What is a true penicillin allergy

Figure. Partners HealthCare System Penicillin Allergy Pathway. Reprinted from (17) with permission from Copyright Clearance Middle.

Test dose procedures use 1/10th of the dose for parenteral beta-lactams and 25% dose for oral beta-lactams followed by 30–60 minutes of observation. If there is no reaction, % of the dose is istered with 60 minutes of observation. If there is no reaction, the next dose of the beta-lactam antibiotic is given per its usual therapeutic schedule. Unlike desensitization procedures, which typically require intensive care unit monitoring, test dose procedures can be performed on the medical floors. Common cephalosporins by generation: 1st cephalexin/cefazolin; 2nd cefoxitin/cefuroxime; 3rd ceftriaxone/cefixime/cefotaxime/cefpodoxime/ceftazidime*; 4th cefepime; 5th ceftaroline* Abbreviations: HSR, hypersensitivity reaction; PCN, penicillin * Antibiotics restricted by Partners antimicrobial stewardship committees.

§ Alternative agents by microbial coverage: Gram positive coverage: Vancomycin, linezolid*, daptomycin*, clindamycin, doxycycline, trimethoprim/sulfamethoxazole Gram negative coverage: Quinolones, sulfamethoxazole/trimethoprim, aminoglycosides, aztreonam*


So, Youve Been Diagnosed with Hives!

by Richard S. Roberts, M.D.

Allergy Hives

So, why are my mast cells releasing histamine and other things when they shouldn’t?

The first question that needs to be asked is for how endless own you had hives? Hives that own been present intermittently or daily for less than 6 weeks are called acute hives, and if longer, chronic hives.

What is a true penicillin allergy

Amongst the numerous possible causes of acute hives those due to allergic reactions get the most attention. In allergic patients the mast cells are coated with an allergy antibody, called IgE, that recognizes a extremely specific target (peanut, penicillin, yellow jacket, etc.). When that substance, such as peanut, becomes attached to that allergy antibody a chain reaction occurs that activates the mast cell which results in the release of histamine and other inflammatory substances. A hive is born! For food allergy reactions, there are 3 useful rules to consider:

  1. Second, it goes away within a few hours or at the most within a day or two.

    Therefore, you never get hives for a week from one serving of peanut butter.

  2. First, the reaction begins quickly, within minutes of eating the food; on rare occasions up to an hour but almost never longer.
  3. Third, the reaction is reproducible, meaning that if hives were caused by eating 4 peanuts on a Monday, eating 4 peanuts the following week will almost always cause the same problem. Despite favorite belief, artificial food colorings and food additives almost NEVER cause hives.

Hives from antibiotics is a diverse situation.

What is a true penicillin allergy

The hive reaction can start anywhere from a few minutes after the first dose to 10 days after finishing the course. Antibiotic related hives can persist for up to approximately 2 weeks.

Allergic hives from stinging insects are generally obvious but occasionally they can be sneaky by occurring while you’re asleep or distracted. They start quickly after the sting and resolve in a few hours to a few days. In the U.S. spiders, flies and mosquitoes almost never cause hives although rare cases own been reported.

Almost any medicine or herbal product can potentially cause hives but one of the most common medicines implicated is the aspirin family (aspirin, ibuprofen, naproxen, etc.).

Isolated swelling without hives is a unique side effect of the ACE inhibitor blood pressure medicines. Soaps, detergents, fabric softeners almost never cause hives but if they do, the hives happen only where the skin is touched. Airborne allergy to pollen, dust, etc. almost never causes hives unless the person is in the midst of a massive hay fever attack. In an allergic person, direct skin contact with a potent allergic substance love animal saliva or latex can cause hives at the site. Every categories of allergic hives are potentially dangerous while chronic hives are generally not.

Chronic Hives

So, if acute hives don’t seem to own an allergic cause what else could be going on? One of the more common presumed causes, especially in children is post-infectious hives.

