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
Correspondence
enhanced antimicrobial stewardship, or mupirocin use) were not introduced throughout their study.3 The World Medical Association’s Declaration of Helsinki4 states that “the benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven intervention(s) except for cases in which due to convincing and scientifically acceptable methodological reasons, the use of any intervention less effective than the best proven one, the use of placebo, or no intervention is necessary provided that the patients who receive any intervention less effective than the best proven one, placebo, or no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention.”4 Because in this study 60% of patients had endotracheal tubes and almost 70% had central venous catheters, the probable risks for patients of not receiving bundles for central-lineassociated bloodstream infection or ventilator-associated pneumonia seem to have been overlooked. Rights and interests of individual research participants should never be superseded by the prime purpose of medical research—ie, to yield new knowledge.4 We declare that we have no competing interests.
Samad E J Golzari, *Ata Mahmoodpoor [email protected]
Liver and Gastrointestinal Disease Research Center (SEJG) and Cardiovascular Research Center (AM), Tabriz University of Medical Sciences, Tabriz, Iran 1
2
3
4
372
Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009; 302: 2323–29. Zilberberg MD, Shorr AF, Kollef MH. Implementing quality improvements in the intensive care unit: ventilator bundle as an example. Crit Care Med 2009; 37: 305–09. Derde LPG, Cooper BS, Goossens H, et al. Interventions to reduce colonisation and transmission of antimicrobial-resistant bacteria in intensive care units: an interrupted time series study and cluster randomised trial. Lancet Infect Dis 2014; 14: 31–39. World Medical Association Declaration of Helsinki—ethical principles for medical research involving human subjects. http:// www.wma.net/en/30publications/10policies/ b3/ (accessed April 4, 2014).
Authors’ reply
We thank Samad Golzari and Ata Mahmoodpoor for their interest and critical reading of our study about reducing antibiotic resistance in intensive care units. Our study was focused on reduction of the overall risk of transmission of antimicrobial-resistant bacteria, thereby aiming to reduce all infections acquired in intensive care units associated with these bacteria, including pneumonia and catheter-related infections. The point we made about care bundles and other interventions was that preventive practices other than the interventions assessed did not change during the study period. It does not imply that best practices, such as using care bundles, were not applied in participating centres. All participating units actually used best care according to national guidelines. Furthermore, ethics committees of all participating hospitals, undoubtedly familiar with the Declaration of Helsinki, approved the study after critically reviewing all aspects of the study protocol. We feel that patients received optimum care with our interventions, which substantially reduced acquisition of antimicrobial-resistiant bacteria (especially meticillinresistance Staphylococcus aureus), probably because of the high level of compliance achieved for hand hygiene and chlorhexidine bodywashing, both major components of patient safety and quality of care. Indeed, the overall quality of care achieved in the intensive care units participating in our study is supported by the fact that rates of meticillin-resistance S aureus and vancomycin-resistant enterococci bacteraemia were too low to allow meaningful statistical analyses. We declare that we have no competing interests.
Marc J M Bonten, Christian Brun-Buisson, Ben S Cooper, *Lennie P G Derde, on behalf of all authors [email protected]
Department of Medical Microbiology and Julius Center for Health Sciences and Primary Care (MB) and Department of Intensive Care Medicine (LD), University Medical Center Utrecht, Utrecht, Netherlands; Service de réanimation médicale and INSERM U657, Institut Pasteur, APHP GH Henri Mondor, Université Paris Est-Créteil, Creteil, France (CB-B); and Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK (BSC) 1
Derde LPG, Cooper BS, Goossens H, et al. Interventions to reduce colonisation and transmission of antimicrobial-resistant bacteria in intensive care units: an interrupted time series study and cluster randomised trial. Lancet Infect Dis 2014; 14: 31–39.
Imiquimod is not an effective drug for molluscum contagiosum In a Review of treatment options for molluscum contagiosum infection, Xiaoying Chen and colleagues 1 include imiquimod, citing three small randomised controlled trials and observational data as evidence of its effectiveness. They do not note that findings from two large, well designed, randomised trials (1494-IMIQ and 1495-IMIQ), completed in 2006 but to date unpublished, definitively showed that imiquimod does not effectively treat molluscum contagiosum in children. The two trials together enrolled 702 participants aged 2–12 years, of whom 470 were randomly assigned to imiquimod 5% cream. At week 18, imiquimod was no more effective than was vehicle-containing cream in clearing molluscum contagiosum (24% vs 26% in one study, 24% vs 28% in the other).2 In 2007, the prescribing information approved by the US Food and Drug Administration (FDA) for imiquimod was updated to incorporate results from these two trials as well as a companion pharmacokinetic study (1490-IMIQ), including a statement that the studies “failed to demonstrate efficacy”, and new safety concerns.2 www.thelancet.com/infection Vol 14 May 2014
*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
Correspondence
enhanced antimicrobial stewardship, or mupirocin use) were not introduced throughout their study.3 The World Medical Association’s Declaration of Helsinki4 states that “the benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven intervention(s) except for cases in which due to convincing and scientifically acceptable methodological reasons, the use of any intervention less effective than the best proven one, the use of placebo, or no intervention is necessary provided that the patients who receive any intervention less effective than the best proven one, placebo, or no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention.”4 Because in this study 60% of patients had endotracheal tubes and almost 70% had central venous catheters, the probable risks for patients of not receiving bundles for central-lineassociated bloodstream infection or ventilator-associated pneumonia seem to have been overlooked. Rights and interests of individual research participants should never be superseded by the prime purpose of medical research—ie, to yield new knowledge.4 We declare that we have no competing interests.
