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Correspondence
60
Influenza vaccination
Influenza-coded health-care encounter
55
50
Cases of Guillain-Barré syndrome
45
40
35
30
25
20
15
10
5
0
1
* * * * ** *
2 3 4 5 6 7
** *
*
* *
**
*
* * **
* * ** * * *
* * * **
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42
Weeks to Guillain-Barré syndrome from influenza vaccination or influenza-coded health-care encounter
Figure: Number of cases of Guillain-Barré syndrome by week after receipt of influenza vaccine and after an influenza-coded health-care encounter
*Five or fewer admissions for Guillain-Barré syndrome; because of a contractual agreement with the data provider, numbers of five or fewer cannot be reported.
advisory board for GlaxoSmithKline. The other
authors declare that they have no competing
interests.
*Jeﬀrey C Kwong, Natasha S Crowcroft,
Kumanan Wilson, Allison J McGeer,
Shelley L Deeks
jeﬀ[email protected]
Institute for Clinical Evaluative Sciences, Toronto,
ON M4N 3M5, Canada (JCK, KW); Department of
Family and Community Medicine, Toronto, ON,
Canada (JCK); Dalla Lana School of Public Health
(JCK, NSC, AJM, SLD) and Department of
Laboratory Medicine and Pathobiology (NSC,
AJM), University of Toronto, Toronto, ON, Canada;
Department of Medicine, Ottawa Hospital
Research Institute (KW) and Department of
Epidemiology & Community Medicine (KW),
University of Ottawa, Ottawa, ON, Canada; and
Public Health Ontario, Toronto, ON, Canada (JCK,
NSC, SLD)
1
2
3
370
Tomljenovic L, Shoenfeld Y. Association
between vaccination and Guillain-Barré
syndrome. Lancet Infect Dis 2013;
13: 730–31.
Kwong JC, Vasa PP, Campitelli MA, et al.
Risk of Guillain-Barré syndrome after
seasonal influenza vaccination and
influenza health-care encounters: a selfcontrolled study. Lancet Infect Dis 2013;
13: 769–76.
Poser CM, Behan PO. Late onset of
Guillain-Barré syndrome. J Neuroimmunol
1982; 3: 27–41.
Access to antifungal
medicines in
resource-poor countries
We read with great interest the
Personal View by Angela Loyse and
colleagues1 about improving access
to essential antifungal medicines for
cryptococcal meningitis in resourcepoor countries. It is an interesting
compilation of existing information
about the availability of various
drugs to treat of systemic fungal
infections, especially cryptococcal
meningitis in patients with HIV/
AIDS in resource-limited settings.
The authors cite our article 2 about
lipid-formulation amphotericin B
(Fungisome [Lifecare Innovations,
India]).
We tested doses of 1 mg/kg per day
and 3 mg/kg per day (not 5 mg/kg
per day as stated in the print article,
now corrected online) in patients
with HIV/AIDS and cryptococcal
meningitis. The dose of 1 mg/kg per
day ultimately was as eﬀective as the
dose of 3 mg/kg per day, reducing
the cost of treatment compared
with other international brands and
increasing the affordability of the
drug for poor people in developing
countries.
This formulation has been
developed by Delhi University, GS
Medical College, and KEM Hospital,
Mumbai, with funding from
Department of Biotechnology of the
Government of India, and has been
tested and is in clinical use at a dose
of 1mg/kg per day in India. 3,4 The
drug has the potential to be widely
used and needs consideration for
funding from various agencies (eg,
WHO, key stakeholders, and other
policy makers) for the benefit of the
poor.
NAK holds a patent from the Government of India
Patent Oﬃce for an improved process for
manufacturing a stable injectable, sterile
synergistic amphotericin B formulation; no
personal financial benefits or royalites are received
from the patent. MPJ declares that he has no
competing interests.
www.thelancet.com/infection Vol 14 May 2014
Correspondence
*Manoj P Jadhav, Nilima A Kshirsagar
[email protected]
Division of Cardiovascular Medicine, College of
Medicine, University of Florida, Gainesville,
FL 32610, USA (MPJ); and Clinical Pharmacology,
Indian Council of Medical Research, Government of
India, ESI PGIMSR, MGM Hospital, Parel,
Mumbai 400012, India (NAK)
1
2
3
4
Loyse A, Thangaraj H, Easterbrook P, et al.
Cryptococcal meningitis: improving access to
essential antifungal medicines in resourcepoor countries. Lancet Infect Dis 2013;
7: 629–37.
Jadhav MP, Bamba A, Shinde VM, et al.
Liposomal amphotericin B (Fungisome™) for
the treatment of cryptococcal meningitis in
HIV/AIDS patients in India: a multicentric,
randomized controlled trial. J Postgrad Med
2010; 56: 71–75.
Kirodian BG, Virani AR, Kshirsagar NA.
Successful treatment of cryptococcal
meningitis with liposomal amphotericin B
(L-AMP-LRC-1) intolerant to conventional
amphotericin B. J Assoc Physicians India 2002;
50: 601–02.
Kshirsagar NA, Pandya SK, Kirodian GB, et al.
Liposomal drug delivery system from
laboratory to clinic. J Postgrad Med 2005;
51 (suppl 1): S5–15.
