Can We Kill Two Birds with This Stone? Anti-Pneumocystis Prophylaxis to Prevent Nocardia Infection in Hematopoietic Stem Cell Transplant Recipients

Nocardiosis is an opportunistic infection caused by Nocardia species (spp.), which are Gram-positive branching filamentous bacteria. In a recent issue of Biology of Blood and Marrow Transplantation, Molina et al. [1Molina A. Winston D.J. Pan D. Schiller G.J. Increased incidence of nocardial infections in an era of atovaquone prophylaxis in allogeneic hematopoietic stem cell transplant recipients.Biol Blood Marrow Transplant. 2018; https://doi.org/10.1016/j.bbmt.2018.03.010Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] studied the relationship between Pneumocystis jirovecii pneumonia (PJP) prophylaxis and Nocardia infections in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Molina et al. [1Molina A. Winston D.J. Pan D. Schiller G.J. Increased incidence of nocardial infections in an era of atovaquone prophylaxis in allogeneic hematopoietic stem cell transplant recipients.Biol Blood Marrow Transplant. 2018; https://doi.org/10.1016/j.bbmt.2018.03.010Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] performed a retrospective study of nocardiosis among HSCT recipients at the University of California, Los Angeles (UCLA), Medical Center between 2000 and 2017. Around 1000 patients underwent allogeneic HSCT at this institution during the study period. Historically, cotrimoxazole was used to prevent PJP after transplantation, and Nocardia infection was very rare (only 1 case between 2000 and 2011). Importantly, the authors observed a dramatic increase in the incidence of Nocardia infections since 2012, when transplant physicians started to use atovaquone to prevent PJP, instead of cotrimoxazole (9 cases between 2012 and 2017). Most patients with nocardiosis (80%, n = 8) were receiving a prophylaxis other than cotrimoxazole when nocardiosis occurred; the 2 other patients were on cotrimoxazole prophylaxis (20%). All 10 patients had pulmonary nocardiosis, and all cases were culture-confirmed. It is concluded that the use of atovaquone for PJP prophylaxis in place of cotrimoxazole may be associated with an increased risk of nocardiosis in HSCT recipients. With the hope to prevent nocardiosis and other opportunistic infections, Molina et al. [1Molina A. Winston D.J. Pan D. Schiller G.J. Increased incidence of nocardial infections in an era of atovaquone prophylaxis in allogeneic hematopoietic stem cell transplant recipients.Biol Blood Marrow Transplant. 2018; https://doi.org/10.1016/j.bbmt.2018.03.010Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] re-emphasized the use of cotrimoxazole prophylaxis after HSCT. In response, we would like to make 3 comments. First, most cases of nocardiosis occurred in 2015 (n = 6). Although the vast majority of Nocardia infections are sporadic, several reports suggested the possibility of Nocardia outbreaks affecting transplant units [2Lovett I.S. Houang E.T. Burge S. et al.An outbreak of Nocardia asteroides infection in a renal transplant unit.Q J Med. 1981; 50: 123-135PubMed Google Scholar, 3Sahathevan M. Harvey F.A. Forbes G. et al.Epidemiology, bacteriology and control of an outbreak of Nocardia asteroides infection on a liver unit.J Hosp Infect. 1991; 18: 473-480Abstract Full Text PDF PubMed Scopus (43) Google Scholar, 4Exmelin L. Malbruny B. Vergnaud M. Prosvost F. Boiron P. Morel C. Molecular study of nosocomial nocardiosis outbreak involving heart transplant recipients.J Clin Microbiol. 1996; 34: 1014-1016PubMed Google Scholar]. The fact that all the cases of nocardiosis described by Molina et al. [1Molina A. Winston D.J. Pan D. Schiller G.J. Increased incidence of nocardial infections in an era of atovaquone prophylaxis in allogeneic hematopoietic stem cell transplant recipients.Biol Blood Marrow Transplant. 2018; https://doi.org/10.1016/j.bbmt.2018.03.010Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] were pulmonary may suggest an airborne outbreak of Nocardia. Also, the fact that only 1 case was found the following year, when approximately the same number or HSCT recipients were given atovaquone to prevent PJP (37 patients in 2016 versus 34 patients in 2015) suggests that a Nocardia outbreak may have occurred in 2015. We would be interested to know whether this possibility has been explored, by combining microbiological and epidemiological data. Second, the ability of laboratories to detect Nocardia infections depends on several factors, including incubation time and culture medium. The authors reported that in 2013—soon after atovaquone started to replace cotrimoxazole to prevent PJP—the local laboratory started to use a buffered charcoal-yeast extract medium for isolation of Nocardia species from clinical specimens. In our experience as well as in the literature [5Vickers R.M. Rihs J.D. Yu V.L. Clinical demonstration of isolation of Nocardia asteroides on buffered charcoal-yeast extract media.J Clin Microbiol. 