Abstract
Background:
Hypersensitivity reactions (HSRs) to tetracyclines and the related compound, tigecycline, can limit the use of these medications and compromise optimal patient care. Despite this, there is little discussion in the literature describing the presentation of these reactions or guiding clinicians on the management of these reactions in adult and pediatric patients.
Objective:
To describe the clinical features, optimal diagnostic approach, and management of HSRs to tetracyclines.
Methods:
Patients with reactions to tetracyclines at our institution from 2011 to 2019 were identified by retrospective chart review. Skin testing protocols were designed for each antibiotic. Graded challenge and desensitization procedures were devised based on medical history, skin testing results when available, and need for readministration.
Results:
The HSRs to tetracyclines, their workup, and management are described for 10 patients, aged 7 to 68 years. Our skin testing protocols for doxycycline, minocycline, and tigecycline described herein had good negative predictive value. When skin testing was negative and the initial reaction was not severe, graded challenge to the culprit drug was performed. Using the included procedures, 3 patients were desensitized to oral doxycycline, 3 to oral minocycline, and 2 to intravenous tigecycline. All the desensitizations were successful.
Conclusions:
Once identified, HSRs to tetracyclines can be further evaluated with skin testing and graded challenge and managed in appropriate cases with desensitization. These procedures can facilitate first-line therapy for patients who require tetracyclines but developed hypersensitivity reactions.
Introduction
Tetracyclines are commonly used antimicrobials with a broad spectrum of activity against a variety of organisms. Doxycycline and minocycline are the most commonly used medications in this class of antibiotics. Glycylcyclines, including tigecycline, are newer tetracycline-derived antibiotics that share similar antimicrobial activity with older tetracyclines. Molecular changes to its parent molecule, minocycline, have augmented tigecycline’s antimicrobial activity and decreased its susceptibility to bacterial resistance.1 In general, tetracyclines are effective against many pathogens, such as Streptococcus pneumoniae, Haemophilus influenzae, and methicillin-resistant Staphylococcus aureus, and they are often the preferred agents in treatment of Mycoplasma, Rickettsia, Chlamydia, Vibrio, and Ehrlichia infections.2 Owing to their widespread utility, tetracyclines are commonly prescribed and sometimes implicated in drug hypersensitivity reactions (HSRs).
Although adverse reactions involving IgE-mediated mechanisms to these medications are rarely reported,3 there have been case reports of anaphylaxis to both doxycycline4 and minocycline.5 IgE-mediated HSRs may include urticaria, angioedema, rash, abdominal pain, bronchospasm, respiratory distress, and hypotension.4,5 Non-IgEemediated reactions mostly comprise HSRs to the tetracycline class. Drug fever without rash has been described for minocycyline.6 Tigecycline-induced drug fever and leukemoid reaction have been described, likely also with a non-IgEemediated mechanism. Other non-IgEemediated HSRs include drug reaction with eosinophilia and systemic symptoms (DRESS), papulosis, and serum sickness-like reactions or systemic lupus erythematosus.7–10
The rate of cross-reactivity between tetracycline antimicrobials has not yet been established, but co-allergy to doxycycline and minocycline has been reported.11 Differences in side chain structures are hypothesized to be responsible for the different reaction rates.3 In general, HSRs are more commonly attributed to minocycline than to doxycycline. A large case series in France reported a lower incidence of drug reactions to doxycycline than to minocycline, with 3 patients developing HSRs to doxycycline and 38 developing HSRs to minocycline over a 12-year period.8
For certain infections, such as methicillin-resistant Staphylococcus aureus and tick-borne diseases, tetracyclines are among the few effective antimicrobials available, and in some cases, such as for Lyme disease, represent first-line therapy.12 Therefore, even with a history of HSR, the use of these antibiotics may be warranted in such cases. Despite the necessity of tetracyclines and glycylcyclines as the first-line agents against many infections, guidelines for the evaluation and management of patients who develop HSRs to these medications are not published.
