Correspondence
Infections related to totally implantable venous-access ports We read with interest the Review by David Lebeaux and colleagues1 that provided interesting insights into challenges associated with totally implantable venous-access port-related infections. The researchers noted that data for microbiological diagnosis of withdrawn venous access ports are scarce,2 and that the main limitations to culture withdrawn ports are lack of standardisation for technical procedures and the absence of a consensus threshold. During 27 months, we prospectively cultured all totally implantable venousaccess ports that were removed in our hospital (Clinica Universidad de Navarra, Spain). Blood cultures were drawn at the same time. We compared the culture after sonication of the septum with the port internal lumen swabbing and catheter tip culture (Maki and Cleri microbiological culture methods). We regarded a confirmed port-related infection when the same microorganism was isolated from blood cultures and in any port culture. 240 totally implantable venous-access ports were removed from 240 patients. Sensitivity of septum sonication was better than that of chamber swabbing (79 vs 68%; p=0·06), and of catheter tip culture (52%; p=0·01). The specificity of the septum sonicate-fluid culture, chamber swabbing culture, and catheter tip culture were 97%, 96%, and 94%, respectively. Positive and negative predictive values for the septum sonicate-fluid culture were 67% and 97%, respectively. Findings of the ROC curve analysis showed that the best threshold for the septum sonicate-fluid culture was 110 CFU/mL (sensitivity 78% and especificity 93%) for any isolated microorganism. Our data suggest that the septum sonicatefluid culture was the most sensitive method for microbiological diagnosis. The high negative predictive value of 676
this technique allowed us to exclude the venous access port as origin of the bloodstream infection if culture was negative. In our opinion, accurate diagnosis in the microbiology laboratory should include septum-port sonication as part of routine management. However, as stated by other groups,3 a combination of techniques could be the best diagnosis approach. The role of molecular techniques in the diagnosis of totally implantable venous-access portrelated infection remains unclear, but could also be helpful.4
Figure: Thoracic CT (three-dimensional reconstruction) showing the migration of the distal part of a venous-access port into the lung parenchyma (arrow)
We declare no competing interests
Jose L del Pozo, M Alonso, M de la Torre, A Aguinaga [email protected] Division of Infectious Diseases (JLdP), Department of Clinical Microbiology (MA, AA, JLdP), Department of Internal Medicine (MdlT), Clínica Universidad de Navarra, Pamplona, Spain; Department of Microbiology, Hospital Universitario DonostiaInstituto Biodonostia, San Sebastián, Spain (MA) 1
2
3
4
Lebeaux D, Fernandez-Hidalgo N, Chauhan A, et al. Management of infections related to totally implantable venous-access ports: challenges and perspectives. Lancet Infect Dis 2014; 14: 146–59. Douard MC, Arlet G, Longuet P, et al. Diagnosis of venous access port-related infections. Clin Infect Dis 1999; 29: 1197–202. Bouza E, Martin-Rabadan P, Echenagusia A, et al. Diagnosis of venous access port colonization requires cultures from multiple sites: should guidelines be amended? Diagn Microbiol Infect Dis; 78: 162–67. Guembe M, Marin M, Martin-Rabadan P, et al. Use of universal 16S rRNA gene PCR as a diagnostic tool for venous access port-related bloodstream infections. J Clin Microbiol; 51: 799–804.
is mostly clinically silent.2,3 Regular flushing of the implantable venousaccess ports, which is done to prevent occlusion, might cause coughing. However, instillation of cytotoxic drugs might cause severe tissue injury and consecutive infection. In patients with bacterial colonisation of the lungs (eg, patients with chronic obstructive pulmonary disease), ascending infection of the implantable venous-access ports might arise. In these cases, a high level of suspicion is required and removal of the implantable venous-access ports is mandatory. It is assumed that small target vessels, pre-existing lung diseases, and close contact of the catheter tip with the vessel wall are predisposing factors for implantable venous-access port migration.4,5 I declare no competing interests.
