Letters
sippi set separate age restrictions for antipsychotic entities based on the FDA-approved minimum pediatric age and diagnosis criteria for these drugs. Of the 31 states, 15 have incorporated a peer review process, wherein the adjudication process usually involves a psychiatrist or other physician specialty (Table 2). The programs without a peer review process use automated systems or nonphysician manual reviews for adjudication. Discussion | Overall, 31 state Medicaid agencies have implemented prior authorization policies targeting pediatric atypical antipsychotic use. Nearly half of these policies have incorporated a clinical peer review process. The findings may inform pediatric research to assess the effect of these policies on atypical antipsychotic use to ensure clinical appropriateness and to minimize unintended consequences. A recent study of a midAtlantic state has, however, shown minimal effect of such a policy in reducing antipsychotic use in children below the age restriction.6 Potential unintended consequences of these restrictive policies include inadequate treatment, substitution of potentially inappropriate, off-label psychotropic medication classes such as anticonvulsant mood stabilizers and antidepressants, and administrative burden on prescribers. Additionally, Medicaid oversight programs should be concerned not only with unnecessary antipsychotic use, but also should ensure adherence to appropriate cardiometabolic monitoring practices at baseline and during antipsychotic treatment, and support access to alternative evidence-based nonpharmacological treatments. Our study does not provide additional details within specific programs (eg, criteria for antipsychotic dosage, concomitant pharmacotherapy, or the extent of clinical information required for adjudication), but does provide an impetus to learn if peer review, a novel approach, advances the quality of care. Ian Schmid, BS Mehmet Burcu, MS Julie M. Zito, PhD Author Affiliations: Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland (Schmid); Department of Pharmaceutical Health Services Research, University of Maryland, Baltimore (Burcu, Zito). Corresponding Author: Julie M. Zito, PhD, Department of Pharmaceutical Health Services Research, University of Maryland, 220 Arch St, Baltimore, MD 21201 ([email protected]). Author Contributions: Dr Zito had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: All authors. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Schmid, Burcu. Critical revision of the manuscript for important intellectual content: All authors. Administrative, technical, or material support: All authors. Study supervision: Zito. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Funding/Support: This study was funded by the US Food and Drug Administration (FDA). Mr Schmid was supported in part by a fellowship administered by the Oak Ridge Institute for Science and Education and funded by the US FDA.
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Role of the Funder/Sponsor: The FDA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation of the manuscript; and decision to submit the manuscript for publication. The FDA did participate in the review and approval of the manuscript; however, the study authors functioned as investigators without direction or interference by the FDA. Disclaimer: The opinions expressed in this research letter are those of the authors and do not necessarily represent the opinions of the US government or the FDA. 1. Olfson M, Blanco C, Liu SM, Wang S, Correll CU. National trends in the office-based treatment of children, adolescents, and adults with antipsychotics. Arch Gen Psychiatry. 2012;69(12):1247-1256. 2. Crystal S, Olfson M, Huang C, Pincus H, Gerhard T. Broadened use of atypical antipsychotics: safety, effectiveness, and policy challenges. Health Aff (Millwood). 2009;28(5):w770-w781. 3. ABIM Foundation’s Choosing Wisely. American Psychiatric Association: five things physicians and patients should question. http://www.choosingwisely.org /doctor-patient-lists/american-psychiatric-association/. Accessed January 21, 2015. 4. Correll CU, Manu P, Olshanskiy V, Napolitano B, Kane JM, Malhotra AK. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA. 2009;302(16):1765-1773. 5. Government Accountability Office. Children’s mental health: concerns remain about appropriate services for children in Medicaid and foster care. http: //www.gao.gov/assets/660/650716.pdf. Accessed January 21, 2015. 6. Stein BD, Leckman-Westin E, Okeke E, et al. The effects of prior authorization policies on Medicaid-enrolled children’s use of antipsychotic medications: evidence from two mid-Atlantic states. J Child Adolesc Psychopharmacol. 2014;24(7):374-381.
