Letters to the Editor / International Journal of Antimicrobial Agents 48 (2016) 569–580
International Medical University, of ca. 1 cm in largest diameter on the shoulders, arms, hands and
Kuala Lumpur, Malaysia
* Corresponding author. Faculty of Medicine and Institute
for Life Sciences and Global Health Research Institute,
University of Southampton, Southampton, UK.
E-mail address: s.c.clarke@southampton.ac.uk (S.C. Clarke)
2 August 2016
28 August 2016
http://dx.doi.org/10.1016/j.ijantimicag.2016.08.011
Histopathological findings of pigmented
lesion and recovery of natural skin colour in
a patient with polymyxin B-associated
diffuse hyperpigmentation
Sir,
Polymyxin B (PMB) has been largely used for the treatment of
extensively drug-resistant Gram-negative bacteria. Nephrotoxic-
ity and neurotoxicity are classical toxicities of this drug. However,
skin hyperpigmentation, especially on the head and neck, has re-
cently been described [1–4]. Although it is not a life-threatening
adverse effect, it can generate aesthetic and psychological damage.
Notwithstanding, several issues regarding this reaction remain
unknown, such as the variety of pigmentation disorders and the
prognosis. In this report, we describe a new skin reaction associ-
ated with PMB, provide a histopathological analysis of the affected
skin, and document a complete recovery of diffuse hyperpigmen-
tation after PMB cessation.
We report the case of a 14-year-old light skin colour female
patient with aplastic anaemia who underwent an allogenic
haematopoietic stem cell transplantation. Before starting the con-
ditioning regimen (Day 1 for this case report), meropenem had been
initiated owing to an episode of fever, diarrhoea and abdominal
pain. On Day 2, PMB was added to the scheme at a dose of 31 830 IU/
kg/day twice daily (total daily dose, 1,200,000 IU). An Enterobacter
cloacae isolate with a meropenem minimum inhibitory concentra-
tion (MIC) of 8 mg/L and a PMB MIC of 0.38 mg/L by Etest was
recovered from blood culture drawn at the onset of fever. PMB plus
meropenem was maintained for 21 days; fever and abdominal com-
plaints were resolved. The transplantation was successful and the
patient was discharged 60 days after the stem cell infusion.
After 5 days of PMB therapy (Day 7), a diffused darkening of the
skin (Supplementary Fig. S1) was noted by the patient, her rela-
tives and the attendant physicians. At the same time, skin darkening
was accompanied by the emergence of round hyperchromic spots
Fig. 1. Histopathological findings on skin biopsy of dark spots. (A) Interface dermatitis (neutrophilic infiltrate and basal membrane oedema) with dermal melanophages
(DM) and vacuolar damage (VD). (B) Fontana–Masson stain demonstrating epidermal melanin granules (EMG) and dermal melanin granules (DMG) inside histiocytes. White
bars correspond to 20 μm.
579
upper thorax that were not associated with pain or pruritus. The
patient had remained in the same bedroom and had not been
exposed to sunlight during her treatment with PMB. In a review of
the patient’s pictures, there was an agreement among the authors
that the baseline skin colour (picture not shown) corresponded to
grade 19 on Von Luschan’s chromatic scale, whilst her head and neck
skin shown in Supplementary Fig. S1 correspond to 26 on the scale.
The patient was conditioned with cyclophosphamide, fludarabine
and anti-thymocyte globulin (Day 9), even with unresolved fever.
A skin biopsy was performed (Day 13) to evaluate the possibility
of disseminated fungal infection. Histopathological findings of the
spotted skin revealed interface dermatitis with vacuolar damage and
dermal melanophages with melanin granules inside epidermal and
dermal histiocytes (Fig. 1).
At the 3-month follow-up visit, complete recovery of the pre-
vious skin colour and partial recovery of the dark spots on the upper
thorax and limbs was noted (only slightly clearer skin had been ob-
served at hospital discharge). A pigmented halo surrounding two
lesions (skin biopsy sites) was observed (Supplementary Fig. S2).