David Lebeaux and colleagues wrote an excellent Review on the causes and the management of infections related to totally implantable venousaccess ports,1 presenting the routes of contamination and risk factors. I want to draw attention to another route of infection, which is important despite its rarity. Sometimes implantable venousaccess ports can migrate into the extravascular tissue (eg, lung parenchyma or pleural cavity), even when used for several years without any problems (figure). The migration
Jens Schreiber [email protected] Otto-von-Guericke-University Magdeburg, Department of Pneumonology, 39120 Magdeburg, Germany 1
2
3
Lebeaux D, Fernández-Hidalgo N, Chauhan A, et al. Management of infections related to totally implantable venous-access ports: challenges and perspectives. Lancet Infect Dis 2014; 14: 146–59. Fallon SC, Larimer EL, Gwilliam NR, et al. Increased complication rates associated with Port-a-Cath placement in pediatric patients: location matters. Pediatr Surg 2013; 48: 1263–68. Oduntan O, Turner J. Empyema thoracis due to intrapleural migration of retained vascular catheter. Ann Thorac Surg. 2013; 95: 123–25.
www.thelancet.com/infection Vol 14 August 2014
Correspondence
4
5
Plumhans C, Mahnken AH, Ocklenburg C, et al. Jugular versus subclavian totally implantable access ports: catheter position, complications and intrainterventional pain perception. Eur J Radiol 2011; 79: 338–42. Wu CY, Fu JY, Feng PH et al. Risk factors and possible mechanisms of intravenous port catheter migration. Eur J Vasc Endovasc Surg 2012; 44: 82–87.
Low-dose primaquine for falciparum malaria We read with interest the Correspondence by Kapil Goyal and colleagues1 on primaquine resistance and Eyal Meltzer and Eli Schwartz2 on primaquine metabolism by CYP2D6 in relation to our report on primaquine for transmission reduction of Plasmodium falciparum. 3 The development of resistance has two discrete phases: de-novo emergence and subsequent spread. Resistance arises during asexual reproduction and not in nonreplicating gametocytes. Although primaquine has been used widely for more than 60 years, including in mass drug administrations of single-dose formulations,4 no conclusive evidence exists of primaquine resistance5 in P falciparum gametocytes. Goyal and colleagues state that drug sensitivity assays are needed to monitor gametocyte resistance to primaquine and refer to an in-vitro screening system for gametocytocidal drugs.6 This approach is unfeasible and uninformative for primaquine because the active metabolites of primaquine are unknown and the parent compound has very little activity in vitro.6 Moreover, the assay relies on a small number of gametocyte-producing laboratory parasite isolates that are unlikely to represent those in natural infections. Primaquine might exert a strong selective advantage to the small proportion of surviving gametocytes. Meltzer and Schwartz use the term failure rate for these surviving gametocytes, linking this to the slow drug metabolism by CY2D6 in some individuals. The densities of surviving www.thelancet.com/infection Vol 14 August 2014
gametocytes were markedly lower than those before primaquine,3 and the drug might further affect their viability.7 Further evidence of this finding with mosquito infectivity assays would allow the investigation of primaquine failure. We agree that more data are needed for the geographical differences in CYP2D6 metaboliser phenotype, and we are establishing CYP2D6 status in our Ugandan cohort to inform primaquine policy considerations. We declare no competing interests.
Teun Bousema, Alice C Eziefula, Helmi Pett, Chris Drakeley* [email protected] Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, UK (TB, ACE, CD); and Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, the Netherlands (TB, HP) 1
2
3
4
5
6
7
Goyal K, Kaur H, Sehgal R. Low-dose primaquine for falciparum malaria. Lancet Infect Dis 2014; 14: 449. Meltzer E, Schwartz E. Low-dose primaquine for falciparum malaria. Lancet Infect Dis 2014; 14: 449. Eziefula AC, Bousema T, Yeung S, et al. Single dose primaquine for clearance of Plasmodium falciparum gametocytes in children with uncomplicated malaria in Uganda: a randomised, controlled, double-blind, doseranging trial. Lancet Infect Dis 2014; 14: 130–39. Poirot E, Skarbinski J, Sinclair D, et al. Mass drug administration for malaria. Cochrane Database Syst Rev 2013; 12: CD008846. Recht J, Ashley E, White NJ. Safety of 8-aminoquinoline antimalarial medicines. Geneva: World Health Organization, 2014. D’Alessandro S, Silvestrini F, Dechering K, et al. A Plasmodium falciparum screening assay for anti-gametocyte drugs based on parasite lactate dehydrogenase detection. J Antimicrob Chemother 2013; 68: 2048–58. White NJ. Primaquine to prevent transmission of falciparum malaria. Lancet Infect Dis 2013; 13: 175–81.