Validated skin testing protocols, drug challenge procedures, and rapid desensitization techniques are paramount for the evaluation and management of the growing population of patients with HSRs to tetracyclines and tigecycline. Skin testing protocols and minimum nonirritating concentrations for doxycycline, minocycline, and tigecycline have not been established. Furthermore, there have only been a few single-case reports of doxycycline desensitization protocols, and these were all in adult patients.13–15 There are no previously reported validated desensitization protocols for use in pediatric patients. In addition, to our knowledge, desensitization protocols for minocycline and tigecycline have not been previously reported.
Here, we present a case series of 10 patients, including 8 pediatric patients, with HSRs to doxycycline, minocycline, and tigecycline (Table 1). We describe the skin testing protocols we have created and implemented. We also present our graded challenges and well-tolerated desensitization procedures. In our case series, all the patients successfully completed either their graded challenge or rapid desensitization.
Methods
We performed a retrospective chart review of patients with HSRs to tetracyclines and tigecycline who underwent skin testing, graded challenge, and desensitization at the Boston Children’s Hospital between 2011 and 2019. An institutional review board approval was obtained.
Skin Testing Protocols
Skin prick and intradermal testing were performed at least 4 weeks after the initial reaction to reduce the likelihood of false- negative results.16 Histamine (10 mg/mL) and saline were used as positive and negative controls, respectively. The minimum nonirritating concentration for these antimicrobials has not been previously reported. As such, protocols were designed on the basis of the maximum nonirritating concentrations of each antibiotic after testing between 1 and 3 control subjects. The concentrations used for the skin testing are shown in Table 2.
Graded Challenge Procedures
When skin testing was negative and the initial reaction was not considered severe based upon the Brown Classification Criteria,17 graded challenge to the culprit drug was performed.
Before the graded challenge or desensitization, informed consent was obtained, and the patient was admitted to a highly monitored unit, either intermediate or intensive care, depending on the severity of the initial reaction. Rescue medications, including intramuscular epinephrine, intravenous diphenhydramine, normal saline, albuterol, and methylprednisolone, were immediately available at the bedside in the event of an IgE-mediated reaction. In all cases, the challenge entailed dosing 1% of the goal dose, followed 30 minutes later by 10% of the goal dose, and followed 30 minutes later by 90% of the goal dose. The patient was monitored for at least 1 hour after the challenge for signs of intolerance.18
Desensitization Approach—Premedication Selection
When skin testing was positive and the reaction was considered moderate or severe by the same criteria,18 desensitization was pursued with the same precautions as described previously. Pretreatment medications were utilized in select cases to minimize breakthrough reactions during the procedure and implemented in cases with more severe initial reactions or in patients with history of failed desensitization procedures to other drugs. Premedications were determined on the basis of the clinician’s preference and concern for reaction during the desensitization. The premedication regimens were administered 1 hour before the start of the desensitization.
Desensitization Approach—Protocols
Patients B, E, and F were desensitized to oral doxycycline following the protocol in Table 3. Patients A, F, and G were desensitized to oral minocycline following the protocol in Table 4. Patients A and F were desensitized to intravenous tigecycline following the protocol in Table 5.
Desensitization Approach—Management of Breakthrough Reactions
When breakthrough reactions occurred, they were addressed by temporarily pausing the protocol, treating the reaction, and continuing after reducing the infusion rate or adding steps to the protocol.
Results
The characteristics of the patients are shown in Table 1. A total of 10 patients were evaluated for reactions to tetracyclines and tigecycline. The patients required antibiotics for Lyme disease, cellulitis, or exacerbations of cystic fibrosis. Erythematous maculopapular rashes during tetracycline or tigecycline exposure were reported by patients A, B, C, D, G, H, and I. Although patient H’s rash was concerning for DRESS while receiving tigecycline, she had been on multiple antibiotics at the time, and tigecycline was not considered the most likely culprit for the reaction. Patient J reported urticaria during the doxycycline treatment. More severe, likely IgE-mediated reactions were reported as well; patient E developed anaphylaxis during the treatment with doxycycline for Lyme meningitis, and patient F developed chest tightness and bronchospasm with minocycline and tigecycline exposure, respectively.