During or within a week of viral, strep or other infections hives may happen through poorly understood mechanisms. This often leads to confusion when antibiotics own been given for the infection. Were the hives from the antibiotic or from the underlying illness? Post-infectious hives can recur for up to 6 weeks. At times, even without infection or any obvious trigger a few hours to a few days of hives happen. These are called acute idiopathic hives. We assume that the immune system is inappropriately activating the skin mast cells but we don’t know why. We don’t ponder that stress is a common cause.

So, your hives own gone on for more than 6 weeks, so they drop into the chronic urticaria category.

Now what? Once again you’re not alone. Approximately 3 million Americans of every ages own the same problem. There are some significant things that you should know. The first is that, unlike acute urticaria, less than 5% of the cases are due to some external cause.

What is a true penicillin allergy

Also, unlike acute urticaria, the hives and /or swelling are rarely dangerous. In this form of hive problem various quirks and idiosyncrasies of the immune system, as they relate to mast cells, are the primary cause.

Our understanding of the problem is improving but there are numerous unanswered questions. The best understood of these idiosyncrasies is called chronic autoimmune urticaria. Approximately 45% of every chronic hives are of this type. In this condition the immune system makes a detectable antibody (for which we own a test) that mistakenly thinks that parts of the mast cell surface are the enemy.

This antibody attacks the skin mast cells which leads to the release of histamine, etc. It’s been known for a endless time that if our body makes one autoantibody type of error it’s easier for it to make other autoantibody mistakes. Therefore, it’s not terribly surprising that in chronic autoimmune urticaria approximately 20% of patients, especially women, will also own autoantibodies that target the thyroid gland. This may lead to Hashimoto’s thyroiditis and periodically blood tests for thyroid function should be checked.

Unfortunately, treating this thyroid condition probably does not benefit the hives.

The next most common type of chronic urticaria is chronic idiopathic urticaria.

What is a true penicillin allergy

This condition is almost certainly due to the immune system’s interaction with mast cells but the details are unknown. Both chronic autoimmune and chronic idiopathic urticaria may worsen during febrile illnesses, with the use of aspirin family medicines, prior to the monthly menstrual period or with sustained pressure to or rubbing of the skin. Individual hives that sting more than itch, leave bruises and final 3 or more days may indicate hives due to vasculitis (inflammation of the blood vessels).

Other forms of chronic hives own to do with the immune system’s reaction to physical triggers.

Hives produced by stroking of the skin is called dermographism. Some people’s hives are triggered just by freezing, heat, skin pressure, vibration, exercise, sun or even water. These conditions are fairly rare. Some exercise induced patients can either react just to exercise while others react only if their exercise follows the consumption of a food to which they are mildly allergic, most commonly wheat, celery and shellfish. These exercise reactions can produce anaphylaxis and may be dangerous. Another dangerous condition, this one involving angioedema and never hives, is called hereditary angioedema. In these patients swelling of the upper airway can be fatal.

Such patients also generally own pronounced abdominal pain from swelling of their intestines. Treatment is available.

So, now that you’ve put your hives into a category how are they treated? For acute hives and rare cases of chronic hives avoidance of triggers is the key. If the acute hives are already present antihistamines and if severe, a short course of oral steroid is used. For chronic hives daily preventative antihistamines are essential. Doses higher than those used for nasal allergy treatment are often needed. If maximum antihistamine dosing has been reached without control, addition of an H2 blocker (e.g.

Tagamet) and/or a leukotriene blocker (e.g. Singulair) may be tried. Maximizing the above therapy should minimize the need for oral steroid. Relying on recurrent courses of oral steroids (prednisone) especially without full antihistamine, H2 blocker and anti-leukotriene support is to be discouraged. In rare cases cyclosporin or other immunomodulatory medicines may be added. Once control has been achieved medicines should be continued for several weeks or longer past the final symptoms.

Slow tapering can then be attempted.

Do you really own the Hives?

