Q J Med 1999; 92: 659-667
© 1999 Association of Physicians
Out-patient parenteral antimicrobial therapy–a viable option for the management of cutaneous leishmaniasis
From the Infection and Immunodeficiency Unit, and 1 Department of Dermatology, Tayside University Hospitals NHS Trust, and 2 Department of Clinical Parasitology, Hospital for Tropical Diseases, London, UK
Received 7 June 1999 and in revised form 25 August 1999
Dr R.A. Seaton, Directorate of Medicine, Tayside University Hospitals NHS Trust, Ninewells Hospital, Dundee DD1 9SY. e-mail: aseaton66{at}aol.com
 |
Summary |
|---|
 Top Summary IntroductionMethodsResultsDiscussionAcknowledgementsReferences |
|---|
Cutaneous infection with Leishmania braziliensis complex requires treatment with parenteral pentavalent antimonials to prevent development of mucocutaneous leishmaniasis. Patients with imported disease are usually managed in hospital because of concerns over drug toxicity. This study describes the clinical features and outcome of infection treated in the UK in an out-patient setting. Thirteen marines (aged 19–35 years) who acquired leishmaniasis in Belize were studied prospectively. Three had at least two lesions (0.6–3 cm diameter), eight had regional lymphadenopathy and one had localized painless lymphatic thickening. Histology for amastigotes and PCR for Leishmania braziliensis complex was positive in all. Culture was positive in six. Patients received 1.5–2 g (mean 1.7 g) (20 mg/kg) sodium stibogluconate intravenously daily for 20 days. All developed transient musculoskeletal symptoms and asymptomatic hepatitis. Eleven developed biochemical pancreatitis, and one thrombocytopenia. Three developed transient ECG changes and one herpes zoster. There were four device-related infections, two requiring hospitalization (one required surgical drainage of an abscess). All lesions re-epithelialized. A total of 250 bed-days were saved over a 67-day period. These results indicate that in selected patients, out-patient therapy for cutaneous leishmaniasis with parenteral high-dose sodium stibogluconate may be appropriate, provided there is adequate monitoring of therapy.
|
Introduction |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionAcknowledgementsReferences |
|---|
Leishmaniasis is a group of parasitic, vector-born diseases caused by a number of different Leishmania species. Infection is acquired in the tropics and sub-tropics following the bite of an infected sand fly. Disease may range from self-limiting skin lesions to life-threatening visceral or muco-cutaneous forms. The natural reservoir for Leishmania species is mammals (usually rodents or dogs). In the UK, there is no formal reporting system or national reference laboratory for leishmaniasis, so estimates of numbers are difficult. Amongst visitors to Central and South America, a group at particular high risk of cutaneous leishmaniasis is servicemen, who may train for weeks in dense jungle with intense exposure to the sand-fly vectors. In such a setting, the main species isolated are Leishmania braziliensis braziliensis and to a lesser extent Leishmania mexicana mexicana.1,2 Patients with L. mexicana complex normally suffer a self-limiting infection with no subsequent sequelae. Patients infected with L. b. braziliensis, however, have the potential to develop the muco-cutaneous form, months to years later.3 To prevent this potentially disfiguring and life-threatening complication, and to hasten healing of the cutaneous lesion, patients are treated with sodium stibogluconate,3,4 a pentavalent antimony compound with well-documented transient adverse effects. These include musculoskeletal symptoms, liver and marrow toxicity, pancreatitis and electrocardiographic abnormalities. In view of the potential toxicity and the need for prolonged intravenous therapy, patients are usually hospitalized for the full treatment course (usually 20 days).
Between September and December 1998, approximately 450 marines from Marine Base Condor, Arbroath, took part in a training exercise in rainforest in southern Belize. Prior to departure from the UK, the marines had been briefed on the risk of leishmaniasis and strategies for avoiding sand-fly bites. On return, a number reported non-healing ulcers on arms and legs. This paper outlines the clinical features, therapy and outcome for 13 marines with confirmed cutaneous Leishmania braziliensis complex infection treated in an out-patient setting.
|
Methods |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionAcknowledgementsReferences |
|---|
Patients with suspected leishmaniasis were referred by the medical officer of Condor to the Infection and Immunodeficiency Unit, Dundee Teaching Hospitals NHS Trust, for assessment. Patients underwent a clinical examination, biopsy of lesion(s), base-line electrolyte measurements, full blood count, liver function tests and electrocardiogram.