Of 10 patients, 9 underwent skin testing to the culprit medication and to other antibiotics within the class if there was a potential need for these medications in the future. In summary, skin testing to doxycycline, minocycline, and tigecycline was completed by 7 patients, 6 patients, and 1 patient, respectively. In 2 cases, patients E and F, skin testing was initially deferred owing to the urgent need for the culprit medication. In patient E, skin testing was performed and was positive 6 months after the patient underwent initial desensitization. Patient F had end-stage cystic fibrosis, and in each case, prompt institution of life-saving antibiotics was required before the completion of skin testing. Desensitization was successfully completed to doxycycline, minocycline, and tigecycline.
When the reaction history was not classified as moderate or severe and skin testing was negative, graded challenges were initiated. Graded challenges occurred to doxycycline in 3 patients (A, H, and I), to minocycline in 2 patients (C and D), and to tigecycline in 2 patients (A and H) and were successful in all.
In total, 3 desensitizations occurred to doxycycline, 4 to minocycline, and 2 to tigecycline. All the desensitizations were completed successfully.
Premedications were only utilized in patient E. The patient received a diagnosis of Lyme meningitis, and intravenous ceftriaxone had been initiated as first-line therapy; however, on day 9 of the therapy, the child developed a pruritic rash that mandated cessation of this antibiotic. Desensitization to ceftriaxone was attempted; however, she developed anaphylaxis during that protocol. On beginning doxycycline instead, she developed angioedema of the lips, facial flushing, and abdominal upset. Desensitization was necessary because there was no other appropriate antibiotic. Premedication with oral prednisolone and cetirizine was instituted owing to her recent history of anaphylaxis during attempted ceftriaxone desensitization.
A total of 2 patients had breakthrough symptoms during desensitization. Both of those breakthrough reactions were easily managed, allowing for successful continuation of desensitization and subsequent completion of the treatment. Patient B received a diagnosis of Lyme arthritis and tested positive by intradermal testing to all oral potential therapies, including amoxicillin and doxycycline. Doxycycline was recommended as the first-line therapy for his Lyme arthritis. A 12-step desensitization to oral doxycycline was devised (Table 3), with initial dose for the desensitization based on the concentration the patient reacted to during skin testing. The child exhibited mild pruritus localized to the shoulder during the final steps of the protocol, but this was resolved with skin cooling measures. The patient received the next full dose of 100 mg 12 hours after the desensitization was started as prescribed and completed his 4-week treatment course without incident.
Despite premedication, patient E, who had Lyme meningitis, developed brightly erythematous cheeks without other associated symptoms immediately following the sixth dose (1 mg) of her doxycycline desensitization. The desensitization was paused for 30 minutes, and she was administered oral diphenhydramine and montelukast. After this period of monitoring, an additional 1-mg dose was repeated as the new step 7, in an effort to improve the child’s tolerance. The desensitization was then completed successfully without additional complications.
Discussion
Despite their common use and first-line indication for many infections, there is paucity of literature regarding management of HSRs to tetracyclines and tigecycline. To our knowledge, this is the first comprehensive case series describing both pediatric and adult patients with HSRs to tetracyclines and their evaluation and management. This represents the first publication of skin testing, graded challenge, and entirely oral desensitization protocols to this class of medication. In addition, although doxycycline and minocycline HSRs and anaphylaxis have been reported,4,5,8,11 we believe this to be the first report of IgE-mediated reaction and desensitization to tigecycline.