Don’t despair. You’re not alone. Approximately 20% of the population will own hives (urticaria) at one time or another during their lifetime. First off, are you certain that they’re really hives? True hives are red, itchy, generally raised lesions that look very much love mosquito bites. They are often circular or oval but can be  irregularly shaped.

Their size may vary from ¼ inch to several inches in diameter. They may blend together. Each spot lasts anywhere from hours and is surrounded by normal looking skin. As they resolve the skin looks normal, not flaky or rough. While the hives are present one spot will be resolving while another nearby is developing. In about 40% of cases localized swelling (angioedema) of the lips, eyelids, hands, feet or tongue also occurs.
So, if these are really hives they must be from an allergy, right? Well, unfortunately it’s not that simple and modern science doesn’t own every of the answers.

The history of how they first appeared and what’s happened to them since can provide significant clues as to what category of hives you own. But first, what actually is a hive? Everyone’s skin is made up of numerous types of cells. One of these cells is called a mast cell. Everyone’s mast cells make and store histamine. They also routinely make leukotrienes and other substances that can cause localized inflammation. Mast cells don’t generally release much of these substances into the surrounding skin but if they do, these substances, especially histamine produce localized redness, itch and swelling we recognize as a hive or if it’s slightly deeper, angioedema.

Conclusion

So, what’s my prognosis Doc?

As noted above:

  1. Less than 30% of idiopathic acute hives will go on to be chronic.
  2. Acute hives resolve spontaneously.
  3. If you own chronic hives that aren’t of the “physical” type at least 50% will resolve in less than a year and another 20% will resolve over the next several years.

    The “physical” hives tend to be more endless lasting.

Research is ongoing in every of these areas. So hold your chin up, take your antihistamine, and get the necessary attention to the type of hives that you have.

The Case

A year-old man with a past medical history of hemorrhagic stroke, coronary artery disease, and severe aplastic anemia required immunosuppressive therapy (antithymocyte globulin, cyclosporine, and prednisone) and regular blood and platelet transfusions. On the day of presentation, the patient arrived at the infusion middle for a scheduled platelet transfusion. Prior to starting the infusion, he became unresponsive and hypotensive (59/26 mm Hg).

The patient was immediately transported to the emergency department (ED) where, after resuscitation, he described a 1-day history of lethargy, abdominal discomfort, diaphoresis, and bloody bowel movements. Additionally, the patient had an allergy to penicillin, with a reaction of hives documented in the electronic health record. However, it was unclear when this reaction had occurred or whether it had been witnessed by a health care provider.

In the ED, the patient’s vital signs were initially stable: temperature °C, blood pressure /60 mm Hg, heart rate 57 beats per minute, respiratory rate 18 breaths per minute, and SpO2 94%.

Physical examination was notable for a tired-appearing man with slight abdominal distention without significant tenderness or peritoneal findings. A finish blood count was notable for platelets of /µL, white blood cell count of /µL, and absolute neutrophil count of /µL. Chemistry panel and liver function tests were within normal limits, and urinalysis was unremarkable.

Soon after the initial evaluation (during which he appeared hemodynamically stable), the patient developed hypothermia (°C), hypotension (70/40 mm Hg), and worsening mental status.

The patient promptly received 3 L of intravenous fluid. Given continued instability and concern for septic shock, vancomycin was istered. However, neither gram-negative nor anaerobic coverage were ordered due to concern for the penicillin allergy and unknown infection source.

The patient remained hypotensive, and a lactate level returned at mg/dL. A CT scan of the abdomen/pelvis with contrast suggested colitis as a possible source of infection. The absence of gram-negative coverage went unrecognized until the primary admitting team took over 4 hours after the patient’s initial presentation, at which point they ordered aztreonam.

However, the aztreonam was not istered for another 2 hours. As the aztreonam was being given, anaerobic coverage with metronidazole was also ordered but not istered for another 9 hours. Thus, despite the patient’s immunocompromised state (neutropenia and on athletic immunosuppressive therapy) and sepsis from a likely intraabdominal source, ordering and istration of antibiotics with gram-negative and anaerobic coverage was significantly delayed.

