

The aminopenicillins – Amoxicillin and ampicillin (often given as the combination drugs amoxicillin and clavulanate and ampicillin and sulbactam)

The extended spectrum penicillins – Carbenicillin, ticarcillin, and piperacillin (often given as piperacillin and tazobactam)

Hypersensitivity reactions to any of these drugs should be considered a penicillin allergy. It is useful to name commonly used penicillins (ie, amoxicillin, ampicillin, specific brand names), as patients may recognize a brand name but not realize it is a penicillin. It is also worthwhile to ask if the patient has avoided penicillins since the reaction, because in some cases, patients had been given a penicillin again despite a reported allergy, and if it was tolerated, then the patient is not allergic to penicillins.

Focused questions — In patients with a history of past reactions to penicillins, the history should focus on symptoms and concomitant illnesses, especially respiratory viral infections in children, as many cutaneous reactions occur when patients are given penicillins in the setting of a viral illness. Another important goal of the history is the detection of severe forms of delayed drug reactions, such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). The history of a drug reaction should ascertain the following:

What penicillin was taken at the time of the reaction

The dose and route of medication taken (if known)

Other concurrent medications, especially if they were new or temporary

The timing of onset of the reaction (both time between the last dose and onset of symptoms, as well as time of symptom onset relative to the start of therapy)

Age of the patient when the reaction occurred or how long ago the reaction occurred

Indication for the drug and whether the patient had symptoms of a viral illness at the time

The signs and symptoms involved and whether there was any blistering or exfoliation of the skin or mucous membrane involvement or signs of organ involvement other than the skin

Any treatment given for the reaction and response to that treatment

How long the reaction took to resolve

Any prior or subsequent history of exposure to the same drug or structurally similar drugs, with or without reactions

If the patient gives a history consistent with one of the serious types of systemic reactions discussed below, a concerted attempt to review the medical records describing the patient's presentation and care should be made. (See 'Rare reactions and subsequent use of related drugs' below.)

Warning signs of potentially severe reactions — Some serious forms of delayed reactions can begin with a maculopapular eruption and then progress to more severe signs and symptoms. Warning signs of serious and potentially life-threatening drug reactions, such as SJS or TEN, include significant fever (>38°C or 100.4°F), involvement of mucosal membranes, skin tenderness or pain, and blistering (table 2). Patients should contact their clinician immediately if any of these signs occur. (See 'Systemic' below.)

COMMON CUTANEOUS REACTIONS — The most common allergic reactions to penicillins are delayed cutaneous reactions. These simple drug eruptions do not involve systemic symptoms or evidence of specific organ involvement, other than the skin. They are believed to be mediated by T cells in the skin [5,6]. Common cutaneous reactions should not involve significant fever, although fever may be present in the context of an underlying infection. In contrast, fever that begins after the acute infection has begun to subside and corresponds with the onset of new cutaneous findings is more concerning for the early stages of one of the more severe drug reactions. In this case, the penicillin should be stopped immediately, and the patient should be evaluated for other signs of severe reactions. (See 'Warning signs of potentially severe reactions' above.)

Types — The two main types of delayed cutaneous reactions reported with penicillins are maculopapular eruptions and urticarial eruptions.

Maculopapular cutaneous eruptions — Maculopapular (also called morbilliform) cutaneous eruptions are the most common type of hypersensitivity reaction to beta-lactam antibiotics [7]. These reactions typically consist of erythematous macules or papules (picture 1A-D). The individual lesions are relatively fixed and stay in place for days once developed. The involved areas tend to expand over several days. Pruritus is variable and when present can be intense. However, nonpruritic maculopapular rashes that develop during the course of therapy are reported in up to 7 percent of children given ampicillin [8], although lower rates (<5 percent) are more typical [9].

Penicillins are among the most common causes of maculopapular eruptions, and the aminopenicillins (ie, amoxicillin and ampicillin) are more often implicated than other penicillins [9-12]. The aminopenicillins are associated with maculopapular eruptions in up to 5 to 10 percent of patients, particularly in children in the setting of a viral infection [13]. The onset of the eruption is usually within one to two weeks after beginning therapy and sometimes much shorter (ie, within days) in a patient who previously reacted [14,15]. Occasionally, an eruption to penicillins may begin as late as three weeks after beginning the antibiotic or first appear up to two weeks after the therapy was completed. Delayed cutaneous reactions resolve once the culprit penicillin is discontinued and sometimes even if the antibiotic is continued. Resolution is usually apparent within 7 to 14 days, although symptoms may initially worsen for a few days after the drug is stopped [16]. This type of drug reaction occurs with multiple antibiotics and is discussed in more detail separately. (See "Exanthematous (maculopapular) drug eruption".)

Delayed urticarial eruptions — Delayed urticarial eruptions (sometimes with associated angioedema) are another common form of cutaneous reaction to penicillins [17]. It is important to make sure that the reaction did not involve other symptoms of an immunoglobulin E (IgE)-mediated reaction (ie, difficulty breathing, bronchospasm [cough, wheeze], throat tightness, voice change, recurrent vomiting, lightheadedness, change of mental status, hypotension). These reactions are particularly prevalent in children [12]. Symptoms begin after multiple doses and may occur immediately or hours after the last administered dose. However, because urticaria and angioedema can be features of IgE-mediated immediate reactions and IgE-mediated reactions can involve anaphylaxis, patients with isolated urticaria and/or angioedema should generally be evaluated by an allergy specialist. This evaluation is reviewed separately (see "Penicillin allergy: Immediate reactions" and "Penicillin skin testing"). The possibility of performing graded challenge without prior skin testing in pediatric patients with delayed maculopapular and urticarial reactions is discussed below. (See 'Studies in children' below.)

Relationship with viral infections — The presence of concurrent systemic viral infections may predispose to delayed cutaneous reactions (both maculopapular and delayed urticaria), particularly in children [8]. The best described example is the occurrence of a nonpruritic morbilliform rash in more than 90 percent of patients treated with ampicillin during acute infections with Epstein-Barr virus (EBV) [18]. Patients with human immunodeficiency virus (HIV) infection also have higher rates of reactions to various antibiotics, including amoxicillin [19].