COMMENT & RESPONSE
Treatment of Late-Stage Syphilis To the Editor Dr Clement and colleagues1 reviewed the available literature on treatment for the early and late stages of syphilis and concluded that benzathine penicillin G is the established treatment for early syphilis (grade A level of evidence). Scarce data are available on treatment of more advanced stages, such as neurosyphilis. Intravenous administration of penicillin G achieves adequate cerebrospinal fluid (CSF) levels and is currently the treatment of choice for neurosyphilis. We noticed that the role of an old drug, probenecid, was hardly mentioned in the review, although it could have a role in treating neurosyphilis. Penicillin G is a ligand both of a low-capacity transport system, which facilitates entry into the intracranial compartment, and of Oat3, an active outward peptide transporter of the choroid plexus, decreasing CSF penicillin concentrations.2 Probenecid has 2 mechanisms of action that both increase the bioavailability of penicillin G. First, it decreases renal tubular secretion, thereby increasing serum levels.3 Second, it inhibits active transport out of the intracranial compartment by inhibiting Oat3, increasing CSF penicillin levels.3 Several clinical and preclinical studies have shown that probenecid could affect outcome. It has been successfully used in combination with oral amoxicillin for treating neurosyphilis.4 Furthermore, given the often limited meningeal inflammation and relatively intact blood-brain barrier, probenecid could theoretically have a role in treating relapses of neurosyphilis. Clinical trials are needed to establish the value of probenecid in treating neurosyphilis. Aram S. A. van Brussel, MD, PhD Gijs W. D. Landman, MD, PhD
JAMA March 3, 2015 Volume 313, Number 9 (Reprinted)
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Author Affiliations: Gelre Hospital Apeldoorn, Utrecht, the Netherlands. Corresponding Author: Aram S. A. van Brussel, MD, PhD, Internal Medicine, Gelre Hospital Apeldoorn, Albert Schweitzerlaan 31, Apeldoorn, Utrecht 7334 DZ, the Netherlands ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Clement ME, Okeke NL, Hicks CB. Treatment of syphilis: a systematic review. JAMA. 2014;312(18):1905-1917. 2. Nau R, Sörgel F, Eiffert H. Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections. Clin Microbiol Rev. 2010;23(4):858-883. 3. Landersdorfer CB, Kirkpatrick CMJ, Kinzig M, et al. Competitive inhibition of renal tubular secretion of gemifloxacin by probenecid. Antimicrob Agents Chemother. 2009;53(9):3902-3907. 4. Morrison RE, Harrison SM, Tramont EC. Oral amoxycillin, an alternative treatment for neurosyphilis. Genitourin Med. 1985;61(6):359-362.
To the Editor The systematic review by Dr Clement and colleagues1 about the treatment of syphilis lacked a critical approach to the problem and provided a tenuous conclusion that “the mainstay of syphilis treatment is parenteral penicillin G despite the relatively modest clinical trial data that support its use.” In addition, the authors did not consider why neurosyphilis may be repeatedly detected in immunocompetent patients despite conventional therapy for early syphilis. The cure of syphilis depends not only on the effect of benzathine penicillin G but also on the integrity of the immune response of the host. The aim of treating early-stage syphilis should be not only to prevent sexual transmission or heal cutaneous lesions but also to prevent progression of disease. When host immune response is compromised (for example, by human immunodeficiency virus [HIV] infection), the inherent weakness of the therapeutic regimen may become more evident. Millions of patients are treated with intramuscular benzathine penicillin G according to official recommendations, but neurosyphilis still takes a heavy toll on them. Despite conventional treatment, 20% of patients without HIV and almost 60% of patients with HIV and early-stage syphilis already have neurosyphilis,2 and almost 13% of syphilis patients have Treponema pallidum in CSF,2 suggesting that treponemes invade the central nervous system early and cannot be eradicated with benzathine penicillin G. Penicillin may fail to achieve sufficient concentrations in CSF, treponemes may develop mechanisms of phenotypic tolerance to penicillin, or treponemes may escape immune surveillance. Regardless of the mechanism, benzathine penicillin G may be inadequate to prevent late-stage complications. The same problem occurs with another spirochetal agent, Borrelia burgdorferi.3 Although antibiotic treatment in earlystage Lyme disease is generally successful, some patients go on to develop persistent disease or neuroborreliosis. In Borrelia infections, cell wall–deficient bacterial forms that may be tolerant to standard antibiotic regimens have been demonstrated.4 Could the same be true for treponemes? Is it time to find alternative antibiotic regimens that could decrease the occurrence of late-stage complications? Francesco Drago, MD Giulia Ciccarese, MD Alfredo Rebora, MD jama.com
Author Affiliations: Department of Dermatology, IRCCS Azienda Ospedaliera Universitaria San Martino–IST, Genoa, Italy. Corresponding Author: Giulia Ciccarese, MD, Department of Dermatology, IRCCS Azienda Ospedaliera Universitaria San Martino–IST, DISSAL, Largo Rosanna Benzi 10, Genoa, 16132 Italy ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Clement ME, Okeke NL, Hicks CB. Treatment of syphilis: a systematic review. JAMA. 2014;312(18):1905-1917. 2. Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. J Infect Dis. 2004;189(3):369-376. 3. Barbour A. Remains of infection. J Clin Invest. 2012;122(7):2344-2346. 4. Hodzic E, Feng S, Holden K, Freet KJ, Barthold SW. Persistence of Borrelia burgdorferi following antibiotic treatment in mice. Antimicrob Agents Chemother. 2008;52(5):1728-1736.