Samad E J Golzari, *Ata Mahmoodpoor [email protected]
Liver and Gastrointestinal Disease Research Center (SEJG) and Cardiovascular Research Center (AM), Tabriz University of Medical Sciences, Tabriz, Iran 1
2
3
4
372
Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009; 302: 2323–29. Zilberberg MD, Shorr AF, Kollef MH. Implementing quality improvements in the intensive care unit: ventilator bundle as an example. Crit Care Med 2009; 37: 305–09. Derde LPG, Cooper BS, Goossens H, et al. Interventions to reduce colonisation and transmission of antimicrobial-resistant bacteria in intensive care units: an interrupted time series study and cluster randomised trial. Lancet Infect Dis 2014; 14: 31–39. World Medical Association Declaration of Helsinki—ethical principles for medical research involving human subjects. http:// www.wma.net/en/30publications/10policies/ b3/ (accessed April 4, 2014).
Authors’ reply
We thank Samad Golzari and Ata Mahmoodpoor for their interest and critical reading of our study about reducing antibiotic resistance in intensive care units. Our study was focused on reduction of the overall risk of transmission of antimicrobial-resistant bacteria, thereby aiming to reduce all infections acquired in intensive care units associated with these bacteria, including pneumonia and catheter-related infections. The point we made about care bundles and other interventions was that preventive practices other than the interventions assessed did not change during the study period. It does not imply that best practices, such as using care bundles, were not applied in participating centres. All participating units actually used best care according to national guidelines. Furthermore, ethics committees of all participating hospitals, undoubtedly familiar with the Declaration of Helsinki, approved the study after critically reviewing all aspects of the study protocol. We feel that patients received optimum care with our interventions, which substantially reduced acquisition of antimicrobial-resistiant bacteria (especially meticillinresistance Staphylococcus aureus), probably because of the high level of compliance achieved for hand hygiene and chlorhexidine bodywashing, both major components of patient safety and quality of care. Indeed, the overall quality of care achieved in the intensive care units participating in our study is supported by the fact that rates of meticillin-resistance S aureus and vancomycin-resistant enterococci bacteraemia were too low to allow meaningful statistical analyses. We declare that we have no competing interests.
Marc J M Bonten, Christian Brun-Buisson, Ben S Cooper, *Lennie P G Derde, on behalf of all authors [email protected]
Department of Medical Microbiology and Julius Center for Health Sciences and Primary Care (MB) and Department of Intensive Care Medicine (LD), University Medical Center Utrecht, Utrecht, Netherlands; Service de réanimation médicale and INSERM U657, Institut Pasteur, APHP GH Henri Mondor, Université Paris Est-Créteil, Creteil, France (CB-B); and Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK (BSC) 1
Derde LPG, Cooper BS, Goossens H, et al. Interventions to reduce colonisation and transmission of antimicrobial-resistant bacteria in intensive care units: an interrupted time series study and cluster randomised trial. Lancet Infect Dis 2014; 14: 31–39.
Imiquimod is not an effective drug for molluscum contagiosum In a Review of treatment options for molluscum contagiosum infection, Xiaoying Chen and colleagues 1 include imiquimod, citing three small randomised controlled trials and observational data as evidence of its effectiveness. They do not note that findings from two large, well designed, randomised trials (1494-IMIQ and 1495-IMIQ), completed in 2006 but to date unpublished, definitively showed that imiquimod does not effectively treat molluscum contagiosum in children. The two trials together enrolled 702 participants aged 2–12 years, of whom 470 were randomly assigned to imiquimod 5% cream. At week 18, imiquimod was no more effective than was vehicle-containing cream in clearing molluscum contagiosum (24% vs 26% in one study, 24% vs 28% in the other).2 In 2007, the prescribing information approved by the US Food and Drug Administration (FDA) for imiquimod was updated to incorporate results from these two trials as well as a companion pharmacokinetic study (1490-IMIQ), including a statement that the studies “failed to demonstrate efficacy”, and new safety concerns.2 www.thelancet.com/infection Vol 14 May 2014