Following the patient’s prolonged ED course, he was admitted to the intensive care unit where his sepsis worsened. Antimicrobial therapy was broadened to meropenem, caspofungin, azithromycin, and vancomycin.

The patient developed anuric renal failure necessitating continuous renal replacement therapy. Ultimately, he was transitioned to comfort care and died.

What is a true penicillin allergy

Autopsy revealed the likely cause of death to be septic shock due to neutropenic enterocolitis.

The cause of the patient’s death was deemed to be multifactorial (i.e., high medical complexity, delayed sepsis recognition, unfamiliarity with antibiotic coverage, prolonged ED boarding time, and multiple involved services). However, given the data on relationship between time to antibiotic istration and sepsis mortality, the delayed antibiotic istration likely contributed to the death. Furthermore, the documented penicillin allergy may own contributed to this delay by preventing reflexive istration of empiric gram-negative antibiotic treatment with piperacillin-tazobactam or cefepime.

Moreover, the lack of familiarity with the limited efficacy of aztreonam in anaerobic coverage led to a delay in the addition of appropriate anaerobic treatment.

by Kimberly G.

What is a true penicillin allergy

Blumenthal, MD, MSc

Sepsis affects more than 1 million Americans per year and is a leading cause of death in the United States.(1) Sepsis requires swift recognition and management of infection, with beta-lactam antibiotics (often piperacillin-tazobactam or cefepime) indicated as empiric therapy. Additional coverage of resistant gram-positive bacteria may be required with vancomycin, and as in this case, anaerobe coverage may be needed for enteric organisms.

Mortality in sepsis increases even with extremely short delays in antimicrobial istration.(2) The patient in this case did not own gram-negative coverage for 6 hours, and the penicillin allergy history likely contributed to the delay to first dose of antibiotic.

Among patients presenting to the ED with pneumonia, urinary tract infection, bacteremia, and sepsis, patients with a penicillin allergy had a longer mean time to first antibiotic dose than patients without a penicillin allergy history ( minutes vs minutes, p=).(3) The antibiotic ultimately istered in this case was aztreonam, which is considered inferior to piperacillin-tazobactam and cefepime, especially for Pseudomonas species. Similarly, one prior study found patients with beta-lactam allergy histories experienced higher clinical failure for gram-negative bloodstream infections compared to patients without (39% vs 27%, p=).(4)

Patients who own a history of penicillin allergy comprise approximately 10% of the US population.(5) However, numerous penicillin allergic patients actually are not allergic to the drug, yet the allergy label prevents them from being treated with beta-lactams.

In fact, patients with historical penicillin reactions own their allergy disproved more than 95% of the time after undergoing formal testing.(5) Additionally, drugs on a patient’s allergy list often include adverse effects and intolerances. These nonimmunologic reactions may be considered allergies by patients, but often do not warrant penicillin avoidance.(6) A history of «hives» or «rash» are among the most commonly reported reactions, but may own been from a childhood viral exanthem rather than a drug allergy. Even if there were an immunoglobulin E (IgE)-mediated penicillin reaction, penicillin allergy wanes over time.

This means that years later, patients are unlikely to be allergic.(5)

Shared chemical structures between penicillins and cephalosporins can be the source for clinical cross-reactivity, including the beta-lactam ring and side chains (e.g., ampicillin shares a side chain with the cephalosporins cefaclor and cephalexin). However, the later generation cephalosporins, such as cefepime, are tolerated in the overwhelming majority of cases, even in patients who own anaphylactic penicillin allergy histories.(7) In patients with a history of nonsevere penicillin allergy, treatment with cephalosporins without preceding penicillin skin testing leads to a reaction rate lower than the expected new rate of reactions to cephalosporins.(7) Even in patients with proven penicillin allergy, only about 2% react to treatment with cephalosporins.(7) Higher reaction rates might be observed in acutely ill patients—one study found % reactions to cefepime and % reactions to ceftazidime in patients with IgE-mediated penicillin allergy histories not confirmed with testing.(8) Carbapenem use in patients with penicillin allergy histories is also safe; even among 56 acutely infected hospitalized patients with IgE-mediated penicillin allergy histories, none reacted to carbapenems.(8)

The choice to not give a penicillin, or beta-lactam antibiotic, due to a penicillin allergy history may own other immediate and longer term consequences.