Increase in sexually transmitted infections during Europride 2013 in Marseille, France We read with interest the news feature by Tony Kirby describing the rise in sexually transmitted diseases in men who have sex with men in the UK.1 Similarly, the findings of Colson and
colleagues,2 who assessed laboratory surveillance data in Marseille in 2012, noted an increase in the incidence of Neisseria gonorrhoeae, syphilis, and HIV seroconversion. Furthermore, 25 cases of sexually transmitted infections, including N gonorrhoeae and Chlamydia trachomatis, were detected in July, 2013, during Europride, a 10 day gay mass event with an attendance of between 5000 and 60 000 people, depending on the source. Previously, the mean number of diagnoses of sexually transmitted infections was six cases per month (range 1–13); this crucial increase prompted us to explore the epidemiological data for the sexually transmitted infections diagnosed in 2013. Although the number of serologically active syphilis cases was stable, the number of C trachomatis infections increased by 2·2 times in 2013 compared with 2012 (85 vs 42 cases), with a maximum peak in July (18 cases), and the number of N gonorrhoeae cases increased by 2·1 times in 2013 compared with 2012 (68 vs 33; figure). 15 patients tested positive for at least two pathogens. Additionally, HIV seroconversions diagnosed in our laboratory increased by 1·3 times between 2012 and 2013 (16 vs 23; figure), and annual HIV seroconversions in 2012 were 1·8 times higher than between 2005 and 2011.2 We assessed the epidemiological data such as age or sex of the patients who had a sexually transmitted infection, and also the HIV status for those infected with C trachomatis or N gonorrhoeae or both. The 22 HIV seroconversions recorded in 2013 were in men with a mean age of 41 years (range 19–62), including six patients younger than 30 years. Of the 22 HIV seroconversions, 20 were in men who have sex with men (90·9%), a 1·8 times increase compared with the seroconversions of men who have sex with men in 2012 (11 cases). For the other sexually transmitted infections diagnosed in 2013, 62% of patients were male and the mean 677
Infections related to totally implantable venous-access ports We read with interest the Review by David Lebeaux and colleagues1 that provided interesting insights into challenges associated with totally implantable venous-access port-related infections. The researchers noted that data for microbiological diagnosis of withdrawn venous access ports are scarce,2 and that the main limitations to culture withdrawn ports are lack of standardisation for technical procedures and the absence of a consensus threshold. During 27 months, we prospectively cultured all totally implantable venousaccess ports that were removed in our hospital (Clinica Universidad de Navarra, Spain). Blood cultures were drawn at the same time. We compared the culture after sonication of the septum with the port internal lumen swabbing and catheter tip culture (Maki and Cleri microbiological culture methods). We regarded a confirmed port-related infection when the same microorganism was isolated from blood cultures and in any port culture. 240 totally implantable venous-access ports were removed from 240 patients. Sensitivity of septum sonication was better than that of chamber swabbing (79 vs 68%; p=0·06), and of catheter tip culture (52%; p=0·01). The specificity of the septum sonicate-fluid culture, chamber swabbing culture, and catheter tip culture were 97%, 96%, and 94%, respectively. Positive and negative predictive values for the septum sonicate-fluid culture were 67% and 97%, respectively. Findings of the ROC curve analysis showed that the best threshold for the septum sonicate-fluid culture was 110 CFU/mL (sensitivity 78% and especificity 93%) for any isolated microorganism. Our data suggest that the septum sonicatefluid culture was the most sensitive method for microbiological diagnosis. The high negative predictive value of 676
this technique allowed us to exclude the venous access port as origin of the bloodstream infection if culture was negative. In our opinion, accurate diagnosis in the microbiology laboratory should include septum-port sonication as part of routine management. However, as stated by other groups,3 a combination of techniques could be the best diagnosis approach. The role of molecular techniques in the diagnosis of totally implantable venous-access portrelated infection remains unclear, but could also be helpful.4
Figure: Thoracic CT (three-dimensional reconstruction) showing the migration of the distal part of a venous-access port into the lung parenchyma (arrow)
We declare no competing interests
Jose L del Pozo, M Alonso, M de la Torre, A Aguinaga [email protected] Division of Infectious Diseases (JLdP), Department of Clinical Microbiology (MA, AA, JLdP), Department of Internal Medicine (MdlT), Clínica Universidad de Navarra, Pamplona, Spain; Department of Microbiology, Hospital Universitario DonostiaInstituto Biodonostia, San Sebastián, Spain (MA) 1
2
3
4
Lebeaux D, Fernandez-Hidalgo N, Chauhan A, et al. Management of infections related to totally implantable venous-access ports: challenges and perspectives. Lancet Infect Dis 2014; 14: 146–59. Douard MC, Arlet G, Longuet P, et al. Diagnosis of venous access port-related infections. Clin Infect Dis 1999; 29: 1197–202. Bouza E, Martin-Rabadan P, Echenagusia A, et al. Diagnosis of venous access port colonization requires cultures from multiple sites: should guidelines be amended? Diagn Microbiol Infect Dis; 78: 162–67. Guembe M, Marin M, Martin-Rabadan P, et al. Use of universal 16S rRNA gene PCR as a diagnostic tool for venous access port-related bloodstream infections. J Clin Microbiol; 51: 799–804.