In evaluating cases of HSR to tetracyclines, it is imperative to first attempt to define the mechanism behind the initial reaction (IgE- or non-IgE—mediated) and understand its severity. Pursuing skin testing in appropriate cases can then assist the allergist in choosing to perform a diagnostic graded challenge or a therapeutic desensitization procedure. Although skin prick testing has been reported to minocycline,19 to our knowledge, our report offers the first intradermal skin testing protocol for these antibiotics. The nonirritating concentration of the medication is used as a point of reference in developing skin testing regimens.20 However, the maximum nonirritating concentration of doxycycline, minocycline, and tigecycline has not been reported. Therefore, we tested control subjects for each of the antimicrobials described to determine the nonirritating concentration of the medication. Skin testing to tetracycline (prick testing only) has been previously described in the literature. Ogita et al report dissolving a 250 mg tetracycline capsule in 10 mg of saline for skin prick testing, with a positive test indicated by a wheal over 5 mm. This method was tested by Ogita and colleagues and negative results were obtained in 5 control subjects.21
In cases in which the medications are needed immediately, skin testing may not be feasible before administration. Furthermore, if the index reaction occurred recently, the probability of false- negative skin testing may be increased.16 However, skin testing may be useful to inform future antibiotic use and can be completed at least a few weeks after desensitization to mitigate the risk of a temporary false-negative result.
Patients B and E with Lyme arthritis and Lyme meningitis, respectively, underwent urgent desensitization without prior skin testing. Subsequently, skin testing was completed to guide future antimicrobial treatment. The 1 patient who did not have skin testing completed, patient F, required the antibiotics urgently during exacerbations of end-stage cystic fibrosis and unfortunately died before skin testing could be completed.
The skin prick testing regimens we developed had excellent negative predictive value for 5 patients (patients A, C, D, H, and I). Each of these patients, whose initial reactions were not severe, successfully tolerated doxycycline, minocycline, or tigecycline graded challenges after negative skin testing.
The case of patient H deserves special attention. The general approach in cases of DRESS is strict avoidance. However, in rare cases, such as that of this patient, when multiple medications are involved and treatment with one of the medications that was not likely to be the culprit is medically necessary, and no other alternative medications are available, then graded challenge may be considered.
The true positive predictive value of the initial skin testing for patient B, who had Lyme disease, is less clear. This patient had positive intradermal skin tests to all the anti-Lyme antibiotic therapies tested, including penicillin, ampicillin, doxycycline, cefuroxime, and ceftriaxone. Jarisch-Herxheimer reactions have been described with the treatment of Lyme disease,22 and this reaction could explain his reactions to both doxycycline and amoxicillin. However, this reaction is typically accompanied by fever, rigors, and vital sign changes in addition to rash, which our patient did not exhibit. Given the positive skin tests and immediate need for the medication, patient B was successfully desensitized to doxycycline. His mild pruritus during the desensitization supports a propensity toward a histamine release with doxycycline exposure. In addition, approximately 2 years after the initial skin testing, patient B’s skin testing was repeated with the same antibiotics, and intradermal testing remained positive to ampicillin and doxycycline but negative to the cephalosporins tested, including ceftriaxone and cefuroxime.
When patients had positive skin testing, as was the case for patients A, B, E, and G, the desensitization procedures described previously and in Tables 3 to 5 were successfully performed. Such procedures are thought to be most effective in IgE-mediated reactions; however, desensitization has also been used successfully previously in non-lgE—mediated HSRs.23 Desensitization was well tolerated by patients A and B who had initial reactions that were delayed in onset and unlikely to be solely mediated by IgE. Furthermore, these patients completed their recommended treatment course without delayed reaction. Overall, these protocols were well tolerated when used in both adult and pediatric patients, and only 1 patient required amendment of the protocol owing to a reaction consistent with lgE-mediated hypersensitivity.
Although there are several case reports involving desensitization to doxycycline that involve protocols that are at least initially intravenously administered, to our knowledge, ours is the first published protocol in which the desensitization to this antibiotic is entirely enteral. Furthermore, our protocols to minocycline and tigecycline represent the first in the literature and were well tolerated by both pediatric and adult patients. An allergist must carefully customize the premedication regimen to a specific patient. A clinician’s judgment must also be used in the management of breakthrough reactions, should they occur.
ln summary, this study represents the first comprehensive description of HSRs to tetracyclines in adult and pediatric patients, their evaluation, including skin testing regimens, and their management with graded challenge procedures or desensitization protocols. To our knowledge, these protocols are novel and valuable to clinicians caring for pediatric and adult patients with a history of HSRs to this class of antimicrobials. ln all the cases, graded challenge or desensitization was safely completed. Assessing the severity of the index reaction, implementing skin testing when safe, and pursuing graded challenge or desensitization based on the data available can facilitate the use of first-line pharmacologic therapy to patients with HSRs to tetracyclines.
