Educational aims
The reader will come to:
Interpret that delayed hypersensitivity reactions (DHRs) are more prevalent in CF, however, true drug allergies (DAs) have similar rates compared to the general population.
Define beta-lactams as the leading causative agents for DHRs followed by sulfamethoxazole.
Recognize that among CF patients anaphylaxis is rare but seems similar to the general population.
Appreciate the most significant DHR risk factor as the cumulative dose of a specific antimicrobial in a given period of time and not lifetime dose as previously assumed.
Abstract
One hurdle in the management of CF, a disease characterized by progressive endobronchial infection, is the presence of hypersensitivity reactions to antimicrobials due to prolonged and repetitive treatment courses. The aim of this review is to compile existing data and provide insight to medical professionals on a long-debated topic for optimum patient care. Clinical studies were inducted from the last 15 years and filtered based on their relativity to drug hypersensitivity reactions (DHRs), antibiotics and CF. After completing the selection process, 10 clinical studies were thoroughly examined. The most frequent antibiotic group related to DHRs were beta-lactams. Frequency of the most common overall type of reaction (immediate or nonimmediate) differed among clinical studies. Although severe reactions seem rare comparatively, they do occur during and even after completion of treatment regimens. The prevalence of true drug allergies should be confirmed using a variety of tests available, however, should not be confused with overall DHR rates. Genetic mutations, gender and lifetime antibiotic dose were not related with an increased risk for DHR development. On the contrary, the most important factor according to most studies was the cumulative antimicrobial dose in a given period of time, especially when delivered parenterally. DHRs are an indisputable problem in the management of CF patients. Understanding possible risk factors and increased awareness is vital in both hospital and outpatient settings as early detection can decrease the severity of the reactions.
INTRODUCTION
Cystic Fibrosis (CF) is an autosomal recessive disorder affecting the gene 7q31 that encodes for the cystic fibrosis transmembrane regulator (CFTR) protein . Respiratory care in CF focuses on chest physiotherapy and timely exacerbation management with antibiotics. Concurrent administration of multiple antibiotics is commonly required considering that multiresistant bacterial strains are constantly emerging . Up to date combination therapies are beneficial due to synergy . Co-administration of selected antibiotics may also slow the development of bacterial resistance. The most common pathogens in CF are Staphylococcus aureus and Pseudomonas aeruginosa. Therefore, it is logical to empirically treat patients with the most organism-effective antibiotics . Thus, the most frequently used antimicrobials in CF include beta-lactams (i.e. penicillins, cephalosporins, piperacillin-tazobactam (PZP-TZB), meropenem and aztreonam), aminoglycosides and quinolones . It is well known that higher doses are necessary in CF management in order to achieve proper serum concentrations.
It has been suggested that delivering antibiotics frequently at high doses for an extended period of time may pose a risk of developing hypersensitivity reactions. Likewise, the combination of increased survival rates and gradually advancing disease indirectly increase DHR risk. DHRs result in premature antimicrobial discontinuation and thus, less efficient therapy . Further investigation of DHR prevalence in CF is essential as it has repercussions in both health and economic sectors. Debate exists on whether DHR prevalence is greater in CF patients compared to that of the general population.
Furthermore, it is important to understand terminology and have a common basis proceeding with the interpretation of results. The terms adverse drug reaction (/s), adverse drug events (AEs) and hypersensitivity reactions at times are imprecisely used interchangeably. According to the World Health Organization (WHO) an adverse reaction is “any response that is noxious, unintended, or undesired, which occurs at doses normally used in humans for prophylaxis, diagnosis, therapy of disease, or modification of physiological function.” An AE, according to the FDA is “any undesirable experience associated with the use of a medical product” caused by proper or improper use of the drug at hand. Therefore, AE is an umbrella term that encompasses the terms AR, hypersensitivity reactions and drug allergy (DA).
ARs are further divided into Type A and Type B reactions. Type A reactions comprise 85–90 % of all ARs and can be seen in anyone. These reactions, also known as augmented reactions, are typically related to an exaggerated response of the pharmacology of the medication at hand. They are both predictable and dose dependent reactions. Examples of Type A reactions that are encountered include diarrhea associated with antibiotic use, bleeding with warfarin and aminoglycoside nephro and ototoxicity.