In Reply Drs van Brussel and Landman highlight the potential role of probenecid in treating neurosyphilis and note the mechanism by which it enhances penicillin concentrations within the central nervous system. The cited study by Morrison et al1 showed that the combination of amoxicillin with probenecid cured syphilitic orchitis in rabbits. However, the human group in this study provided evidence only that adequate treponemicidal CSF concentrations were achieved with combined amoxicillin-probenecid. Although this study was not designed to demonstrate clinical efficacy in treating neurosyphilis, it helped form the basis for a randomized clinical trial that compared an enhanced regimen of amoxicillin-probenecid with standard early-stage syphilis treatment and included a subset of patients with central nervous system involvement.2 Detection of T pallidum in CSF after treatment was no more common in those treated with standard therapy (penicillin alone) compared with those receiving the enhanced regimen. Observations are limited by the small number of patients with complete follow-up, but they represent the best available data from a contemporary treatment trial of syphilis. Guideline-recommended treatment includes procaine penicillin plus probenecid as an alternative therapy for neurosyphilis. We agree that probenecid may be of utility in neurosyphilis treatment but believe that further clinical trials are needed to establish its true value. We agree with Dr Drago and colleagues that the goal of treating early-stage syphilis should be not only to treat the clinical manifestations but also to prevent progression of disease. The authors voice concern that a high proportion of patients with early syphilis already have neurosyphilis. Although it is undeniable that treponemes invade the central nervous system early in syphilitic infection, the significance of this is unclear because upward of 80% go on to clear the CSF.3 In the preantibiotic era, there was increased relevance to CSF abnormalities (asymptomatic neurosyphilis) because they were predictive of progression to definite (symptomatic) neurosyphilis. However, after the introduction of penicillin, the rates of clinical neurosyphilis declined drastically.4 Clinicians abandoned routine CSF examination, and only 1 case of progression from asymptomatic to symptomatic neurosyphilis after treatment with 3 weekly injections of intramuscular benzathine penicillin G was reported in 23 years.5 (Reprinted) JAMA March 3, 2015 Volume 313, Number 9
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However, the onset of the HIV epidemic brought about a shift. As Drago and colleagues note, successful outcomes depend on the integrity of the immune response of the host, a crucial issue given multiple reports of neurological relapses occurring after recommended penicillin treatment in individuals with HIV. These reports, however, surfaced before the advent of effective antiretroviral therapy. Patients with HIV have been shown to have lower rates of neurosyphilis when their HIV infection is treated,6 and the availability of effective antiretroviral therapy has helped alleviate concerns regarding HIV-induced immunosuppression. Given the advantages of single-dose therapy for earlystage syphilis and the relatively low rate of posttreatment clinical neurosyphilis in the contemporary era, we believe that improved outcomes overall will result from investment in better surveillance systems for early-stage syphilis, increased adherence to therapy, close follow-up of all infected patients, and expanded access to effective antiretroviral therapy for those with HIV infection. Meredith E. Clement, MD N. Lance Okeke, MD Charles B. Hicks, MD Author Affiliations: Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina (Clement, Okeke); Division of Infectious Diseases, University of California, San Diego (Hicks). Corresponding Author: Charles B. Hicks, MD, Divisions of General Internal Medicine/Infectious Diseases, University of California, San Diego, 200 W Arbor Dr, San Diego, CA 92103 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