The prevalence of concomitant viral infections was evaluated in a study of 88 children presenting to the emergency department with delayed cutaneous reactions while taking beta-lactam antibiotics, in which all patients were tested for common childhood viral infections and then later evaluated for drug reactions [12]. Two-thirds of the children had one or more positive viral studies, suggesting that viral infection is important in the pathogenesis of many drug-related eruptions in this age group. Reactions consisted of morbilliform rashes (41 patients) or urticarial rashes (47 patients) (without other symptoms of anaphylaxis). Symptoms appeared more than one hour after the last administered dose (for inclusion in the study) and an average of 4.9 days after the start of the medication. The signs and symptoms lasted an average of 3.8 days after the medication was stopped. The results of subsequent allergy testing and challenge in this study are discussed below. (See 'Studies in children' below.)

The mechanism by which viral infections modify immune responses to antibiotics is not clear. One theory proposes that the release of interferons during viral infections leads to increased expression of major histocompatibility complex (MHC) receptors (along with processed drug) on antigen-presenting cells in the skin [20].

Diagnosis — Delayed cutaneous reactions to penicillins are diagnosed based on clinical history, in most cases. However, if the patient/caregiver cannot provide a detailed description of the previous reaction, caution is warranted. The more distant a reaction, the more uncertain are its manifestations and the more difficult it is to obtain the medical record. If there is any doubt about the nature of the previous reaction, an objective allergy evaluation to exclude immediate allergy is warranted. Because penicillins are such a common cause of immediate allergy, clinicians should not assume that a vague reaction history (eg, "rash") represents a simple cutaneous reaction.

If there is any uncertainty about the accuracy of the history, the safest approach is to refer the patient for an allergy evaluation before additional use of penicillins is considered. (See 'Referral for allergy evaluation' below.)

Maculopapular cutaneous eruptions – It can reasonably be assumed that the patient had a delayed maculopapular cutaneous reaction if the history clearly suggests macular or papular lesions limited to the skin, with or without pruritus, which began more than one hour (and usually several hours) after the last administered dose and did not feature urticaria or angioedema, systemic symptoms, or warning signs of the more severe forms of delayed drug reactions. (See 'Warning signs of potentially severe reactions' above and 'Rare reactions and subsequent use of related drugs' below.)

Delayed urticarial eruptions – Reactions that involve isolated urticaria or urticaria and angioedema, without other symptoms of an IgE-mediated allergic reaction (ie, difficulty breathing, bronchospasm [cough, wheeze], throat tightness, voice change, recurrent vomiting, lightheadedness, change of mental status, hypotension) that begin more than one hour after the last administered dose are consistent with delayed urticarial eruptions. We advocate referral of patients with these reactions to an allergy specialist. (See 'Referral for allergy evaluation' below.)

Laboratory studies and skin biopsy are not necessary for delayed cutaneous reactions, unless more serious reactions are in the differential diagnosis. In the United States, neither in vitro (eg, lymphocyte activation tests) nor skin testing (intradermal testing with delayed reading or patch testing) is widely utilized in the diagnosis of delayed cutaneous reactions, although these techniques are more commonly employed in other countries at specialty referral centers [13,21-23]. (See "Exanthematous (maculopapular) drug eruption", section on 'Laboratory testing'.)

Management of symptoms — Delayed cutaneous reactions resolve once the culprit drug is discontinued, usually within one to two weeks, although symptoms may worsen for a few days even after the drug is stopped [16]. Oral antihistamines may be administered at age-appropriate doses if there is a pruritic component. Oral glucocorticoids may be considered in patients with severe eruptions who do not respond to or are unable to tolerate antihistamines. Specific treatment measures are reviewed separately. (See "Exanthematous (maculopapular) drug eruption", section on 'Symptomatic treatment'.)

A drug may occasionally be continued in spite of a delayed cutaneous reaction, in rare instances, when no alternative therapy is available [24]. Antihistamines, and less frequently, oral glucocorticoids are helpful in controlling symptoms in this setting. (See "Exanthematous (maculopapular) drug eruption", section on ''Treating through''.)

Referral for allergy evaluation — If the patient/caregiver cannot provide a detailed description of the previous reaction, caution is warranted, and referral is indicated.

In addition, if the patient's past reaction may have involved urticaria or angioedema, he/she should be referred to an allergy specialist for an evaluation for an IgE-mediated reaction before future use of penicillins and related drugs is considered. This evaluation is reviewed separately. (See "Penicillin allergy: Immediate reactions" and "Penicillin skin testing".)

Future use of penicillins in patients with low-risk reactions — If the clinician believes that the patient's past reaction was a delayed-onset eruption that had no features of immediate allergy, was not accompanied by any systemic symptoms, and did not involve blistering or exfoliation of the skin or mucous membranes, then it is reasonable to consider treatment with the same or other penicillins in the future using a test dose procedure. We advocate that readministration be supervised by an allergy specialist when possible and occur in a medically supervised setting equipped to treat possible anaphylaxis. However, recognizing that allergy experts may not be available, the recommendations in this section could be enacted by generalists if necessary, although large-scale outcomes of outpatient challenges performed in primary care or emergency department settings have not been published, so clinical judgement is essential [25].

An approach to antibiotic use in penicillin-allergic hospitalized patients at low risk for serious reaction, with or without access to allergy consultation, is presented separately. (See "Choice of antibiotics in penicillin-allergic hospitalized patients", section on 'Management of mild reactions WITHOUT history of features of immediate allergy (minimal risk of immediate allergy)'.)

Studies in children — In children, delayed cutaneous eruptions to penicillins are common and often occur in the setting of viral infections [12,26,27]. (See 'Relationship with viral infections' above.)

A small number of studies have demonstrated that the same or similar drugs can be safely readministered to such children using graded oral challenges in medically supervised settings [12,28,29]. Note that these studies were carried out in speciality allergy centers, and the safety of this approach in a primary care or urgent care setting has not been examined.