Use of non–beta-lactam alternatives in patients reporting penicillin allergies leads to more treatment failures in methicillin-sensitive Staphylococcus aureus bacteremia and more surgical site infections.(9,10) Infected hospitalized patients not treated with a beta-lactam had a threefold increased odds of adverse events that included drug toxicities and Clostridium difficile colitis.(11) Penicillin allergy reporters also had a 26% increased risk of Clostridium difficile and a 69% increased incidence of methicillin-resistant Staphylococcus aureus colonization or infection over a mean follow-up time of 6 years.(12)

To make better antibiotic choices, it is crucial to do a systematic evaluation of the history of penicillin response, beginning with a thorough allergy history.

Numerous patients report symptoms that were highly unlikely to be a true allergy, such as family history or gastrointestinal intolerance. Patients whose allergy history is an adverse effect or intolerance should own the «allergy» deleted or the «reaction type» changed to indicate there was no genuine allergy. When time and resources permit, penicillin allergies that may be IgE-mediated (such as hives, angioedema, shortness of breath, anaphylaxis) can be evaluated with a penicillin skin test. While historically performed by allergy specialists, penicillin allergy testing in hospital-based patients has been performed by nurses, pharmacists, and physicians from other specialties (medicine, infectious diseases).

Penicillin skin testing takes about 1 hour to act out. If tests are negative, one full dose of a penicillin (usually amoxicillin) is given under observation. If there is no reaction, then the penicillin allergy is deleted from the record. When penicillin skin testing is not possible (or not necessary because of low risk), drug challenges or test doses can be considered, either with amoxicillin to disprove the underlying penicillin allergy or with the indicated therapeutic beta-lactam.

One example test dose protocol gives 1/10th drug dose followed by % dose 1 hour later under observation.

Decision support around penicillin allergies can be incorporated into antibiotic prescribing and sepsis bundles to ensure the quick and safe istration of a beta-lactam antibiotic. Decision support might indicate which patients can own piperacillin-tazobactam and cefepime. For patients with higher risk beta-lactam allergy histories, decision support can still indicate that full dose carbapenems and the monobactam aztreonam are safe for use.

At Massachusetts General Hospital and other academic and community Partners Healthcare System hospitals in the greater Boston area, we use test dose challenges in the ED and inpatient areas to optimize beta-lactam antibiotic use in patients with penicillin and cephalosporin allergy histories.(13) Our data indicate that inpatient penicillin and cephalosporin use increased approximately twofold; moreover, among more than test doses analyzed, fewer than 4% of patients had reactions (three patients needed intramuscular epinephrine).(8,14) Our penicillin allergy algorithm modified based on our most recent data is shown in the Figure.

Clinical decision support tools to urge standardized approaches to penicillin allergy in inpatients might include alerts, order sets, or web-based tools.(13) Alternative approaches to skin testing and test dose methods include implementation of allergy consultations (even virtually with telehealth [15]) and/or drug desensitization protocols to facilitate safe drug istration in patients who are truly allergic (e.g., recurrent IgE-mediated reactions or skin test positive), or too acutely ill to discover out (i.e., the patient would be unlikely to recover from anaphylaxis).

Allergy documentation in health records is often inaccurate and incomplete.