is mostly clinically silent.2,3 Regular flushing of the implantable venousaccess ports, which is done to prevent occlusion, might cause coughing. However, instillation of cytotoxic drugs might cause severe tissue injury and consecutive infection. In patients with bacterial colonisation of the lungs (eg, patients with chronic obstructive pulmonary disease), ascending infection of the implantable venous-access ports might arise. In these cases, a high level of suspicion is required and removal of the implantable venous-access ports is mandatory. It is assumed that small target vessels, pre-existing lung diseases, and close contact of the catheter tip with the vessel wall are predisposing factors for implantable venous-access port migration.4,5 I declare no competing interests.
David Lebeaux and colleagues wrote an excellent Review on the causes and the management of infections related to totally implantable venousaccess ports,1 presenting the routes of contamination and risk factors. I want to draw attention to another route of infection, which is important despite its rarity. Sometimes implantable venousaccess ports can migrate into the extravascular tissue (eg, lung parenchyma or pleural cavity), even when used for several years without any problems (figure). The migration
Jens Schreiber [email protected] Otto-von-Guericke-University Magdeburg, Department of Pneumonology, 39120 Magdeburg, Germany 1
2
3
Lebeaux D, Fernández-Hidalgo N, Chauhan A, et al. Management of infections related to totally implantable venous-access ports: challenges and perspectives. Lancet Infect Dis 2014; 14: 146–59. Fallon SC, Larimer EL, Gwilliam NR, et al. Increased complication rates associated with Port-a-Cath placement in pediatric patients: location matters. Pediatr Surg 2013; 48: 1263–68. Oduntan O, Turner J. Empyema thoracis due to intrapleural migration of retained vascular catheter. Ann Thorac Surg. 2013; 95: 123–25.
www.thelancet.com/infection Vol 14 August 2014
Correspondence
4
5
Plumhans C, Mahnken AH, Ocklenburg C, et al. Jugular versus subclavian totally implantable access ports: catheter position, complications and intrainterventional pain perception. Eur J Radiol 2011; 79: 338–42. Wu CY, Fu JY, Feng PH et al. Risk factors and possible mechanisms of intravenous port catheter migration. Eur J Vasc Endovasc Surg 2012; 44: 82–87.
Low-dose primaquine for falciparum malaria We read with interest the Correspondence by Kapil Goyal and colleagues1 on primaquine resistance and Eyal Meltzer and Eli Schwartz2 on primaquine metabolism by CYP2D6 in relation to our report on primaquine for transmission reduction of Plasmodium falciparum. 3 The development of resistance has two discrete phases: de-novo emergence and subsequent spread. Resistance arises during asexual reproduction and not in nonreplicating gametocytes. Although primaquine has been used widely for more than 60 years, including in mass drug administrations of single-dose formulations,4 no conclusive evidence exists of primaquine resistance5 in P falciparum gametocytes. Goyal and colleagues state that drug sensitivity assays are needed to monitor gametocyte resistance to primaquine and refer to an in-vitro screening system for gametocytocidal drugs.6 This approach is unfeasible and uninformative for primaquine because the active metabolites of primaquine are unknown and the parent compound has very little activity in vitro.6 Moreover, the assay relies on a small number of gametocyte-producing laboratory parasite isolates that are unlikely to represent those in natural infections. Primaquine might exert a strong selective advantage to the small proportion of surviving gametocytes. Meltzer and Schwartz use the term failure rate for these surviving gametocytes, linking this to the slow drug metabolism by CY2D6 in some individuals. The densities of surviving www.thelancet.com/infection Vol 14 August 2014
gametocytes were markedly lower than those before primaquine,3 and the drug might further affect their viability.7 Further evidence of this finding with mosquito infectivity assays would allow the investigation of primaquine failure. We agree that more data are needed for the geographical differences in CYP2D6 metaboliser phenotype, and we are establishing CYP2D6 status in our Ugandan cohort to inform primaquine policy considerations. We declare no competing interests.