In a preliminary study, Liangos et al2 found rapid increases in the levels of several chemokines and adhesion molecules after cardiopulmonary bypass in patients developing AKI, suggesting a strong interaction between hemodynamic and inflammatory mechanisms. The therapeutic intervention was performed a median of 32 hours (interquartile range, 26-52 hours) after initiation of the surgery. This late initiation of treatment might have contributed to the negative findings of the study. Although inclusion of patients at development of AKI might be perceived as early recognition and the performed intervention as timely, the authors’ definition of AKI required an increase in serum creatinine level of at least 50%. The trends in serum creatinine level reported in Figure 2 in the article suggest that patients experienced their initial renal insult during rather than after surgery. Furthermore, at intensive care unit admission an increase in serum creatinine level was already observed despite expected positive fluid balance during surgery, showing that a substantial drop in glomerular filtration rate (GFR) had already occurrred.3 The early increase in renal tubule injury biomarkers compared with the later elevation in serum creatinine level after cardiopulmonary bypass has been found in several studies. 4 By the second postoperative day, when fenoldopam was initiated, patients already had wellestablished AKI, and dopamine agonists would be expected to lack effectiveness in reversing renal hypoperfusion and may even have worsened renal perfusion.5 Although the study adds important information, the success of a therapeutic intervention may depend on early inclusion of patients after renal insult. In future interventional trials, treatment should be based on biomarkers allowing early detection of kidney injury and not on late detection of loss of function.
1. Morrison RE, Harrison SM, Tramont EC. Oral amoxycillin, an alternative treatment for neurosyphilis. Genitourin Med. 1985;61(6):359-362. 2. Rolfs RT, Joesoef MR, Hendershot EF, et al; Syphilis and HIV Study Group. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. N Engl J Med. 1997;337(5): 307-314. 3. Ghanem KG. Neurosyphilis: a historical perspective and review. CNS Neurosci Ther. 2010;16(5):e157-e168. 4. Perdrup A, Jørgensen BB, Pedersen NS. The profile of neurosyphilis in Denmark: a clinical and serological study of all patients in Denmark with neurosyphilis disclosed in the years 1971-1979 incl by Wassermann reaction (CWRM) in the cerebrospinal fluid. Acta Derm Venereol Suppl (Stockh). 1981;96: 1-14. 5. Jaffe HW, Kabins SA. Examination of cerebrospinal fluid in patients with syphilis. Rev Infect Dis. 1982;4:S842-S847. 6. Ghanem KG, Moore RD, Rompalo AM, Erbelding EJ, Zenilman JM, Gebo KA. Neurosyphilis in a clinical cohort of HIV-1-infected patients. AIDS. 2008;22(10): 1145-1151.
Fenoldopam and Acute Kidney Injury To the Editor The trial by Dr Bove and colleagues1 found that the renal vasodilator fenoldopam did not reverse acute kidney injury (AKI) after cardiac surgery, in contrast to previous trials and meta-analyses. The failure of this selective renal vasodilator to prevent further deterioration of AKI supports current concepts that several pathophysiological mechanisms besides renal hypoperfusion are involved in AKI associated with on-pump cardiac surgery. 970
Matthieu Legrand, MD, PhD Michael Darmon, MD, PhD Michael Joannidis, MD, PhD Author Affiliations: Department of Anesthesiology and Critical Care and Burn Unit, AP-HP, St Louis Lariboisière, Paris, France (Legrand); Medical-Surgical ICU, Hôpital Nord, St Priest en Jarez, Saint-Etienne, France (Darmon); Division of Intensive Care and Emergency Medicine, Medical University of Innsbruck, Innsbruck, Austria (Joannidis). Corresponding Author: Matthieu Legrand, MD, PhD, Department of Anesthesiology and Critical Care and Burn Unit, St Louis Hospital, Université Paris Diderot–Paris 7, 1 Rue Claude Vellefaux, 75010 Paris, France (matthieu.m [email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Legrand reported receiving lecture fees from Alere and Gilead and consulting fees from Astellas. Dr Darmon reported receiving logistical research support from Astutos Medical; receiving a grant and logistical research support from Saint-Etienne University Hospital; and being a moderator at a symposium for Hospal. Dr Joannidis reported receiving speaking fees from Baxter, Gambro, Fresenius, CLS Behring, Braun, and Astute and consulting fees from AM Pharma. 1. Bove T, Zangrillo A, Guarracino F, et al. Effect of fenoldopam on use of renal replacement therapy among patients with acute kidney injury after cardiac surgery: a randomized clinical trial. JAMA. 2014;312(21):2244-2253. 2. Liangos O, Addabbo F, Tighiouart H, Goligorsky M, Jaber BL. Exploration of disease mechanism in acute kidney injury using a multiplex bead array assay: a nested case-control pilot study. Biomarkers. 2010;15(5):436-445. 3. Waikar SS, Bonventre JV. Creatinine kinetics and the definition of acute kidney injury. J Am Soc Nephrol. 2009;20(3):672-679.