The largest study included 818 young children (one to four years of age) consecutively referred to an allergy clinic for past cutaneous reactions to amoxicillin, most commonly given for acute otitis media [29]. No children had past reactions that were consistent with anaphylaxis, although mild immediate reactions were not excluded. Children were excluded from the study if their past reaction had any features suggestive of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). More than one-half had reacted during their first exposure to amoxicillin, making IgE-mediated reactions unlikely, since these require previous exposure to generate drug-specific IgE. All eligible children underwent monitored challenge with oral amoxicillin without preceding skin testing to assess the safety of this approach. The amoxicillin challenge was given as two doses: the first consisting of 10 percent of a weight-based therapeutic dose, followed by 20 minutes of observation. If no symptoms developed, the child was given the other 90 percent of the dose and observed for at least one hour. The challenge elicited no symptoms in 94 percent, immediate reactions (within 1 hour) in 2 percent (all were isolated urticaria), and delayed reactions in 3.8 percent (median time 12 hours, range 5 to 26 hours: maculopapular rashes, sometimes with angioedema, and one serum sickness-like reaction). In addition, follow-up was available on a subset of 55 children who had no reaction to the amoxicillin challenge to determine if they tolerated subsequent full courses of amoxicillin. Subsequent courses were tolerated in 49 of 55 children, while 6 had delayed cutaneous reactions.

Additional studies evaluated the utility of penicillin skin testing in children with convincing histories of delayed reactions and concluded that it was not necessary [12,14,28].

In a prospective study of 88 children (aged 0.5 to 14 years) with delayed urticarial or maculopapular rashes on beta-lactam antibiotics (mostly amoxicillin), the authors concluded that allergy testing was not helpful and that if the initial reaction was limited to cutaneous findings, well-documented, and reviewed by an experienced allergist, a one-step challenge procedure was a safe and effective approach. In these 88 children, reactions occurred in just 7 percent of children given the same medication two months after the initial reaction [12]. The protocol involved intradermal skin testing with immediate reading, which was positive in 12.5 percent of patients. This was followed by a one-step challenge (150 percent of full dose) for children with negative skin tests or a two-step challenge (50 percent, then 100 percent) for children with positive skin tests. All patients then continued standard doses of the penicillin for 48 hours at home. Of the 88 children challenged, only 7 percent reacted again when given the same antibiotic. The reactions were all mild and similar to the original reactions, with one occurring in 30 minutes and the others after 8 to 12 hours. Four of these six reactors had positive skin tests. Patch testing and delayed reading of intradermal skin tests, which are other testing methods that have been investigated for the diagnosis of nonimmediate drug reactions, were also performed and were negative in all 88 patients.

A retrospective study of children evaluated the reaction rate if a five-day challenge was used, which is essentially a subsequent course of the drug given when the patient was well, and found that 11 percent of children had recurrent reactions [28]. The study population consisted of 152 children who were referred to an allergy clinic for past delayed reactions to amoxicillin. Reaction types were maculopapular eruption (46 percent), urticaria (36 percent), urticaria and angioedema (12 percent), and undefined rash (6 percent). Skin testing was performed with amoxicillin, although regardless of the results of skin testing, all patients were offered a five-day challenge and 141 accepted. In total, 16 of 141 children (11 percent) had recurrent reactions similar to those they initially experienced. Five reacted on day 1, five on day 2, and four on day 5. All reactions were mild.

It would be helpful to have a validated set of questions that could be asked at the point of care to determine if a child's past reaction was sufficiently low-risk that a penicillin could be used again, but this is not available. In a study of children presenting to an urban emergency department with histories of past penicillin reactions, nearly 600 parents/caregivers completed questionnaires about the children's past reactions, and 434 children were deemed low-risk for true allergy [30]. The questionnaire included hives as a low-risk feature but considered facial angioedema as a high-risk feature [31]. After chart review and discussion with the child's primary care provider, 302 were eligible for allergy evaluation, but only 100 underwent penicillin skin testing. Thus, these 100 patients may not have been representative of the original 434. Ninety-seven had negative skin tests and then passed an oral challenge with amoxicillin. Three children had positive skin tests and were later retested and challenged, because skin tests had reverted to negative. Ultimately, all 100 children passed oral challenge to amoxicillin with the passage of time. The results of this study are helpful, but we consider both hives and angioedema to be high-risk features and would not advocate this approach until much larger numbers of patients have been evaluated. Data from other studies have shown that even among children with histories of mild adverse reactions, a small percentage will have positive penicillin skin tests and thus be at risk for acute allergy.

Our approach to children — Taken together, the studies above demonstrate that children with low-risk, delayed cutaneous reactions can be safely challenged with penicillins in outpatient allergy clinic settings. We would classify a child's cutaneous reaction as low risk if the clinician performed a detailed history and all of the following were true of the past reaction:

The initial signs and symptoms were either observed directly by the clinician or well-documented in the medical record

The reaction was limited to the skin and consisted of maculopapular rash (most common)

The reaction occurred days into the antibiotic course (as compared with hours after the first dose)

It did not involve the mucous membranes or blistering or peeling of the skin

It did not involve joint swelling or fever

It did not require systemic glucocorticoids to control symptoms (since this could indicate a more severe reaction)

In children with delayed reactions consisting of isolated hives or angioedema without other features of anaphylaxis, graded oral challenge appears to be safe based on the studies above, although we advocate a more cautious approach. We suggest referral to an allergist when possible, because published challenge protocols have largely been performed by drug allergy specialists. Although the allergy literature is evolving toward more widespread use of graded oral challenges without skin testing for delayed reactions, many allergists still perform skin testing in such children. If negative, the children can be challenged under observation. If positive, a graded challenge could still be considered depending on the importance of reintroducing penicillins.

If an allergy consultation is not possible, then the generalist can either use a nonpenicillin (which is safer but may have other disadvantages) or perform a graded oral challenge to the desired penicillin in an appropriate setting. Detailed instructions for safe performance of graded challenges are found separately. (See "Choice of antibiotics in penicillin-allergic hospitalized patients", section on 'Test dose procedure (graded challenge)'.)