Biopsies were performed at the edge of the skin lesion and were sent formalin-fixed to histology and in sterile saline to the Department of Parasitology, Hospital for Tropical Diseases, London. Half the sample was used for culture on modified Novy-MacNeal-Nicolle biphasic media, using tryptose agar base, with either defibrinated rabbit or human blood and quarter-strength Ringer's solution overlay. Streptomycin and penicillin were incorporated to prevent bacterial contamination, and the plates were incubated at 26 °C for 21 days. The other half of the sample was used for a Giemsa-stained impression smear and DNA extraction for PCR. Primers working on the minicircles in the kinetoplast DNA, specific for L. braziliensis complex and L. mexicana complex were used.5
Patients with suspected leishmaniasis were commenced on intravenous sodium stibogluconate 20 mg/kg (no upper limit), and were treated for at least 20 days until the lesions were healed. Sodium stibogluconate was administered in 5% dextrose solution via an aseptically placed peripherally inserted central catheter over 30 min. Patients were advised on potential and likely side-effects, were advised to abstain from alcohol for the duration of therapy, and were taught by a nurse practitioner to prepare and self-administer the infusion and to care for the intravascular device. The unit pharmacist provided each patient with information regarding potential adverse effects of the drug. The first dose was administered by the nurse practitioner in the ward out-patient area. The second, third, and fourth doses were self-prepared and administered under supervision in the marine base. Subsequent doses were provided by the hospital pharmacy and administered in the marine base sick bay under the supervision of the medical orderly. The nurse practitioner provided advice and liaised with medical staff on the infectious disease unit regarding problems. An existing 24-h help line for out-patients was made available to the marines. Patients were reviewed at least weekly by the infectious disease physician. Intravascular device dressings were changed, and renal function, liver function, amylase, full blood count and electrocardiographic measurements were made on days 4, 7, 14, 20, and again 3 weeks after cessation of therapy.
|
Results |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionAcknowledgementsReferences |
|---|
Clinical features
A total of 13 patients were treated between 31st December 1998 and 7th March 1999 (Table 1
). All were male (aged 19–35 years). All gave typical histories of papules which appeared on an extremity whilst in the Belize jungle. These increased in size and became ulcerated over 1–3 months. Ten had single lesions, and three had at least two lesions. Lesions were typically 0.6–3 cm diameter with central crusting and ulceration with an erythematous indurated margin (Figure 1). In one patient there was an associated staphylococcal cellulitis. Eight had regional lymphadenopathy (including two with lymphangitis) and one had localized painless lymphatic thickening associated with a forearm lesion. There were no other systemic features of leishmaniasis.
|
|
Microscopy of formalin-fixed Giemsa-stained skin biopsies confirmed intracellular amastigotes in all patients. Giemsa-stained impression smears were positive in 10 patients, and culture grew typical promastigotes after 7 days in six patients. In two patients, culture was contaminated by fungal or bacterial growth, and in five the parasites failed to grow by 21 days of incubation. PCR of tissue samples in all 13 was positive for L. braziliensis complex. PCR for L. mexicana complex was negative in all.
Outcome and complications of therapy
Twelve patients completed 20 days uninterrupted treatment with sodium stibogluconate with dosages of 1.5–2 g daily (mean 1.7 g) (Table 2). One patient interrupted treatment for one day due to thrombocytopenia. One patient was treated on an out-patient basis for 5 days of the 20-day course in Newcastle Infectious Disease Unit because of work commitments in that region.
|
All patients developed moderately severe myalgia, arthralgia or headaches and malaise which restricted activities whilst on treatment. All patients had elevation in alanine aminotransferase above the normal range during therapy, and 11 patients had an asymptomatic increase in serum amylase. The median time to peak ALT level was 14 days (6–20 days). At follow-up 3 weeks later (12 patients), all had declined significantly from peak levels, although in five patients levels were slightly above the normal range (Table 2
). In the eleven patients with elevation in serum amylase, the median time to peak was 16 days (3–20 days). In ten patients, levels declined to normal levels following cessation of therapy. One patient with an ALT of 69 IU/L and an amylase of 193 IU/L at completion of therapy (5-day peak level of 287 IU/L) failed to attend for review as he had been posted overseas. There were no abnormalities of renal function during therapy. Three patients developed ECG changes with ST flattening in antero-lateral or infero-lateral leads in the third week of treatment. These changes had resolved by 3 weeks post treatment.