Table 1.
Patient Characteristics
| Patient | Age (y), sex | Indication | Reaction history | Severity | Skin testing | Procedures | Outcome |
|---|---|---|---|---|---|---|---|
| A | 13, Female | CF exacerbation | Minocycline: developed pruritic maculopapular rash on day 4 of therapy, resolved with drug cessation Tigecycline: no prior trial, GC completed owing to severity of minocycline allergy |
Mild | Doxycycline: negative Minocycline: positive |
Doxycycline: graded challenge Minocycline: desensitized Tigecycline: graded challenge |
Successful |
| B | 12, Male | Lyme arthritis | Doxycycline: pruritic maculopapular rash on day 5 of therapy | Mild | Doxycycline: positive | Doxycycline: desensitized | Successful |
| C | 17, Female | CF exacerbation | Tolerated doxycycline Minocycline: generalized, pruritic, maculopapular rash on day 9 of therapy |
Mild | Minocycline: negative | Minocycline: graded challenge | Successful |
| D | 68, Female | Cellulitis | Tetracycline: pruritic, erythematous rash | Mild | Doxycycline: positive Minocycline: negative |
Minocycline: graded challenge | Successful |
| E | 7, Female | Lyme meningitis | Doxycycline: angioedema of lip, facial flushing, abdominal upset | Moderate | Doxycycline: positive Minocycline: positive |
Doxycycline: desensitized | Successful |
| F | 40, Female | CF exacerbation | Doxycycline: no prior use, desensitized owing to severity of other tetracycline reactions Minocycline: chest tightness, oral tingling Tigecycline: bronchospasm on day 17 |
Moderate | Deferred owing to urgency of illness | Doxycycline: desensitized Minocycline: desensitized Tigecycline: desensitized |
Successful |
| G | 20, Female | CF exacerbation | Doxycycline: tolerates Minocycline: erythematous maculopapular rash |
Mild | Minocycline: positive | Minocycline: desensitized | Successful |
| H | 17, Female | CF exacerbation | Doxycycline: rash, pruritus, knee pain Tigecycline: possible, but unlikely culprit in DRESS, starting on day 14 Tolerates minocycline |
Moderate | Doxycycline: negative Tigecycline: negative |
Doxycycline: graded challenge Tigecycline: graded challenge |
Successful |
| I | 13, Male | MRSA cellulitis | Doxycycline: pruritic, erythematous rash on arms and buttocks, mild dyspnea | Moderate | Doxycycline: negative | Doxycycline: graded challenge | Successful |
| J | 17, Male | MRSA cellulitis | Doxycycline: self-limited urticaria on day 5 of therapy | Mild | Doxycycline: negative Minocycline: positive |
Pending |
Abbreviations: CF, cystic fibrosis; DRESS, drug reaction with eosinophilia and systemic symptoms; MRSA, methicillin-resistant Staphylococcus aureus.
NOTE. Severity on the basis of Brown Classification Criteria: mild (skin and subcutaneous involvement only); moderate (features suggestive of respiratory, cardiovascular, or gastrointestinal involvement; severe (hypoxia, hypotension, or neurologic involvement). Patient F was successfully desensitized to minocycline and tigecycline twice.
Table 2.
Doxycycline, Minocycline, and Tigecycline Skin Testing Regimens
| Doxycycline |
Minocycline |
Tigecycline |
|||
|---|---|---|---|---|---|
| Method | Concentration (mg/mL) | Method | Concentration (mg/mL) | Method | Concentration (mg/mL) |
| SPT | 10 | SPT | 0.2 | SPT | 1 |
| ID | 0.0001 | ID | 0.0002 | ID | 0.01 |
| 0.001 | 0.002 | 0.1 | |||
Abbreviations: SPT, skin prick test; ID, intradermal.