Studies in adults — In adults, the ability to tolerate penicillins after a delayed cutaneous reaction is less well-documented, and there are few studies similar to those described above in children. In one study that included both children and adults, 642 patients (two-thirds of whom were children) whose histories were either unclear (ie, unsure if past reaction was immediate or delayed) or suggestive of a delayed reaction, were evaluated to determine if skin testing was useful in predicting outcomes of challenge [32]. All patients underwent intradermal testing (without prior epicutaneous testing) and 617 agreed to a graded challenge, regardless of the testing result. Nine patients (1.5 percent) developed mild immediate cutaneous reactions to the full dose, and 4 percent developed later day 1 reactions, which did not correlate with skin test results. Of the 491 patients who agreed to continue penicillins for an extended five-day challenge, 6 percent had mild reactions (mild rashes, pruritus, or abdominal discomfort). Thus, in this study, which used clinical histories taken by allergy specialists, skin testing did not appear to be helpful, and no serious reactions occurred, although larger numbers may need to be studied to determine if prior skin testing before graded oral challenge are useful to predict low reaction rate events.

Until additional data are available, we have a more cautious approach in adults, for the following reasons:

In adults who reacted to penicillins as adults, the association with common respiratory viral infections is not as well-characterized as it is in children. However, there are a few viral infections, such as EBV and HIV, in which adults are known to develop increased rates of exanthema when antimicrobials are given. These associations are discussed separately. (See "Infectious mononucleosis", section on 'Rash' and "Fever and rash in patients with HIV", section on 'Drug reactions'.)

In adults who experienced a penicillin reaction as a child, the clinical history may have been relayed from a parent, and the patient often has no recollection of the nature of the reaction.

It is our clinical experience that adults are more likely to have a recurrence of the original reaction if re-exposed to the causative drug, particularly if the initial reaction occurred in adulthood.

Our approach in adults — In adults with suspected delayed reactions to penicillin, we perform penicillin skin testing to exclude immediate penicillin allergy. (See "Penicillin skin testing".)

If testing is negative, a full dose of the desired penicillin is given under medical supervision (and in a setting with staff that are trained to recognize and treat immediate reactions), and the patient is observed for at least one hour. If no symptoms occur, the patient can receive penicillins normally in the future. It is important to tell the patient to inform their other practitioners and pharmacies that they are no longer allergic to penicillin antibiotics or their previous allergic history will continue to appear in electronic medical records.

Outcomes using a similar approach were reported in a study of 405 adults with previous immediate and delayed reactions to beta-lactams (mostly penicillins), in which all subjects were evaluated to exclude immediate-type allergy with skin testing and in vitro testing (not commonly used in the United States) [33]. If testing was negative, intravenous and oral challenges were administered. Of the original group, 320 patients had no symptoms to challenge and were then given a seven-day course of oral penicillin (800 mg phenoxymethylpenicillin three times daily for seven days). Thirteen reactions (4 percent of patients) occurred, with the latest reaction on day 10, and none were serious. Of the 13 reactions, 3 began immediately after dosing, and 10 were delayed.

If referral to an allergist is not possible, the generalist can either use an alternative nonpenicillin antibiotic (which is safer but may have other disadvantages) or perform a graded challenge. Detailed instructions for safe performance of graded challenges are found separately. (See "Choice of antibiotics in penicillin-allergic hospitalized patients", section on 'Test dose procedure (graded challenge)'.)

Future use of other beta-lactam antibiotics — Nonpenicillin beta-lactam antibiotics include cephalosporins, carbapenems, and monobactams. In a case series of patients with past maculopapular eruptions to penicillins (mostly the aminopenicillins: amoxicillin and ampicillin), all subjects tolerated beta-lactams that did not share a common side-chain with these two aminopenicillins (ie, cefuroxime, ceftriaxone, aztreonam, and carbapenems) [34]. Although the importance of side-chain groups in predicting cross-reactivity has largely been studied in immediate hypersensitivity reactions, these same groups appear to have some relevance to delayed reactions as well, based on a small number of studies [35,36].

Delayed readings of intradermal skin tests appear to be useful in predicting lack of cross-reactivity [34,35]. Positive reactions consist of swelling and induration at the intradermal test site, which develops after 6 to 24 hours, is assessed at 48 hours, and persists for greater than 72 hours. Delayed reading of intradermal testing is performed at a small number of centers in the United States and more commonly in Europe.

RARE REACTIONS AND SUBSEQUENT USE OF RELATED DRUGS — Penicillins have also been associated with several rare delayed-onset reactions, some of which can be serious or life-threatening. Evaluation of patients who experienced these reactions in the past, and the use of related beta-lactams are reviewed below for the specific types of delayed reactions. Nonpenicillin beta-lactam antibiotics include cephalosporins, carbapenems, and monobactams. The significance of side-chain groups in predicting cross-reactivity has been established only for immunoglobulin E (IgE)-mediated immediate reactions. However, these same groups appear to have some relevance to delayed reactions as well, based on a small number of studies [34-36].

Cutaneous

Fixed drug eruption — Fixed drug eruption (FDE) is a cutaneous drug reaction that characteristically recurs in the same locations upon re-exposure to the offending drug. It has been reported with multiple penicillins [37-42]. Fixed drug eruption typically presents with solitary round to oval, dusky red to brown/black macules that may evolve into edematous plaques or bullae (picture 2A-C). Sites of predilection include the lips, genitalia, perianal area, and extremities. Acute lesions usually develop 30 minutes to 8 hours after drug administration and resolve spontaneously in 7 to 10 days after the drug is discontinued, leaving a persistent gray/brown or slate gray postinflammatory hyperpigmentation (picture 3). (See "Fixed drug eruption".)

Testing to confirm that a reaction was FDE, such as patch testing or delayed reading of an intradermal test, may add additional information but generally has a sensitivity <50 percent and must be performed in the site of the previous reaction. Patch testing is discussed separately. (See "Fixed drug eruption", section on 'Patch testing'.)