Type B reactions are hypersensitivity reactions. Unlike Type A, these reactions only occur in susceptible individuals and cannot be anticipated. Additionally, they are not related to drug pharmacology nor dose-dependent. Type B reactions are characterized by an underlying mechanism that is either immune or inflammatory mediated or both. Examples include anaphylaxis, urticaria and DHRs. Moreover, a reaction that is not mediated by the immune system or inflammatory mechanism is known as an idiosyncratic or exaggerated sensitivity reaction . Therefore, caution is needed so that allergic reactions are not confused with pharmacologic side effects .
DHRs comprise 10–15 % of all ARs and are divided into four different categories . Type I-III are considered immediate reactions since they occur in less than 24 h . Nonimmediate or delayed DHRs occur afterwards. Delayed hypersensitivity reactions, or Type IV reactions, are further divided into early (more than 1 h but less than or equal to 24 h) and late (more than 24 h) . Both types of DHRs can be life threatening. In type I reactions, anaphylactic symptoms can be observed whereas serious delayed reactions, which can occur 2 to 6 weeks later, can also lead to serious cutaneous adverse reactions (SCARS) such as: drug rash with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) . Allergic reactions are unpredictable, however, understanding who is at higher risk is beneficial.
It cannot be stressed enough that premature termination of certain antimicrobials may hinder treatment outcomes and consequently patient survival. The significance of properly identifying true antimicrobial DAs is extremely crucial as patients have been denied lung transplants due to multi-drug hypersensitivity.
The aim of this review was to clarify and summarize results from clinical studies regarding antimicrobial hypersensitivity reactions due to their prolonged and repetitive use in CF, in order to set a common battleground for the fight for survival and better quality of life for patients among CF centers.
METHODS
The electronic database used to gather literature was PubMed. Search queries included hypersensitivity reactions, antibiotics, cystic fibrosis, adverse events, drug induced and allergy.
Inclusion criteria
Literature was selected according to relevance regarding hypersensitivity reactions seen with prolonged use of antibiotics in CF patients. Studies dated back up to 15 years were inducted in this review. Case reports, editorials, and studies lacking clear information on the subject were excluded. Furthermore, articles regarding desensitization, reintroduction and management techniques were omitted as their subject was beyond the scope of this review. Initial filters were language (English) and clinical studies from 2008 to 2023.
Data collection
Article selection was performed through PubMed. The utilized keywords included “hypersensitivity reactions,” “antibiotics,” “cystic fibrosis,” “adverse events,” “drug-induced,” and “allergy.” Overall, 581 results were available. Initially duplicates (n = 183) were removed leaving a total of 398 studies for further analysis. An additional 353 articles were excluded during the title review phase, and an additional 33 articles were removed after the abstract review. Out of the 12 remaining articles, one was further excluded because it focused on specific antibiotic pharmacology, and another was removed because it discussed the tolerance of high-dose administration. Ultimately, 10 studies remained and were included in this systematic review. The details of the article selection process are elucidated in the flowchart depicted in Fig. 1 . The determined risk factors from the clinical studies were assessed and presented in detail in Fig. 2 . More specifically, risk factors are classified as verified and disproved. Verified describes the number of studies that found the risk factor assessed as significant, while disproved represents the number of studies which identified the risk factors as insignificant.
RESULTS
Τable 1 shows the 10 studies that were examined in this review. Rates of DHRs in the general population are referred to make up 10–15 % of total adverse events. DAs provoked only by beta-lactams are estimated to have a prevalence of 1–10 % . Evidently, based on earlier clinical studies, DHRs are comparatively more frequently observed among patients with CF . Indeed, reports indicate that these reactions occur up to three times more frequently in CF patients .
The majority of studies examined in this systematic review are retrospective in nature. Only a small number of the clinical studies validated their results with allergic confirmation testing. Consequently, the conclusions largely rely on reactions that lack thorough documentation. This also created a notable discrepancy attributed to differences in terminology.