NOTE. Three control patients were tested for doxycycline, 2 for minocycline, and 1 for tigecycline.
Table 3.
Protocol for Desensitization to Oral Doxycycline, With Goal of 100 mg Every 12 Hours
| Step | Dose (mg) | Time (min) | Cumulative dose (mg) |
|---|---|---|---|
| 1 | 0.00001 | 30 | 0.00001 |
| 2 | 0.0001 | 30 | 0.00011 |
| 3 | 0.001 | 30 | 0.00111 |
| 4 | 0.01 | 30 | 0.01111 |
| 5 | 0.1 | 30 | 0.11111 |
| 6 | 1 | 30 | 1 |
| 7 | 2 | 30 | 3 |
| 8 | 4 | 30 | 7 |
| 9 | 8 | 30 | 15 |
| 10 | 12 | 30 | 27 |
| 11 | 25 | 30 | 52 |
| 12 | 50 | 30 | 102 |
NOTE. Low starting dose for the desensitization was based on the skin test concentration that the patient reacted to.
Table 4.
Protocol for Desensitization to Oral Minocycline, With Goal of 100 mg Every 12 Hours
| Step | Dose (mg) | Time (min) | Cumulative dose (mg) |
|---|---|---|---|
| 1 | 0.01 | 15 | 0.01 |
| 2 | 0.02 | 15 | 0.03 |
| 3 | 0.04 | 15 | 0.07 |
| 4 | 0.08 | 15 | 0.15 |
| 5 | 0.16 | 15 | 0.31 |
| 6 | 0.32 | 15 | 0.63 |
| 7 | 0.64 | 15 | 1.27 |
| 8 | 1.28 | 15 | 2.55 |
| 9 | 2.56 | 15 | 5.11 |
| 10 | 5.0 | 15 | 10.11 |
| 11 | 10.0 | 15 | 20.11 |
| 12 | 20 | 15 | 40.11 |
| 13 | 40 | 15 | 80.11 |
| 14 | 60 | 15 | 140 |
Table 5.
Intravenous Desensitization Protocol for Tigecycline, With Goal of 50 mg Every 12 Hours
| Solution number | Volume of diluent (mL) | Drug concentration (mg/mL) | Total drug to be injected into each bottle (mg) | ||
| Solution 1 | 250 | 0.002 | 0.50 | ||
| Solution 2 | 250 | 0.020 | 5.0 | ||
| Solution 3 | 250 | 0.198 | 49.607 | ||
| Step | Solution | Rate (mL/h) | Time (min) | Administered dose (mg) | Cumulative dose (mg) |
| 1 | 1 | 2 | 15 | 0.0010 | 0.0010 |
| 2 | 1 | 5 | 15 | 0.0025 | 0.0035 |
| 3 | 1 | 10 | 15 | 0.0050 | 0.0085 |
| 4 | 1 | 20 | 15 | 0.0100 | 0.0185 |
| 5 | 2 | 5 | 15 | 0.0250 | 0.0435 |
| 6 | 2 | 10 | 15 | 0.0500 | 0.0935 |
| 7 | 2 | 20 | 15 | 0.1000 | 0.1935 |
| 8 | 2 | 40 | 15 | 0.2000 | 0.3935 |
| 9 | 3 | 10 | 15 | 0.4961 | 0.8896 |
| 10 | 3 | 20 | 15 | 0.9921 | 1.8817 |
| 11 | 3 | 40 | 15 | 1.9843 | 3.8660 |
| 12 | 3 | 75 | 186 | 46.1340 | 50.0000 |
| Total infusion time | 351 | ||||
Acknowledgments
Funding: This research is supported by the National Institutes of Health, T32 AI007512 (to Dr Maciag).
Footnotes
Disclosures: The authors have no conflict of interest to report.
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