If another penicillin or a different beta-lactam drug is desired in the future, patients who had FDE consisting of a limited number of flat lesions can be challenged, because this type of FDE is not a severe or life-threatening reaction. In contrast, patients with generalized or generalized bullous FDE, which can behave clinically more like Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), should avoid all beta-lactams aside from aztreonam in the future [43].

Acute generalized exanthematous pustulosis — Acute generalized exanthematous pustulosis (AGEP) is a cutaneous eruption characterized by the development of distinct, numerous nonfollicular, sterile pustules on a background of edematous erythema (picture 4A-D). Fever and leukocytosis with neutrophilia are often present. Symptoms begin hours to days after starting the causative drug. Aminopenicillins are among the most common drugs implicated and reactions often occur quickly, ie, within 24 to 72 hours of dosing [44-46].

Delayed reading of intradermal skin testing and patch testing may be helpful in the diagnosis of AGEP. Diagnosis and management are discussed separately. (See "Acute generalized exanthematous pustulosis (AGEP)".)

If a different penicillin or beta-lactam drug is desired in the future, the alternative drug can be evaluated with delayed reading of intradermal skin testing and patch testing. There may be cross-reactivity among penicillins and among penicillins and cephalosporins sharing a common R1 side-chain [35,47]. One report included three patients with AGEP to amoxicillin who tolerated beta-lactams not sharing a common side-chain with amoxicillin (eg, cefuroxime, ceftriaxone, aztreonam, and carbapenems) [34].

Systemic

Stevens-Johnson syndrome or toxic epidermal necrolysis — SJS and TEN are severe mucocutaneous reactions, characterized by extensive necrosis and detachment of the epidermis. According to a widely accepted classification, SJS and TEN are considered variants of a disease continuum and are distinguished chiefly by severity, based on the percentage of body surface involved with blisters and erosions. Penicillins are not among the most commonly implicated drugs in adults, but amoxicillin and ampicillin have been implicated in case reports [48,49]. Penicillins have been more regularly implicated in children [50].

Patients have usually been exposed to the causative medication for between one to four weeks (average 14 days) when symptoms appear. A prodrome of fever and malaise is followed by the development of erythematous macules, targetoid lesions, or diffuse erythema progressing to vesicles and bullae (picture 5 and picture 6). Mortality ranges from 10 to 30 percent, and survivors may have long-term cutaneous, mucosal, ocular, and pulmonary complications. Diagnosis and management are discussed separately. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

The history should always be revisited in patients with a history of SJS/TEN to a penicillin, to make sure that all drugs started within the two months prior to development of symptoms were considered as possible culprits. Penicillins are sometimes mistakenly blamed because they are prescribed for fever and pharyngitis that were thought to be infectious but were actually early symptoms of SJS/TEN (ie, protopathic bias).

Delayed intradermal testing in SJS/TEN is not recommended, and other in vivo (patch testing) and ex vivo (interferon-gamma enzyme-linked immunospot [ELISpot]) have low sensitivity.

In general, it is recommended that all beta-lactams be avoided in a patient who has experienced SJS/TEN to a penicillin and when there are alternative antibiotics. However, both the author and section editor of this topic have encountered very difficult situations in which extremely ill patients (eg, in burn units) have complex, multidrug resistant infections and have been labeled as having a serious T cell mediated reaction to a penicillin or cephalosporin. Such patients may have developed pseudomonal infections that are resistant to fluoroquinolones, and other choices such as aminoglycosides, which have significant toxicities and may not be adequate, or polymyxin and colistin, which are very difficult to tolerate, have real disadvantages. In this setting, a carbapenem or aztreonam has been started because risk of death or severe morbidity due to the infection is deemed greater than the uncertain risk of cross-reactivity. In addition, the author has challenged approximately five patients with a history of penicillin-induced SJS with cephalosporins, which were tolerated. This clinical experience is largely unpublished. Therefore, if there is a strong indication for a cephalosporin, carbapenem, or aztreonam in the absence of alternative drug choices, a drug allergy expert should be consulted if available to review the details of the case and assess the risk of using a related medication.

DRESS/DiHS — Drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DiHS) is a variable syndrome that usually begins two to six weeks after the initiation of the offending medication, which is a considerably longer period than that of other delayed reactions [51]. Common early symptoms include fever (38 to 40°C [100.4 to 104°F]), malaise, lymphadenopathy, facial edema, and skin eruption (picture 7A-B). Asymptomatic alterations in lymphocyte blood count or liver function tests begin earlier. Involvement of at least one internal organ, such as the liver, kidneys, or lungs, occurs in approximately 90 percent of patients. Once the causative drug is stopped, patients usually recover in weeks to months, although mortality is 5 to 10 percent. Diagnosis and management are discussed separately. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

In patients with a past episode of DRESS/DiHS related to a penicillin, the safest approach is to avoid all penicillins and cephalosporins in the future. However, in the event that a beta-lactam is medically critical and no equivalent alternative is available, a drug allergy expert should be consulted to assess the risk. In vivo testing such as delayed intradermal or patch testing may be useful in assessing the likelihood of cross-reactivity. Ex vivo testing, such as interferon-gamma ELISpot (where available) may also provide additional information on cross-reactivity [22,35,52]. Because DRESS can relapse as a result of skin testing (or be coincidentally associated with early skin testing), intradermal skin testing with delayed reading and patch testing should be deferred until the patient has been successfully weaned off steroids or a minimum of six months following the acute reaction. A case series that included four patients with DRESS/DiHS related to various penicillins demonstrated skin test cross-reactivity among penicillins and tolerance (based on skin-testing and oral challenge) of a cephalosporin with a dissimilar R-group side-chain [35].