JAMA March 3, 2015 Volume 313, Number 9 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
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sippi set separate age restrictions for antipsychotic entities based on the FDA-approved minimum pediatric age and diagnosis criteria for these drugs. Of the 31 states, 15 have incorporated a peer review process, wherein the adjudication process usually involves a psychiatrist or other physician specialty (Table 2). The programs without a peer review process use automated systems or nonphysician manual reviews for adjudication. Discussion | Overall, 31 state Medicaid agencies have implemented prior authorization policies targeting pediatric atypical antipsychotic use. Nearly half of these policies have incorporated a clinical peer review process. The findings may inform pediatric research to assess the effect of these policies on atypical antipsychotic use to ensure clinical appropriateness and to minimize unintended consequences. A recent study of a midAtlantic state has, however, shown minimal effect of such a policy in reducing antipsychotic use in children below the age restriction.6 Potential unintended consequences of these restrictive policies include inadequate treatment, substitution of potentially inappropriate, off-label psychotropic medication classes such as anticonvulsant mood stabilizers and antidepressants, and administrative burden on prescribers. Additionally, Medicaid oversight programs should be concerned not only with unnecessary antipsychotic use, but also should ensure adherence to appropriate cardiometabolic monitoring practices at baseline and during antipsychotic treatment, and support access to alternative evidence-based nonpharmacological treatments. Our study does not provide additional details within specific programs (eg, criteria for antipsychotic dosage, concomitant pharmacotherapy, or the extent of clinical information required for adjudication), but does provide an impetus to learn if peer review, a novel approach, advances the quality of care. Ian Schmid, BS Mehmet Burcu, MS Julie M. Zito, PhD Author Affiliations: Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland (Schmid); Department of Pharmaceutical Health Services Research, University of Maryland, Baltimore (Burcu, Zito). Corresponding Author: Julie M. Zito, PhD, Department of Pharmaceutical Health Services Research, University of Maryland, 220 Arch St, Baltimore, MD 21201 ([email protected]). Author Contributions: Dr Zito had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: All authors. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Schmid, Burcu. Critical revision of the manuscript for important intellectual content: All authors. Administrative, technical, or material support: All authors. Study supervision: Zito. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Funding/Support: This study was funded by the US Food and Drug Administration (FDA). Mr Schmid was supported in part by a fellowship administered by the Oak Ridge Institute for Science and Education and funded by the US FDA.
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Role of the Funder/Sponsor: The FDA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation of the manuscript; and decision to submit the manuscript for publication. The FDA did participate in the review and approval of the manuscript; however, the study authors functioned as investigators without direction or interference by the FDA. Disclaimer: The opinions expressed in this research letter are those of the authors and do not necessarily represent the opinions of the US government or the FDA. 1. Olfson M, Blanco C, Liu SM, Wang S, Correll CU. National trends in the office-based treatment of children, adolescents, and adults with antipsychotics. Arch Gen Psychiatry. 2012;69(12):1247-1256. 2. Crystal S, Olfson M, Huang C, Pincus H, Gerhard T. Broadened use of atypical antipsychotics: safety, effectiveness, and policy challenges. Health Aff (Millwood). 2009;28(5):w770-w781. 3. ABIM Foundation’s Choosing Wisely. American Psychiatric Association: five things physicians and patients should question. http://www.choosingwisely.org /doctor-patient-lists/american-psychiatric-association/. Accessed January 21, 2015. 4. Correll CU, Manu P, Olshanskiy V, Napolitano B, Kane JM, Malhotra AK. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA. 2009;302(16):1765-1773. 5. Government Accountability Office. Children’s mental health: concerns remain about appropriate services for children in Medicaid and foster care. http: //www.gao.gov/assets/660/650716.pdf. Accessed January 21, 2015. 6. Stein BD, Leckman-Westin E, Okeke E, et al. The effects of prior authorization policies on Medicaid-enrolled children’s use of antipsychotic medications: evidence from two mid-Atlantic states. J Child Adolesc Psychopharmacol. 2014;24(7):374-381.