Teun Bousema, Alice C Eziefula, Helmi Pett, Chris Drakeley* [email protected] Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, UK (TB, ACE, CD); and Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, the Netherlands (TB, HP) 1
2
3
4
5
6
7
Goyal K, Kaur H, Sehgal R. Low-dose primaquine for falciparum malaria. Lancet Infect Dis 2014; 14: 449. Meltzer E, Schwartz E. Low-dose primaquine for falciparum malaria. Lancet Infect Dis 2014; 14: 449. Eziefula AC, Bousema T, Yeung S, et al. Single dose primaquine for clearance of Plasmodium falciparum gametocytes in children with uncomplicated malaria in Uganda: a randomised, controlled, double-blind, doseranging trial. Lancet Infect Dis 2014; 14: 130–39. Poirot E, Skarbinski J, Sinclair D, et al. Mass drug administration for malaria. Cochrane Database Syst Rev 2013; 12: CD008846. Recht J, Ashley E, White NJ. Safety of 8-aminoquinoline antimalarial medicines. Geneva: World Health Organization, 2014. D’Alessandro S, Silvestrini F, Dechering K, et al. A Plasmodium falciparum screening assay for anti-gametocyte drugs based on parasite lactate dehydrogenase detection. J Antimicrob Chemother 2013; 68: 2048–58. White NJ. Primaquine to prevent transmission of falciparum malaria. Lancet Infect Dis 2013; 13: 175–81.
Increase in sexually transmitted infections during Europride 2013 in Marseille, France We read with interest the news feature by Tony Kirby describing the rise in sexually transmitted diseases in men who have sex with men in the UK.1 Similarly, the findings of Colson and
colleagues,2 who assessed laboratory surveillance data in Marseille in 2012, noted an increase in the incidence of Neisseria gonorrhoeae, syphilis, and HIV seroconversion. Furthermore, 25 cases of sexually transmitted infections, including N gonorrhoeae and Chlamydia trachomatis, were detected in July, 2013, during Europride, a 10 day gay mass event with an attendance of between 5000 and 60 000 people, depending on the source. Previously, the mean number of diagnoses of sexually transmitted infections was six cases per month (range 1–13); this crucial increase prompted us to explore the epidemiological data for the sexually transmitted infections diagnosed in 2013. Although the number of serologically active syphilis cases was stable, the number of C trachomatis infections increased by 2·2 times in 2013 compared with 2012 (85 vs 42 cases), with a maximum peak in July (18 cases), and the number of N gonorrhoeae cases increased by 2·1 times in 2013 compared with 2012 (68 vs 33; figure). 15 patients tested positive for at least two pathogens. Additionally, HIV seroconversions diagnosed in our laboratory increased by 1·3 times between 2012 and 2013 (16 vs 23; figure), and annual HIV seroconversions in 2012 were 1·8 times higher than between 2005 and 2011.2 We assessed the epidemiological data such as age or sex of the patients who had a sexually transmitted infection, and also the HIV status for those infected with C trachomatis or N gonorrhoeae or both. The 22 HIV seroconversions recorded in 2013 were in men with a mean age of 41 years (range 19–62), including six patients younger than 30 years. Of the 22 HIV seroconversions, 20 were in men who have sex with men (90·9%), a 1·8 times increase compared with the seroconversions of men who have sex with men in 2012 (11 cases). For the other sexually transmitted infections diagnosed in 2013, 62% of patients were male and the mean 677