Serum sickness-like reactions — Serum sickness-like reactions (SSLR) present with annular, edematous plaques, fever, malaise, and polyarthralgias or polyarthritis, which occur one to two weeks after first exposure to the responsible agent and resolve within a few weeks of discontinuing the drug (picture 8 and picture 9). Penicillin, amoxicillin, and cefaclor are among the most commonly implicated agents [53,54]. Patients with SSLR do not have internal organ involvement and the reaction is not life-threatening or associated with long-term sequelae. In patients who have been previously exposed to the agent, the syndrome starts earlier (ie, usually within days of receiving the inciting agent), and the illness has a more severe and "explosive" onset. When the causative drug is discontinued, new skin lesions stop forming within 48 hours of this intervention, and fevers and arthralgias resolve within days, in most cases. Diagnosis and management, as well as future use of other beta-lactams, are discussed separately. (See "Serum sickness and serum sickness-like reactions" and "Serum sickness and serum sickness-like reactions", section on 'Future use of related drugs'.)

There is a report of one patient with serum sickness from parenteral nafcillin who subsequently tolerated cefazolin [55]. The author has challenged approximately a dozen patients with past SSLR to amoxicillin with cephalosporins, all of which were tolerated [56].

Drug fever — Drug fever may be defined as fever coinciding with administration of a drug and disappearing after the discontinuation of the drug, when no other cause for the fever is evident after a careful evaluation. Drug fever is variably accompanied by a cutaneous eruption, leukocytosis, or eosinophilia, although these changes are found in a minority of patients [57]. Drug fever can also precede the onset of DRESS. Drug fever may arise from different mechanisms and represent different pathophysiologic processes that have fever as the predominant symptom. Diagnosis and management are discussed separately (see "Drug fever"). Drug fever appears to be associated more prevalently with specific cephalosporins and penicillins. It can confuse the clinical picture but is not known to be harmful or life-threatening. In the setting of drug fever, it is recommended that the specific drug be avoided, but other penicillins or beta-lactams could be introduced using a challenge procedure where there are no equivalent alternatives.

Drug-induced cytopenias — Thrombocytopenia, hemolytic anemia, neutropenia, and agranulocytosis have each been attributed to penicillins. These disorders are reviewed separately. Piperacillin/tazobactam has been implicated in multiple case reports of drug-induced thrombocytopenia [58,59], with recurrence upon re-exposure [60-62]. (See "Drug-induced immune thrombocytopenia" and "Drug-induced hemolytic anemia" and "Drug-induced neutropenia and agranulocytosis".)

Drug-induced cytopenias tend to be drug-specific, but published data on cross-reactivity between penicillins and cephalosporins specifically are scarce. A case report described tolerance of cefepime in a patient with previous piperacillin/tazobactam-induced thrombocytopenia [63].

Organ-specific drug injury — Organ-specific drug injury includes acute interstitial nephritis (AIN), drug-induced liver injury (DILI), and drug-induced pulmonary eosinophilia.

Amoxicillin-clavulanic acid is one of the leading causes of DILI worldwide. Flucloxacillin is another common cause in Europe. (See "Drug-induced liver injury", section on 'Associated drugs'.)

Nafcillin, penicillin, and methicillin (no longer available in the United States) have been implicated in AIN. There is a report that includes three patients with AIN from parenteral nafcillin who subsequently tolerated cefazolin [55]. (See "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Drugs'.)

Ampicillin and piperacillin/tazobactam have been associated with pulmonary eosinophilia [64,65]. (See "Overview of pulmonary eosinophilia", section on 'Medications and toxins'.)

Organ-specific drug toxicity is often drug-specific, as illustrated by human leukocyte antigen (HLA) class I and II associations with specific beta-lactams such as flucloxacillin (used in Europe and Australia) and amoxicillin-clavulanate. Although data are limited, there is some literature to suggest that patients who develop interstitial nephritis with semi-synthetic penicillins tolerate cefazolin for treatment of life-threatening methicillin-sensitive Staphylococcus aureus infections and that patients who develop hepatitis associated with amoxicillin-clavulanate tolerate other beta-lactams [55]. The decision to treat with other beta-lactams in patients who have developed organ-specific toxicity associated with penicillins should always weigh the benefits of treatment against any small risk of a reaction.

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

Delayed (nonimmediate) drug reactions usually appear after more than one dose of drug and typically after days of treatment. The symptoms typically begin several hours after the last administered dose. Depending on the type of delayed reaction, symptoms may begin days to weeks into a course of treatment or even shortly after the course has ended. (See 'Definitions' above.)

A thorough clinical history is the essential first step in the evaluation of any patient with a drug reaction. (See 'Taking a useful drug allergy history' above.)

The most common forms of delayed allergic reaction to penicillins are cutaneous reactions, without involvement of other organs. These include maculopapular exanthems (picture 1A-D) and delayed urticarial eruptions. Delayed cutaneous reactions are usually mild and often related to a concomitant respiratory viral infection, especially in children. (See 'Common cutaneous reactions' above.)

Diagnosis of delayed cutaneous reactions is largely based on the clinical history. However, skin testing for immediate reactions should be performed if the reaction included urticaria or angioedema (since these signs are also features of immediate allergy) or if the history is unknown or too vague to categorize and future penicillin use is desired. (See 'Diagnosis' above.)

For patients with previous mild forms of delayed cutaneous reactions, penicillins can often be readministered safely. We advocate that readministration be supervised by an allergy specialist when possible and occur in a medically supervised setting equipped to treat possible anaphylaxis. Our approach in children and adults is slightly different. (See 'Future use of penicillins in patients with low-risk reactions' above.)

Penicillins have also been associated with various rare delayed-onset reactions, such as fixed drug eruption, acute generalized exanthematous pustulosis (AGEP), serum sickness-like syndromes, drug fever, Stevens-Johnson syndrome (SJS), hypersensitivity syndromes (drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome [DRESS or DiHS]), immune cytopenias, or other exfoliating dermatoses. With rare exceptions, patients with these reactions should not receive penicillins again under any circumstances, because re-exposure can trigger recurrent symptoms. However, if a related drug such as a cephalosporin, carbapenem, or aztreonam is needed and no equivalent antibiotic is available, a drug allergy expert should be consulted to guide use of these agents. (See 'Rare reactions and subsequent use of related drugs' above.)