Upon a thorough examination of the aforementioned studies, the key findings of this systematic review are as follows:
Prevalence
CF patients are said to be in a state of immune hyperactivity . Thus, it can be assumed that this can indirectly lead to increased DHR susceptibility since DHRs are either immune or inflammatory-mediated. Patients with CF experience frequent and prolonged exposure to antimicrobials, rendering them more susceptible to sensitization . On the other hand, increased exposure may provoke tolerance . The prevalence of DHRs among CF patients in previous studies ranged from 29 % to 62 % and were roughly reported three times more frequently compared to the general population.
Within the studies incorporated in this review, it is important to be cautious when evaluating the prevalence of DHRs. Two studies, namely Braun et al. and Tugcu et al. , documented a prevalence of 10 %. Tugcu et al. focused exclusively on children, which could possibly account for the lower frequency observed in their study. Higher rates were documented by Roehmel et al. , Anstey et al. , and Kowalik et al . Specifically, the prevalence rates reported were 60 %, 60.1 %, and 31 % respectively. Roehmel et al. and Anstey et al. investigated the overall antimicrobial ARs. Anstey et al. reported that 14.9 % of the reactions were categorized as intolerance reactions. Hence, when calculating the average prevalence from the provided statistics, these reactions were excluded, resulting in a prevalence of 45.2 % (the initial overall prevalence was 60.1 %). The three aforementioned studies by Roehmel et al. , Anstey et al. , and Kowalik et al. examined various antibiotic groups. However, it’s worth noting that Roehmel et al. focused exclusively on parenterally administered antimicrobials. This may explain why Roehmel et al. observed a high prevalence rate for DHRs among these patients. Additionally, Anstey et al. only evaluated adults.
These prevalence rates coincide with older studies. For example, Koch et al observed a frequency of 62 % and Wills et al 34 %. It should be clarified, however, that both of these studies investigated the prevalence of ARs in CF patients. On the contrary, Braun et al , a study conducted across all age groups and multiple antimicrobial categories, expressed an AR frequency of 10 %. In summary, DHRs in the general population account for approximately 10–15 % of the total adverse events. Thus, while rates among CF patients might be either overestimated or underestimated, it remains clear that DHRs present a significant challenge in patient management.
Regarding prevalence of true DAs confirmatory tests such as skin prick tests (SPTs), intradermal tests (IDTs) and drug provocation tests (DPTs) were utilized. Articles that analyzed reactions via confirmatory allergy testing had varying results. Indeed, the true DA rates in the preceding six studies that examined this aspect were comparable, if not lower, than those observed in the general population. These rates ranged from 0.17 % to 7.5 %. Findings from Casimir-Brown et al were excluded due to the absence of total CF patient numbers from other centers, which hindered a proper evaluation of the results. Low rates were described by Matar et al , Braun et al and Tugcu et al . Several possible explanations exist. One reason, as aforementioned, is the retrospective character of the studies. Other possible reasons are the absence of patient follow-up and the potential limitation of routine allergy testing used in the studies to identify the underlying mechanism responsible for specific DHRs. Interestingly, Matar et al only investigated beta-lactam induced reactions and stated a confirmed prevalence of 0.71 %. On the other hand, Tugcu et al found a true DA prevalence of 0.91 % and did not confirm any beta-lactam reactions. Only one study by Caimmi S. et al conducted a reevaluation of patients one year after the initial analysis and reported a DA prevalence of 4.09 %. These results do not seem favor either sensitization or tolerance due to frequent exposure and, additionally, contradict previously published studies. Burrows et al and Pleasants et al claimed a DA rate of 36 % and 28.9 % respectively. However, it is crucial to mention that allergy confirmation tests were not performed in their studies.
It appears that the prevalence of true DA might involve other immunological mechanisms that are not discernible through the methods employed in current standard clinical practice. Alternatively, true DA in CF patients might not be as widespread as previously believed. One main problem is that terminology (AR, hypersensitivity reaction and DA) and differentiation of documentation techniques can lead to confusion and mislabeling. Hypersensitivity reactions by definition encompass DAs. Once again, it’s important to emphasize that drug hypersensitivity is more common within this particular group of patients. Moreover, when trying to ascertain the accurate prevalence, it’s essential to clarify that this pertains to true DA. Given that true DA rates are either lower or comparable to those in the general population, alternative approaches like antihistamine administration and desensitization should be considered to ensure continued therapy for optimal efficacy. Ceasing treatment would be futile if true drug allergy isn’t present.