COMMENT & RESPONSE
Treatment of Late-Stage Syphilis To the Editor Dr Clement and colleagues1 reviewed the available literature on treatment for the early and late stages of syphilis and concluded that benzathine penicillin G is the established treatment for early syphilis (grade A level of evidence). Scarce data are available on treatment of more advanced stages, such as neurosyphilis. Intravenous administration of penicillin G achieves adequate cerebrospinal fluid (CSF) levels and is currently the treatment of choice for neurosyphilis. We noticed that the role of an old drug, probenecid, was hardly mentioned in the review, although it could have a role in treating neurosyphilis. Penicillin G is a ligand both of a low-capacity transport system, which facilitates entry into the intracranial compartment, and of Oat3, an active outward peptide transporter of the choroid plexus, decreasing CSF penicillin concentrations.2 Probenecid has 2 mechanisms of action that both increase the bioavailability of penicillin G. First, it decreases renal tubular secretion, thereby increasing serum levels.3 Second, it inhibits active transport out of the intracranial compartment by inhibiting Oat3, increasing CSF penicillin levels.3 Several clinical and preclinical studies have shown that probenecid could affect outcome. It has been successfully used in combination with oral amoxicillin for treating neurosyphilis.4 Furthermore, given the often limited meningeal inflammation and relatively intact blood-brain barrier, probenecid could theoretically have a role in treating relapses of neurosyphilis. Clinical trials are needed to establish the value of probenecid in treating neurosyphilis. Aram S. A. van Brussel, MD, PhD Gijs W. D. Landman, MD, PhD
JAMA March 3, 2015 Volume 313, Number 9 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
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Letters
Author Affiliations: Gelre Hospital Apeldoorn, Utrecht, the Netherlands. Corresponding Author: Aram S. A. van Brussel, MD, PhD, Internal Medicine, Gelre Hospital Apeldoorn, Albert Schweitzerlaan 31, Apeldoorn, Utrecht 7334 DZ, the Netherlands ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Clement ME, Okeke NL, Hicks CB. Treatment of syphilis: a systematic review. JAMA. 2014;312(18):1905-1917. 2. Nau R, Sörgel F, Eiffert H. Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections. Clin Microbiol Rev. 2010;23(4):858-883. 3. Landersdorfer CB, Kirkpatrick CMJ, Kinzig M, et al. Competitive inhibition of renal tubular secretion of gemifloxacin by probenecid. Antimicrob Agents Chemother. 2009;53(9):3902-3907. 4. Morrison RE, Harrison SM, Tramont EC. Oral amoxycillin, an alternative treatment for neurosyphilis. Genitourin Med. 1985;61(6):359-362.