Four patients developed Staphylococcus aureus intravascular-device-related infections. Two were hospitalized for 5 days, and both received intravenous then oral flucloxacillin. One of these developed an abscess (which required surgical drainage) and thrombocytopenia (platelet count of 96 000/mm3) which improved following treatment of the soft tissue infection and omission of one dose of sodium stibogluconate. Two patients were managed with oral flucloxacillin as out-patients without complication. Two further patients developed leaks in their intravascular devices which required replacement. One patient developed herpes zoster whilst on treatment, although he was not lymphopenic at any time.
All patients were reviewed on completion of therapy and all lesions had re-epithelialized (Figure 2).
|
As a result of our out-patient home parenteral antibiotic programme, a total of 250 bed-days were saved over a 67-day period, or the equivalent of approximately four occupied beds for the same period. During this same period there were 200 acute admissions to our unit with an average stay of 6.33 days, and bed occupancy rate was approximately 90%.
|
Discussion |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionAcknowledgementsReferences |
|---|
Cutaneous leishmaniasis is an unusual condition in the UK which should be considered in any person with a slow-to-heal ulcer who has travelled to the tropics or sub-tropics. Species complex diagnosis is important in New World cutaneous leishmaniasis, in view of the propensity for the braziliensis complex to progress to muco-cutaneous leishmaniasis. There is some debate over the pathogenicity of the braziliensis subspecies in Belize. Up until 1984, infection with L. braziliensis complex was not described in Belize, L. mexicana mexicana being the sole isolate described.2 Subsequently, isoenzyme characterisation of isolates has shown the dominant species to be indistinguishable from L. braziliensis braziliensis but distinct from L. b. panamensis and guyanensis.2 This finding has been confirmed more recently in a large series of British troops with cutaneous leishmaniasis where 78/107 were infected with L. b. braziliensis.1 To our knowledge, muco-cutaneous leishmaniasis has only been described in one patient from Belize.6 However, cutaneous lesions have recurred up to 19 months after successful treatment, demonstrating that infection may lie dormant,1 and the high incidence of lymphadenopathy suggests possible early dissemination.7 It is possible that muco-cutaneous leishmaniasis appears to be infrequent in Belize because the patients described with L. braziliensis complex infection are usually servicemen who have all been treated with sodium stibogluconate after acute infection.1,6
In this series, PCR enabled rapid species complex identification, and enabled us to make informed decisions about treatment. Such identification would not have been possible otherwise for all patients since two parasite cultures were contaminated, and five positive smears failed to grow. Hence only 6/13 patients could have gone on to species diagnosis by isoenzyme analysis without PCR. These findings are consistent with those of others who found PCR to be consistently more sensitive than other methods of diagnosis.8
The clinical features described are in keeping with the experience of others.1,3,6,7 Although another series from Belize described a high proportion (27%) of isolates to be L. mexicana mexicana1 we only detected L. braziliensis complex using highly sensitive PCR for both species complexes. Since the infections in our series occurred at around the same time and in the same well-defined geographical area, it is not unlikely that the infecting organism was the same in all 13 patients.
The response to high-dose treatment was good, all lesions having re-epithelialized at 3 weeks post-treatment. Ballou et al. demonstrated 100% cure in 19 patients at 9 weeks post-cessation of therapy with 20 mg/kg stibogluconate compared to 76% cure in 21 patients treated with 10 mg/kg.9 Others have reported cure rates of between 48.5% and 63.9% after shorter course treatment with 600–800 mg daily for 10 days or 1200 mg given for 10–14 days.1 Aronson et al. used 20 mg/kg daily for 20 days in 83 patients with New World cutaneous leishmaniasis, and effected cure in 91% of cases.6 Confirmation of cure is difficult and usually relies on culture of post-treatment biopsies. This was not performed in our patients, as only 6/13 pre-treatment had positive cultures. The PCR technique which detects kinetoplast DNA can not differentiate between live and dead parasites, so cannot be used to assess cure.