Major antimicrobial offenders causing DHRs
The majority of clinical studies assessed in this review claim that beta-lactams are the most common offenders. This finding is not surprising as it reflects the situation observed in the general population . These antimicrobials are used empirically to target both Staphylococcus aureus and Pseudomonas aeruginosa infections. The high incidence of beta-lactam related hypersensitivity reactions can be attributed to their susceptibility to haptenization , which renders them highly immunogenic. Their side chain is usually the target for antibody formation. They account for approximately 80 % of all DHRs in CF patients. In the general population, the DHRs to beta-lactams are estimated to have a prevalence of 1–10 %. However, the overall prevalence of antimicrobial DAs has been estimated to be around 20 % or lower.
Overall, PZP-TZB seems to be the most common single culprit followed by ceftazidime. PZP-TZB is not only the most frequent cause of DHRs but also provokes the most severe reactions . Tugcu et al was the only study that found TMP-SMX (trimethoprim-sulfamethoxazole), a non beta-lactam antibiotic, as the most prevalent DHR causative agent. A potential explanation for this difference could be the low confirmation rate observed in this study following allergy testing for the beta-lactam group. In fact, only reactions to TMP-SMX were confirmed. TMP-SMX made up 6.06 % of all reactions, while beta-lactams constituted approximately 36.4 % of all DHRs recorded prior to allergy testing. However, it should be noted that PZP-TZB alone made up only 3.03 % of all DHRs recorded.
TMP/SMX has recently been considered the second most common DHR provocateur among CF patients since SMX antigenicity was described . As per Braun et al , TMP/SMX-related DHRs accounted for 18.4 % of the cases, whereas in the general population, they range from 2 % to 9 %. Comparatively, this antibiotic is used more frequently among CF patients. Quinolones are associated with a low risk of DHRs , whereas aminoglycosides, particularly neomycin and streptomycin, carry a risk of more than 2 % for DHRs. For detailed reference regarding the most common antibiotics leading to drug hypersensitivity reactions (DHRs) in each clinical study assessed within this review, please refer to Table 2 .
| Reference No | Author, Publication Date | Study Population | Main Type of Reaction (Immediate/ Nonimmediate) (%) | Anaphylaxis (%) |
|---|---|---|---|---|
| 1 | Tugcu et al, 2022 | Children | Nonimmediate (66.6 %) Immediate (33.4 %) | None |
| 4 | Peckham et al, 2013 | Unspecified | Nonimmediate (94) Immediate (6) | (6) (includes both anaphylaxis and urticaria) |
| 10 | Kowalik et al, 2022 | Children/Adults | Nonimmediate 1 (67) Immediate (28) | 2.3 (3/131) Piperacillin, meropenem, colistimethate |
| 12 | Roehmel et al, 2014 | Children/Adults | Nonimmediate (12) Immediate (81 %) | (15) Total: PZP-TZB (4.86) Ceftazidime (3.78) Highest risk with Aztreonam (6) and Cefuroxime (6) |
| 14 | Caimmis S. et al, 2012 | Children/Adults | Nonimmediate (54.5) Immediate (45.5) | (17.1) (not specified) |
| 28 | Matar et al,2014 | Children | For all HRs : Nonimmediate (51.3) Immediate (48.7) After DA confirmation : Nonimmediate (43.5) Immediate (56.5) | (28.2) Ticarcillin, Tazocillin, amoxicillin, aztreonam (in 6 courses), ceftazidime piperacillin |
| 32 | Braun et al, 2020 | Children/Adults | Nonimmediate (10.5) Immediate (38.2) Missing Data (51.3) | 6.9 Cotrimoxazole |
| 33 | Anstey et al, 2020 | Adults | Immediate (33.8) 2 → (20.8) to beta-lactams and (5.2) to sulfonamides | N/A |
| 38 | Casimir-Brown et al 3 , 2021 | Children/Adults | Nonimmediate (65.2) Immediate (34) | N/A |
| 39 | Suleyman et al, 2022 | Children | Nonimmediate (20) Immediate (80) | 13.3 (2/15) To ceftazidime and ciprofloxacin |
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