Two cases of skin hyperpigmentation induced by polymyxin B Dois casos de hiperpigmentação cutânea induzido pela polimixina B

Introduction: The skin hyperpigmentation process involves biochemical and immunological mechanisms that stimulate melanogenesis and although nephrotoxicity consists of the most relevant adverse reaction of polymyxin B, it is also associated with this changes. Case report: Case 1: male patient, diagnosed with Hodgkin’s Lymphoma, who developed skin hyperpigmentation after starting treatment with meropenem, anidulafungin and polymyxin B due to a septic shock. Case 2: male patient, admitted to the ICU for decreased level of consciousness and suspected STEMI, diagnosed with endocarditis and pericarditis, who also presented skin hyperpigmentation during therapy with amphotericin B and polymyxin B. Conclusion: After careful evaluation of chronological order and drugs used by patients, we conclude that polymyxin B caused hyperpigmentation in both patients. Finally, based on the mechanism of this reaction and the scientific findings, clinical studies that may evidence a probable pharmacological effect with the use of H2 antagonists are required.


INTRODUTION
Adverse cutaneous reactions represent an important percentage of problems related to the use of drugs in hospital services and may predispose to serious complications, including death 1 .
Among the possible clinical manifestations, we highlight the alterations in skin color with a significant aesthetic and psychosocial impact 2 , but without major damage to health.
Polymyxins represent a group of antibiotics for the treatment of gram-negative bacterial infections, however, due to their toxicity and the emergence of safer drugs, their use was practically discon- Therefore, considering the wide use of polymyxin B in hospital services, we report two cases of patients who developed skin hyperpigmentation during treatment with polymyxin B. This report was approved by the Research Ethics Committee of our institution (CAAE nº: 70957917.7.0000.5292) and the consent term was signed by those responsible.  Table 1.  Rodrigues CAO, Martins RR, Cunha EQ, Lima MS, Saldanha V hours). In addition to antimicrobial therapy, the patient used the medications as shown in Table 1.

CASE REPORT
The progressive darkening of the face started on the 12th day of admission, 8 days after therapy with polymyxin B and amphotericin B ( Figure 1B). The antibacterial agents were administered for 14 days, but even after discontinuation and discharge from the ICU, there was no regression of hyperpigmentation.
During the entire hospitalization period (four months), pigmentation persisted.

DISCUSSION
Hyperpigmentation caused by medications are reported in the literature and more recently the reaction has been described for polymyxin B 4 , affecting adults 4,7,8 and pediatric/neonatal patients 6,7,8,9 , whose percentage varying between 8-15% of the patients who presented the reaction with the use of the drug in two studies 2,5 .
Men were most affected by this reaction 2,4-9 , however, skin color seems to have more relevance in this process. In one study only 11.1% of patients with hyperpigmentation were Caucasian, who would be classified among the I-III 10 phototypes on the Fitzpatrick scale, however, this same group represented 78.4% of the patients who did not present skin hyperpigmentation 5 , while most reports describe patients who would be classified from phototype IV (Table 2).
Polymyxin B potentiates the release of histamine in the organism 11 and causes morphological changes in human melanocytes from increased of tyrosinase activity, and in addition, histamine generates accumulation of intracellular cAMP and increases the activity of protein kinase A, stimulating melanogenesis in melanocytes 2,12 . This whole process, therefore, results in increased production of melanin. According to Yoshida et al. 12 , this process is mediated through H2 receptors which is also present in human melanocytes.
From an in vivo study, Yoshida et al. 13 observed that the use of H2 antagonists, famotidine and ranitidine, suppressed melanogenesis in melanocytes. The same author had already obtained similar results in an in vitro study that allowed him to highlight a probability of the new therapeutic option for treating hyperpigmentation 12 . However, only one study evidenced some action of this class of drugs in the skin 14 , the in vivo analysis of Yoshida et al. 13 was performed with animals and part of the experiment was done with topical application of the drug. To our knowledge, there are no topical formulations of available H2 antagonists. Furthermore, we realized using proton pump inhibitors (PPIs) in all hyperpigmentation reports which described the use of drugs 4,7 , which was not different from our report. Thus, we questioned whether the use of ranitidine to replace the PPIs could not have had any pharmacological action as discussed by Yoshida et al. 12 .
But there are still no studies that can prove it.
Hyperpigmentation was observed only in the head and neck region of both patients, where the largest number of melanocytes

Hyperpigmentation induced by polymyxin B
in the body is concentrated 2 , which may explain the fact that it has not been found in other areas of the body. In addition, the patients were in an environment with artificial and controlled light, without contact with external light.
Applying the Naranjo algorithm, polymyxin B was probably associated with hyperpigmentation in both cases (6 points) and after the application of the Fitzpatrick scale to evaluate the cutaneous phototype in the patients, they were classified as type IV that varied for the VI in the reaction. Regarding the use of drugs, in case 1 only amitriptyline, bleomycin and tigecycline have cases of alterations in skin pigmentation, however, they were initiated when hyperpigmentation already existed. In case 2, we did not find cases of hyperpigmentation for all drugs used by the patient except for polymyxin B.
We conclude that hyperpigmentation was induced by polymyxin B Men's and dark-skinned populations are the most affected.
Finally, based on the mechanism of this reaction and the findings of Yoshida et al. 12,13 , clinical studies that may evidence a probable pharmacological effect with the use of H2 antagonists are required.