Adverse events were frequent and in keeping with others' experience.1,3,6,9–11 The most clinically significant were musculoskeletal symptoms, which were experienced by all patients to some degree. Biochemical pancreatitis and hepatitis were also common, but clinically insignificant and transient. Ballou et al. showed that hepatitis was more marked in patients receiving 20 mg/kg than 10 mg/kg, although transaminases all returned to baseline following cessation of therapy.9 Musculoskeletal symptoms were also more frequent in the group receiving 20 mg/kg.9 Likewise, transient electrocardiographic changes which are well described4,6,9,11 were seen in one quarter of our patients. Herpes zoster infection complicated treatment in one patient. It has been suggested that this complication arises as a result of lymphopenia secondary to stibogluconate.11 Although our patient maintained a lymphocyte count within the normal range throughout therapy, a transient decrease cannot be excluded.
Despite the range of adverse effects, none was severe enough to necessitate discontinuation of therapy, and all were transient in nature. This is in contrast to the experience of Aronson et al. who interrupted treatment in 28% of 96 patients treated with 20 mg/kg.6
Death attributable to antimony is rare, and is probably due to accumulation of the drug due to renal insufficiency, leading to cardiac or pancreatic toxicity. In Aronson's series of 96 patients treated with 20 mg/kg pentostam there were no deaths during treatment. The three patients who died did so because of causes unrelated to their infection or the treatment.6 Likewise in Ballou's series of 19 patients there were no deaths.9 In Herwaldt and Berman's review, deaths due to the cardiotoxicity of pentostam occurred only rarely, and only in patients receiving >30 mg/kg/day.4 Three deaths due to cardiac toxicity occurred in eight patients with visceral leishmaniasis who had been treated with a faulty batch of high-osmolarity antimony.12 Deaths due to antimony may be under-reported or unrecognized, although studies in healthy servicemen suggest that 20 mg/kg/day is safe.4 Others experienced in its use attest to its safety in developing countries.13
Since cutaneous leishmaniasis usually occurs sporadically in UK travellers, it is unusual for a single infectious disease unit in the UK to treat a large cluster of patients within such a short time period. Prior to this episode, only one or two cases per annum were seen in our unit. Treating 13 patients over a 67-day period (each requiring 20 days of parenteral therapy) could have put an enormous strain on the inpatient work-load of our unit at a time of year when bed occupancy was high. The provision of a nurse-led out-patient and home parenteral antibiotic therapy programme (OHPAT) following strict selection and management guidelines14 allowed these patients to be managed and monitored successfully and safely at home. This service was developed in April 1998, and to date has managed over 100 patients with serious infections (mainly infections of skin and soft tissue, bone and joint and endocarditis) with 94% clinical cure (unpublished data). In the present series, two serious device-related infections occurred. One responded promptly to device removal and parenteral antibiotic therapy, the other to drainage of the abscess and parenteral antibiotic therapy. Such adverse events in patients receiving parenteral therapy (either as in-patients or out-patients) are well recognized and probably a major reason for the lack of use of this resource in the UK.15 Results from a US survey of out-patient antibiotic therapy indicated a 9% complication rate in patients receiving antibiotics through a peripherally inserted central catheter. Only 2% of patients developed device-related infections and 3% required rehospitalization.16 The relatively high complication rate seen in our patients was also higher than our own experience to date when treating bacterial infections. In 88 patients treated, six (7%) have required readmission, and five (6%) have had microbiologically-proven device-related infections (unpublished data). The high rate of device-related infections in our marine cohort is likely to reflect poor compliance with asepsis and over-manipulation of the device by the patients.
In summary, an out-patient and home parenteral antibiotic programme is a safe and cost-effective means of treating cutaneous leishmaniasis, provided patients are carefully selected and monitored appropriately.
|
Acknowledgements |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionAcknowledgementsReferences |
|---|
The authors are grateful to Dr Anthony Bryceson, Hospital for Tropical Diseases, London for helpful advice during the writing of this paper and for advice on patient management. We are also grateful to Dr Edmond Ong, Newcastle Infectious Diseases Unit, who supervised therapy for one patient whilst visiting Newcastle.
|
References |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionAcknowledgementsReferences |
|---|
1. Hepburn NC, Tidman MJ, Hunter JA. Cutaneous Leishmaniasis in British troops from Belize. Br J Dermatol 1993; 128:63–8.[ISI][Medline]
2. Evans DA, Lanham SM, Baldwin CI, Peters W. The isolation and isoenzyme characterisation of L. braziliensis sub species from patients with cutaneous Leishmaniasis acquired in Belize. Trans Roy Soc Trop Med Hyg 1984; 78:35–42.[ISI][Medline]
3. Bryceson ADM. Leishmaniasis. In: Cook GC, ed. Manson's tropical diseases, 20th edn. Philadelphia: WB Saunders, 1996:1213–14.