  1. Lee CE, Zembower TR, Fotis MA, et al. The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and emerging bacterial resistance. Arch Intern Med 2000; 160:2819.
  2. Park M, Markus P, Matesic D, Li JT. Safety and effectiveness of a preoperative allergy clinic in decreasing vancomycin use in patients with a history of penicillin allergy. Ann Allergy Asthma Immunol 2006; 97:681.
  3. Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology, Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol 2010; 105:259.
  4. Demoly P, Adkinson NF, Brockow K, et al. International Consensus on drug allergy. Allergy 2014; 69:420.
  5. Blanca-López N, Zapatero L, Alonso E, et al. Skin testing and drug provocation in the diagnosis of nonimmediate reactions to aminopenicillins in children. Allergy 2009; 64:229.
  6. Romano A, Blanca M, Torres MJ, et al. Diagnosis of nonimmediate reactions to beta-lactam antibiotics. Allergy 2004; 59:1153.
  7. Cohen AD, Friger M, Sarov B, Halevy S. Which intercurrent infections are associated with maculopapular cutaneous drug reactions? A case-control study. Int J Dermatol 2001; 40:41.
  8. Bass JW, Crowley DM, Steele RW, et al. Adverse effects of orally administered ampicillin. J Pediatr 1973; 83:106.
  9. Ibia EO, Schwartz RH, Wiedermann BL. Antibiotic rashes in children: a survey in a private practice setting. Arch Dermatol 2000; 136:849.
  10. Bigby M, Jick S, Jick H, Arndt K. Drug-induced cutaneous reactions. A report from the Boston Collaborative Drug Surveillance Program on 15,438 consecutive inpatients, 1975 to 1982. JAMA 1986; 256:3358.
  11. Arndt KA, Jick H. Rates of cutaneous reactions to drugs. A report from the Boston Collaborative Drug Surveillance Program. JAMA 1976; 235:918.
  12. Caubet JC, Kaiser L, Lemaître B, et al. The role of penicillin in benign skin rashes in childhood: a prospective study based on drug rechallenge. J Allergy Clin Immunol 2011; 127:218.
  13. Mirakian R, Leech SC, Krishna MT, et al. Management of allergy to penicillins and other beta-lactams. Clin Exp Allergy 2015; 45:300.
  14. Yawalkar N. Drug-induced exanthems. Toxicology 2005; 209:131.
  15. Segal AR, Doherty KM, Leggott J, Zlotoff B. Cutaneous reactions to drugs in children. Pediatrics 2007; 120:e1082.
  16. Shear NH, Knowles SR, Shapiro L. Cutaneous reactions to drugs. In: Fitzpatrick's Dermatology in General Medicine, 7th ed, Wolff K, Goldsmith LA, Katz SI, et al (Eds), McGraw Hill, New York 2008. p.355.
  17. Solensky R. Drug desensitization. Immunol Allergy Clin North Am 2004; 24:425.
  18. Patel BM. Skin rash with infectious mononucleosis and ampicillin. Pediatrics 1967; 40:910.
  19. Pirmohamed M, Park BK. HIV and drug allergy. Curr Opin Allergy Clin Immunol 2001; 1:311.
  20. Park BK, Pirmohamed M, Kitteringham NR. Idiosyncratic drug reactions: a mechanistic evaluation of risk factors. Br J Clin Pharmacol 1992; 34:377.
  21. Mayorga C, Celik G, Rouzaire P, et al. In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy 2016; 71:1103.
  22. Phillips EJ, Bigliardi P, Bircher AJ, et al. Controversies in drug allergy: Testing for delayed reactions. J Allergy Clin Immunol 2019; 143:66.
  23. Mayorga C, Ebo DG, Lang DM, et al. Controversies in drug allergy: In vitro testing. J Allergy Clin Immunol 2019; 143:56.
  24. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994; 331:1272.
  25. Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and Management of Penicillin Allergy: A Review. JAMA 2019; 321:188.
  26. Ponvert C, Weilenmann C, Wassenberg J, et al. Allergy to betalactam antibiotics in children: a prospective follow-up study in retreated children after negative responses in skin and challenge tests. Allergy 2007; 62:42.
  27. Mattheij M, de Vries E. A suspicion of antibiotic allergy in children is often incorrect. J Allergy Clin Immunol 2012; 129:583; author reply 583.
  28. Mori F, Cianferoni A, Barni S, et al. Amoxicillin allergy in children: five-day drug provocation test in the diagnosis of nonimmediate reactions. J Allergy Clin Immunol Pract 2015; 3:375.
  29. Mill C, Primeau MN, Medoff E, et al. Assessing the Diagnostic Properties of a Graded Oral Provocation Challenge for the Diagnosis of Immediate and Nonimmediate Reactions to Amoxicillin in Children. JAMA Pediatr 2016; 170:e160033.
  30. Vyles D, Adams J, Chiu A, et al. Allergy Testing in Children With Low-Risk Penicillin Allergy Symptoms. Pediatrics 2017; 140.
  31. Vyles D, Chiu A, Simpson P, et al. Parent-Reported Penicillin Allergy Symptoms in the Pediatric Emergency Department. Acad Pediatr 2017; 17:251.
  32. Confino-Cohen R, Rosman Y, Meir-Shafrir K, et al. Oral Challenge without Skin Testing Safely Excludes Clinically Significant Delayed-Onset Penicillin Hypersensitivity. J Allergy Clin Immunol Pract 2017; 5:669.
  33. Hjortlund J, Mortz CG, Skov PS, et al. One-week oral challenge with penicillin in diagnosis of penicillin allergy. Acta Derm Venereol 2012; 92:307.
  34. Romano A, Gaeta F, Valluzzi RL, et al. Cross-reactivity and tolerability of aztreonam and cephalosporins in subjects with a T cell-mediated hypersensitivity to penicillins. J Allergy Clin Immunol 2016; 138:179.
