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
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