4. Herwaldt BL, Berman JD. Recommendations for treating Leishmaniasis with sodium stibogluconate (pentostam) and review of pertinent clinical studies. Am J Trop Med Hyg 1992; 46:296–306.
5. de Bruijn MHL, Barker DC. Diagnosis of New World Leishmaniasis: specific detection of species of the Leishmania braziliensis complex by amplification of kinetoplast DNA. Acta Tropica 1992; 52:45–58.[ISI][Medline]
6. Aronson NE, Wortmann GW, Johnson SC, Jackson JE, Gasser RA, Magill AJ, Endy TP, Coyne PE, Grogl M, Benson PM, Beard JS, Tally JD, Gambel JM, Kreutzer RD, Oster CN. Safety and efficacy of intravenous sodium stibogluconate in the treatment of Leishmaniasis: Recent US Military experience. Clin Infect Dis 1998; 27:1457–64.[ISI][Medline]
7. Barral A, Barral-Netto M, Almeida R, De Jesus AR, Grimaldi G, Netto EM, Santos I, Bacellar O, Carvalho EM. Lymphadenopathy associated with Leishmania braziliensis cutaneous infection. Am J Trop Med Hyg 1992; 47:587–92.
8. de Bruijn MHL, Labrada LA, Smyth AJ, Santrich C, Barker DC. A comparative study of diagnosis by the polymerase chain reaction and by current clinical methods using biopsies from Colombian patients with suspected Leishmaniasis. Trop Med Parasitol 1993; 44:201–7.[ISI][Medline]
9. Ballou WR, Gordon DM, Andujar J, McClain JB, Shanks GD, Berman JD, Chulay JD. Safety and efficacy of high-dose sodium stibogluconate therapy of American cutaneous Leishmaniasis. Lancet 1987; 2:13–16.[ISI][Medline]
10.
Hepburn NC, Nolan J, Fenn L, Herd RM, Neilson JMM, Sutherland GR, Fox KAA. Cardiac effects of sodium stibogluconate: myocardial, electrophysiological and biochemical studies. Q J Med 1994; 87:465–72.
11. Wortmann GW, Aronson NE, Byrd JC, Grever MR, Oster CN. Herpes Zoster and lymphopenia associated with sodium stibogluconate therapy for cutaneous Leishmaniasis. Clin Infect Dis 1998; 27:509–12.[ISI][Medline]
12. Sundar S, Sinha PR, Agrawal NK, et al. A cluster of cases of severe cardiotoxicity among Kala-azar patients treated with a high-osmolarity lot of sodium antimony gluconate. Am J Trop Med Hyg 1998; 59:139–43.[Abstract]
13. Bryceson A. Therapy in man. In: Peters W, Killick-Kendrick R, eds. The Leishmaniasis in Biology and Medicine. Volume II: clinical aspects and control. London, Academic Press, 1987:848–907.
14. Nathwani D, Conlon C. Outpatient and home parenteral antibiotic therapy (OHPAT) in the UK: a consensus statement by a working party. Clin Microbiol Infect 1998; 4:537–51.
15.
Nathwani D, Davey P. Intravenous antimicrobial therapy in the community: under used, inadequately resourced or irrelevant to health care in Britain. Br Med J 1997; 313:1541–3.
16. Hoffman-Terry ML, Fraimow HS, Fox TR, Swift BG, Wolf JE. Adverse effects of outpatient parenteral antibiotic therapy. Am J Med 1999; 106:44–9.[ISI][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Blum, P. Desjeux, E. Schwartz, B. Beck, and C. Hatz Treatment of cutaneous leishmaniasis among travellers J. Antimicrob. Chemother., February 1, 2004; 53(2): 158 - 166. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D.K. Kochar, S. Aseri, B.V. Sharma, R.A. Bumb, R.D. Mehta, and S.K. Purohit The role of rifampicin in the management of cutaneous leishmaniasis QJM, November 1, 2000; 93(11): 733 - 737. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||