Authors’ reply
The study by Manoj Jadhav and
colleagues was a small randomised
trial comparing treatment of HIVassociated cryptococcal meningitis
with a liposomal amphotericin B
formulation develop ed and
manufactured in India (Fungisome,
Lifecare Innovations Ltd, India) at a
dose of 3 mg/kg per day (15 patients)
versus 1 mg/kg per day (11 patients).1
It was planned to enrol a total of
64 patients, assuming a doubling
of response rate with the higher
dose, but the study was terminated
prematurely on cost grounds. As
stated in the paper’s discussion,
the higher dose resulted in faster
clinical and mycological response
compared with the lower dose of
Fungisome. Given the extremely
small numbers of evaluable patients,
it was not possible to detect any
significant diﬀerences in eﬃcacy and,
in our view, a much larger, adequately
powered study would be needed to
address this and to give reassurance
as to the comparable clinical eﬃcacy
of the 1 mg/kg per day dose of this
formulation.
www.thelancet.com/infection Vol 14 May 2014
Current WHO and Infectious Diseases Society of America (IDSA) treatment guidelines for HIV-associated
cryptococcal meningitis recommend
2 weeks of amphotericin B
deoxycholate (0·7–1·0 mg/kg per
day intravenously) plus flucytosine
(100 mg/kg per day orally in four
divided doses) as the gold standard.2,3
The IDSA guidelines also include liposomal amphotericin B (3–4 mg/kg per
day intravenously), or amphotericin B
lipid complex (5 mg/kg per day
intravenously) for 4–6 weeks as an
alternative treatment regimen. 3
However, liposomal or lipid complex
formulations of amphotericin B
are unregistered and unavailable
or prohibitively expensive for large
parts of Africa and Asia. Liposomal
formulations of amphotericin B are
already used in the treatment of
visceral leishmaniasis via the Gilead
donation programme, 4 providing
scope for synergy in advocacy eﬀorts
for access to treatment for both
diseases.
We very much agree with Jadhav
and colleagues that a coordinated
international eﬀort involving public
and private stakeholders is needed
to improve access to essential
antifungal drugs for the treatment
of HIV-associated cryptococcal
meningitis, 1 including the use of
less nephrotoxic formulations
of amphotericin B. A phase 2
randomised trial is planned to start
this year comparing alternative
dosing schedules for liposomal
amphotericin B (AmBisome, Gilead
Sciences, USA), combined with highdose fluconazole, for cryptococcal
meningitis induction therapy in
sub-Saharan Africa (AMBITION-CM,
ISCRTN 10248064).
NPG has received honoraria from MSD and Pfizer
for speaking engagements, has been awarded an
investigator-initiated research grant from Pfizer
for an unrelated surveillance project, and has
acted as a consultant for Fujifilm
Pharmaceuticals. TB has received payment from
Gilead for an advisory board. TH is in receipt of an
investigator-led award from Gilead Sciences.
The other authors declare that they have no
competing interests.
Angela Loyse, Harry Thangaraj,
Nelesh P Govender, Thomas Harrison,
Tihana Bicanic, on behalf of all
authors
[email protected]
St George’s University of London, UK (AL, HT, TH,
TB); and National Institute for Communicable
Diseases, Centre for Opportunistic, Tropical and
Hospital Infections and Faculty of Health Sciences,
University of the Witwatersrand, Johannesburg,
South Africa (NG)
1
2
3
4
Jadhav MP, Bamba A, Shinde VM, et al.
Liposomal amphotericin B (FungisomeTM) for
the treatment of cryptococcal meningitis in
HIV/AIDS patients in India: a multicentric,
randomised controlled trial. J Postgrad Med
2010; 56: 71–75.
WHO. Rapid advice: diagnosis, prevention and
management of cryptococcal disease in
HIV-infected adults, adolescents and children.
December, 2011. http://www.who.int/hiv/
pub/cryptococcal_disease2011/en/index.html
(accessed April 1, 2014).
Perfect JR, Dismukes WE, Dromer F, et al.
Clinical practice guidelines for the
management of cryptococcal disease: 2010
update by the infectious diseases society of
America. Clin Infect Dis 2010; 50: 291–322.
Loyse A. Thangaraj H, Easterbrook P, et al.
Cryptococcal meningitis: improving access to
essential antifungal medicines in resourcepoor countries. Lancet Infect Dis 2013;
13: 629–37.
Care bundles in
intensive care units
Ventilator-associated pneumonia and
central-line-associated bloodstream
infections are common complications
for patients in intensive care units
receiving mechanical ventilation
and contribute to increased length
of stay and mortality.1 Many studies
have shown the effectiveness of
care bundles to reduce rates of these
complications.2 In their Article, Lennie
Derde and colleagues3 report that
improved hand hygiene plus unitwide chlorhexidine body-washing
reduced acquisition of antimicrobialresistant bacteria, particularly
meticillin-resistant Staphylococcus
aureus. Surprisingly, they mention that
interventions likely to aﬀect outcomes
(ie, central-line-associated bloodstream
infection bundles or ventilatorassociated pneumonia bundles,
selective digestive decontamination,
371

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