1992; 30: 227-228Crossref PubMed Google Scholar, 6Garrett M.A. Holmes H.T. Nolte F.S. Selective buffered charcoal-yeast extract medium for isolation of nocardiae from mixed cultures.J Clin Microbiol. 1992; 30: 1891-1892PubMed Google Scholar, 7Coussement J. Lebeaux D. Rouzaud C. Lortholary O. Nocardia infections in solid organ and hematopoietic stem cell transplant recipients.Curr Opin Infect Dis. 2017; 30: 545-551Crossref PubMed Scopus (32) Google Scholar], this culture medium has been found to be useful for the detection of Nocardia in clinical samples. The fact that 8 of the 10 cases (80%) of nocardiosis are reported by Molina et al. [1Molina A. Winston D.J. Pan D. Schiller G.J. Increased incidence of nocardial infections in an era of atovaquone prophylaxis in allogeneic hematopoietic stem cell transplant recipients.Biol Blood Marrow Transplant. 2018; https://doi.org/10.1016/j.bbmt.2018.03.010Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] to have occurred after this microbiological change may suggest that this modification increased their capacity to detect nocardiosis in HSCT recipients since 2013. However, we acknowledge that the absence of cases of nocardiosis in 2014 does make this hypothesis less likely. Last, but not least, it is unclear whether cotrimoxazole (ie, the drug historically used to prevent PJP at the UCLA Medical Center) is efficient to prevent nocardiosis in transplant recipients. Despite the in vitro activity of cotrimoxazole against a vast majority of Nocardia spp. strains, and the undeniable efficacy of high-dose cotrimoxazole to treat nocardiosis (usually 10 to 20 mg/kg/day of trimethoprim), Nocardia infections may occur in transplant recipients receiving low-dose cotrimoxazole prophylaxis in the prevention of PJP [7Coussement J. Lebeaux D. Rouzaud C. Lortholary O. Nocardia infections in solid organ and hematopoietic stem cell transplant recipients.Curr Opin Infect Dis. 2017; 30: 545-551Crossref PubMed Scopus (32) Google Scholar, 8Bambace N.M. Poirier L. Cohen S. et al.Nocardiosis in allogeneic hematopoietic stem cell transplant recipients: a matched case-control study of risk factors, clinical features and outcomes.Biol Blood Marrow Transplant. 2013; 19: S279-S312Abstract Full Text Full Text PDF Google Scholar, 9van Burik J.A. Hackman R.C. Nadeem S.Q. et al.Nocardiosis after bone marrow transplantation: a retrospective study.Clin Infect Dis. 1997; 24: 1154-1160Crossref PubMed Scopus (108) Google Scholar]. Along the same line, 2 case-control studies concluded that the use of low-dose cotrimoxazole prophylaxis was not protective against nocardiosis in organ transplant recipients [10Peleg A.Y. Husain S. Qureshi Z.A. et al.Risk factors, clinical characteristics, and outcome of Nocardia infection in organ transplant recipients: a matched case-control study.Clin Infect Dis. 2007; 44: 1307-1314Crossref PubMed Scopus (281) Google Scholar, 11Coussement J. Lebeaux D. van Delden C. et al.Nocardia infection in solid organ transplant recipients: a multicenter European case-control study.Clin Infect Dis. 2016; 63: 338-345Crossref PubMed Scopus (126) Google Scholar]. To our knowledge, this question has not been directly addressed in the field of HSCT. Whether the particular protocol used for cotrimoxazole prophylaxis at UCLA since the 1970s (trimethoprim 240 mg/sulfamethoxazole 1200 mg 3 times daily on 2 consecutive days of each week) is beneficial in the prevention of nocardiosis after transplantation, as compared with usual low-dose prophylaxis (eg, ≤160/800 mg 3 times weekly in the previously mentioned case-control studies), is an interesting question that has yet to be answered. As a conclusion, we believe that cotrimoxazole has not consistently been demonstrated to prevent nocardiosis after transplantation. Given the multiple reports of Nocardia infections breaking through cotrimoxazole prophylaxis, and the possible severity of this opportunistic infection, it is important for clinicians to maintain a high degree of suspicion for nocardiosis in HSCT recipients, independently of the prophylaxis used to prevent PJP. Financial disclosure: The authors have nothing to disclose. Conflict of interest statement: There are no conflicts of interest to report.