Although every allergy entries warrant attention to improve quality and safety, penicillin allergy documentation is a priority.(6) Large-scale efforts to improve the characterization of penicillin allergies include a recent professional society–endorsed review (5) and Centers for Disease Control and Prevention support in proclaiming a National Penicillin Allergy Day (September 28).(16)


References

1. Howell MD, Davis AM. Management of sepsis and septic shock.

JAMA. ; [go to PubMed]

2. Kim RY, Ng AM, Persaud AK, et al. Antibiotic timing and outcomes in sepsis. Am J Med Sci. ; [go to PubMed]

3. Conway EL, Lin K, Sellick JA, et al. Impact of penicillin allergy on time to first dose of antimicrobial therapy and clinical outcomes. Clin Ther. ; [go to PubMed]

4. Jeffres MN, Narayanan PP, Shuster JE, Schramm GE. Consequences of avoiding ß-lactams in patients with ß-lactam allergies. J Allergy Clin Immunol. ; [go to PubMed]

5.

Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and management of penicillin allergy: a review. JAMA. ; [go to PubMed]

6. Blumenthal KG, Park MA, Macy EM. Redesigning the allergy module of the electronic health record. Ann Allergy Asthma Immunol. ; [go to PubMed]

7. Macy E, Blumenthal KG. Are cephalosporins safe for use in penicillin allergy without prior allergy evaluation? J Allergy Clin Immunol Pract. ; [go to PubMed]

8.

Blumenthal KG, Li Y, Hsu JT, et al. Outcomes from an inpatient beta-lactam allergy guideline across a large US health system. Infect Control Hosp Epidemiol.

What is a true penicillin allergy

; [go to PubMed]

9. Blumenthal KG, Parker RA, Shenoy ES, Walensky RP. Improving clinical outcomes in patients with methicillin-sensitive Staphylococcus aureus bacteremia and reported penicillin allergy. Clin Infect Dis. ; [go to PubMed]

Blumenthal KG, Ryan EE, Li Y, Lee H, Kuhlen JL, Shenoy ES. The impact of a reported penicillin allergy on surgical site infection risk.

What is a true penicillin allergy

Clin Infect Dis. ; [go to PubMed]

MacFadden DR, LaDelfa A, Leen J, et al. Impact of reported beta-lactam allergy on inpatient outcomes: a multicenter prospective cohort study. Clin Infect Dis. ; [go to PubMed]

Blumenthal KG, Lu N, Zhang Y, Li Y, Walensky RP, Choi HK. Risk of methicillin resistant Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin allergy: population based matched cohort study. BMJ. ;k [go to PubMed]

Blumenthal KG, Shenoy ES, Wolfson AR, et al. Addressing inpatient beta-lactam allergies: a multihospital implementation.

J Allergy Clin Immunol Pract. ;e7. [go to PubMed]

Blumenthal KG, Wickner PG, Hurwitz S, et al. Tackling inpatient penicillin allergies: assessing tools for antimicrobial stewardship. J Allergy Clin Immunol. ;e6. [go to PubMed]

Staicu ML, Holly AM, Conn KM, Ramsey A. The use of telemedicine for penicillin allergy skin testing. J Allergy Clin Immunol Pract. ; [go to PubMed]

National Penicillin Allergy Day. [Available at]

Wolfson AR, Huebner EM, Blumenthal KG. Acute care beta-lactam allergy pathways: approaches and outcomes. Ann Allergy Asthma Immunol. Apr 19; [Epub ahead of print]. [go to PubMed]


Take-Home Points

  1. Most patients who own a history of penicillin allergy are not allergic when the allergy is formally evaluated.
  2. Unverified penicillin allergy leads to increased treatment failures and delay to first antibiotic dose in sepsis patients.
  3. Even patients with true, IgE-mediated penicillin allergy can safely get most cephalosporins, and every carbapenems and monobactams.
  4. Other harms of unverified penicillin allergy labels include increased risk of adverse events, Clostridium difficile infection, surgical site infection, and colonization with antibiotic resistant organisms.
  5. Systemwide approaches to hospitalized patients with beta-lactam allergies are needed to improve the quality and safety of care.

Kimberly G.

Blumenthal, MD, MSc
Assistant Professor of Medicine
Quality and Safety Officer for Allergy
Professor of Radiology and Neuroradiology


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