  35. Trubiano JA, Chua KYL, Holmes NE, et al. Safety of cephalosporins in penicillin class severe delayed hypersensitivity reactions. J Allergy Clin Immunol Pract 2020; 8:1142.
  36. Buonomo A, Nucera E, Pecora V, et al. Cross-reactivity and tolerability of cephalosporins in patients with cell-mediated allergy to penicillins. J Investig Allergol Clin Immunol 2014; 24:331.
  37. Coskey RJ, Bryan HG. Letter: Fixed drug eruption due to penicillin. Arch Dermatol 1975; 111:791.
  38. Santosa A, Teo BW, Shek LP. Fixed drug eruption caused by piperacillin-tazobactam. J Investig Allergol Clin Immunol 2013; 23:132.
  39. Ponce Guevara LV, Yges EL, Gracia Bara MT, et al. Fixed drug eruption due to amoxicillin and quinolones. Ann Allergy Asthma Immunol 2013; 110:61.
  40. Pérez-Ezquerra PR, Sanchez-Morillas L, Alvarez AS, et al. Fixed drug eruption caused by amoxicillin-clavulanic acid. Contact Dermatitis 2010; 63:294.
  41. Rahman MH. Fixed drug eruption in Bangladeshi population: confirmed by provocative test. Int J Dermatol 2014; 53:255.
  42. Kornmehl H, Gorouhi F, Konia T, et al. Generalized fixed drug eruption to piperacillin/tazobactam and review of literature. Dermatol Online J 2018; 24.
  43. White KD, Abe R, Ardern-Jones M, et al. SJS/TEN 2017: Building Multidisciplinary Networks to Drive Science and Translation. J Allergy Clin Immunol Pract 2018; 6:38.
  44. Matsumoto Y, Okubo Y, Yamamoto T, et al. Case of acute generalized exanthematous pustulosis caused by ampicillin/cloxacillin sodium in a pregnant woman. J Dermatol 2008; 35:362.
  45. Talati S, Lala M, Kapupara H, Thet Z. Acute generalized exanthematous pustulosis: a rare clinical entity with use of piperacillin/tazobactam. Am J Ther 2009; 16:591.
  46. Riten K, Shahina Q, Jeannette J, Palma-Diaz MF. A severe case of acute generalized exanthematous pustulosis (AGEP) in a child after the administration of amoxicillin-clavulanic acid: brief report. Pediatr Dermatol 2009; 26:623.
  47. Phillips E, Knowles SR, Weber EA, Blackburn D. Cephalexin tolerated despite delayed aminopenicillin reactions. Allergy 2001; 56:790.
  48. Yang SC, Hu S, Zhang SZ, et al. The Epidemiology of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in China. J Immunol Res 2018; 2018:4320195.
  49. Belver MT, Michavila A, Bobolea I, et al. Severe delayed skin reactions related to drugs in the paediatric age group: A review of the subject by way of three cases (Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS). Allergol Immunopathol (Madr) 2016; 44:83.
  50. Ferrandiz-Pulido C, Garcia-Patos V. A review of causes of Stevens-Johnson syndrome and toxic epidermal necrolysis in children. Arch Dis Child 2013; 98:998.
  51. Jurado-Palomo J, Cabañas R, Prior N, et al. Use of the lymphocyte transformation test in the diagnosis of DRESS syndrome induced by ceftriaxone and piperacillin-tazobactam: two case reports. J Investig Allergol Clin Immunol 2010; 20:433.
  52. Trubiano JA, Strautins K, Redwood AJ, et al. The Combined Utility of Ex Vivo IFN-γ Release Enzyme-Linked ImmunoSpot Assay and In Vivo Skin Testing in Patients with Antibiotic-Associated Severe Cutaneous Adverse Reactions. J Allergy Clin Immunol Pract 2018; 6:1287.
  53. Tatum AJ, Ditto AM, Patterson R. Severe serum sickness-like reaction to oral penicillin drugs: three case reports. Ann Allergy Asthma Immunol 2001; 86:330.
  54. Clark BM, Kotti GH, Shah AD, Conger NG. Severe serum sickness reaction to oral and intramuscular penicillin. Pharmacotherapy 2006; 26:705.
  55. Blumenthal KG, Youngster I, Shenoy ES, et al. Tolerability of cefazolin after immune-mediated hypersensitivity reactions to nafcillin in the outpatient setting. Antimicrob Agents Chemother 2014; 58:3137.
  56. Unpublished clinical experience of Dr. Roland Solensky.
  57. Linares T, Fernández A, Soto MT, et al. Drug fever caused by piperacillin-tazobactam. J Investig Allergol Clin Immunol 2011; 21:250.
  58. Shaik S, Kazi HA, Ender PT. Rapid-onset piperacillin-tazobactam induced thrombocytopenia. J Pharm Pract 2015; 28:204.
  59. Lin SY, Huang JC, Shen MC, et al. Piperacillin-induced thrombocytopenia reversed by high-flux hemodialysis in an uremic patient. Hemodial Int 2012; 16 Suppl 1:S50.
  60. Alzahrani M, Alrumaih I, Alhamad F, Abdel Warith A. Rapid onset severe thrombocytopenia following reexposure to piperacillin-tazobactam: report of two cases and review of the literature. Platelets 2018; 29:628.
  61. Nguyen VD, Tourigny JF, Roy R, Brouillette D. Rapid-Onset Thrombocytopenia Following Piperacillin-Tazobactam Reexposure. Pharmacotherapy 2015; 35:e326.
  62. Boyce K, Brar H, Stabler SN. Piperacillin/tazobactam-induced immune-mediated thrombocytopenia in the intensive care unit. J Clin Pharm Ther 2016; 41:730.
  63. Beaulieu C, Kurczewski L, Yajnik V. Cefepime challenge after piperacillin/tazobactam-induced thrombocytopenia. J Thromb Thrombolysis 2019; 48:167.
  64. Tseng OL, Kelsall JT, Wilcox PG. Piperacillin-associated pulmonary infiltrates with eosinophilia: a case report. Can Respir J 2010; 17:e24.
  65. García-Moguel I, Bobolea I, Diéguez Pastor MC, et al. Acute eosinophilic pneumonia due to piperacillin/tazobactam. Ann Allergy Asthma Immunol 2019; 122:334.
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References

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