At the 6-month visit, there was almost complete recovery of the
round spotted lesions but the halos surrounding the two right shoul-
der lesions were only slightly clearer.
We showed that beyond diffuse pigmentation changes, localised
spots histopathologically resembling fixed drug eruption reac-
tions are another pigmentation disorder associated with this
antibiotic. Fixed drug eruptions are histologically characterised by
the presence of dermal melanophages, which are often the only
finding in non-inflammatory lesions. Neutrophilic infiltrate and basal
membrane oedema are also often described. Nonetheless, clinical
presentation of fixed drug eruption differs from that of our patient
[5]. Cyclophosphamide has been associated with nail hyperpig-
mentation and, rarely, with skin hyperpigmentation and might have
occasionally worsened the effects observed in our patient, but it is
important to point out that skin changes were observed before cy-
clophosphamide administration. No other drug known to be
associated with pigmentation disorders had been prescribed to the
patient.
We also showed that diffuse hyperpigmentation may be com-
pletely resolved in a few months after PMB interruption, potentially
obviating further aesthetic damage and psychological disabilities.
Spotted lesions were almost totally resolved within 6 months, and
the persistent pigmented halos around two lesions were likely
reactional to the biopsy in a skin susceptible to this kind of reaction.
The pathological mechanisms remain unknown but may involve
oxidative stress reactions that have been associated with polymyx-
ins or, as speculated by Mattos et al. [4], histamine release, which
has a melanogenic effect, triggered by PMB. The localised pig-
mented spots may share the underlying mechanisms.
580 Letters to the Editor / International Journal of Antimicrobial Agents 48 (2016) 569–580
Future studies should address whether this toxicity is only as-
sociated with PMB or whether colistin may also cause skin
pigmentation disorders, as well as possible interventions to de-
crease the incidence of this reaction. Risk factors for skin
hyperpigmentation must also be assessed, including baseline skin
colour and relationship to sun and light exposure during
hospitalisation.
In summary, we showed that diffuse skin hyperpigmentation
is reversible after PMB cessation and that pigmented spotted
lesions histopathologically resembling fixed drug eruption are
another possible pigmentation disorder associated with this
antibiotic.
Acknowledgements
The authors are very grateful to the patient for agreeing to pub-
lication as well as her legal representative. The authors also thank
Prof. André Cartel for providing the skin biopsy slides.
Funding: Fundo de Incentivo à Pesquisa e Eventos do Hospital
de Clínicas de Porto Alegre (Porto Alegre, Brazil) [14–0713].
Competing interests: None declared.
Ethical approval: Not required; the patient’s legal representa-
tive signed a consent for publication of the pictures, which was
available to the Editor.
Appendix. Supplementary data
Supplementary data associated with this article can be found,
in the online version, at doi:10.1016/j.ijantimicag.2016.08.010.
References
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[3] Zavascki AP, Manfro RC, Maciel RA, Falci DR. Head and neck hyperpigmentation
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[4] Mattos KP, Lloret GR, Cintra ML, Gouvêa IR, Betoni TR, Mazzola PG, et al. Acquired
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Alexandre P. Zavascki *
Infectious Diseases Service, Hospital de Clínicas de Porto Alegre,
2350 Ramiro Barcelos St., Porto Alegre, RS 90.035-903, Brazil
Luiza F. Schuster
Infectious Diseases Service, Hospital de Clínicas de Porto Alegre,
2350 Ramiro Barcelos St., Porto Alegre, RS 90.035-903, Brazil
Rodrigo P. Duquia
Federal University of Health Sciences of Porto Alegre, Porto Alegre,
Brazil
* Corresponding author. Fax: +55 51 3359 8152.
E-mail address: azavascki@hcpa.edu.br (A.P. Zavascki)
1 June 2016
28 August 2016
http://dx.doi.org/10.1016/j.ijantimicag.2016.08.010