To the Editor The systematic review by Dr Clement and colleagues1 about the treatment of syphilis lacked a critical approach to the problem and provided a tenuous conclusion that “the mainstay of syphilis treatment is parenteral penicillin G despite the relatively modest clinical trial data that support its use.” In addition, the authors did not consider why neurosyphilis may be repeatedly detected in immunocompetent patients despite conventional therapy for early syphilis. The cure of syphilis depends not only on the effect of benzathine penicillin G but also on the integrity of the immune response of the host. The aim of treating early-stage syphilis should be not only to prevent sexual transmission or heal cutaneous lesions but also to prevent progression of disease. When host immune response is compromised (for example, by human immunodeficiency virus [HIV] infection), the inherent weakness of the therapeutic regimen may become more evident. Millions of patients are treated with intramuscular benzathine penicillin G according to official recommendations, but neurosyphilis still takes a heavy toll on them. Despite conventional treatment, 20% of patients without HIV and almost 60% of patients with HIV and early-stage syphilis already have neurosyphilis,2 and almost 13% of syphilis patients have Treponema pallidum in CSF,2 suggesting that treponemes invade the central nervous system early and cannot be eradicated with benzathine penicillin G. Penicillin may fail to achieve sufficient concentrations in CSF, treponemes may develop mechanisms of phenotypic tolerance to penicillin, or treponemes may escape immune surveillance. Regardless of the mechanism, benzathine penicillin G may be inadequate to prevent late-stage complications. The same problem occurs with another spirochetal agent, Borrelia burgdorferi.3 Although antibiotic treatment in earlystage Lyme disease is generally successful, some patients go on to develop persistent disease or neuroborreliosis. In Borrelia infections, cell wall–deficient bacterial forms that may be tolerant to standard antibiotic regimens have been demonstrated.4 Could the same be true for treponemes? Is it time to find alternative antibiotic regimens that could decrease the occurrence of late-stage complications? Francesco Drago, MD Giulia Ciccarese, MD Alfredo Rebora, MD jama.com
Author Affiliations: Department of Dermatology, IRCCS Azienda Ospedaliera Universitaria San Martino–IST, Genoa, Italy. Corresponding Author: Giulia Ciccarese, MD, Department of Dermatology, IRCCS Azienda Ospedaliera Universitaria San Martino–IST, DISSAL, Largo Rosanna Benzi 10, Genoa, 16132 Italy ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Clement ME, Okeke NL, Hicks CB. Treatment of syphilis: a systematic review. JAMA. 2014;312(18):1905-1917. 2. Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. J Infect Dis. 2004;189(3):369-376. 3. Barbour A. Remains of infection. J Clin Invest. 2012;122(7):2344-2346. 4. Hodzic E, Feng S, Holden K, Freet KJ, Barthold SW. Persistence of Borrelia burgdorferi following antibiotic treatment in mice. Antimicrob Agents Chemother. 2008;52(5):1728-1736.
In Reply Drs van Brussel and Landman highlight the potential role of probenecid in treating neurosyphilis and note the mechanism by which it enhances penicillin concentrations within the central nervous system. The cited study by Morrison et al1 showed that the combination of amoxicillin with probenecid cured syphilitic orchitis in rabbits. However, the human group in this study provided evidence only that adequate treponemicidal CSF concentrations were achieved with combined amoxicillin-probenecid. Although this study was not designed to demonstrate clinical efficacy in treating neurosyphilis, it helped form the basis for a randomized clinical trial that compared an enhanced regimen of amoxicillin-probenecid with standard early-stage syphilis treatment and included a subset of patients with central nervous system involvement.2 Detection of T pallidum in CSF after treatment was no more common in those treated with standard therapy (penicillin alone) compared with those receiving the enhanced regimen. Observations are limited by the small number of patients with complete follow-up, but they represent the best available data from a contemporary treatment trial of syphilis. Guideline-recommended treatment includes procaine penicillin plus probenecid as an alternative therapy for neurosyphilis. We agree that probenecid may be of utility in neurosyphilis treatment but believe that further clinical trials are needed to establish its true value. We agree with Dr Drago and colleagues that the goal of treating early-stage syphilis should be not only to treat the clinical manifestations but also to prevent progression of disease. The authors voice concern that a high proportion of patients with early syphilis already have neurosyphilis. Although it is undeniable that treponemes invade the central nervous system early in syphilitic infection, the significance of this is unclear because upward of 80% go on to clear the CSF.3 In the preantibiotic era, there was increased relevance to CSF abnormalities (asymptomatic neurosyphilis) because they were predictive of progression to definite (symptomatic) neurosyphilis. However, after the introduction of penicillin, the rates of clinical neurosyphilis declined drastically.4 Clinicians abandoned routine CSF examination, and only 1 case of progression from asymptomatic to symptomatic neurosyphilis after treatment with 3 weekly injections of intramuscular benzathine penicillin G was reported in 23 years.5 (Reprinted) JAMA March 3, 2015 Volume 313, Number 9
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Nanyang Technological University User on 05/21/2015
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Letters
However, the onset of the HIV epidemic brought about a shift. As Drago and colleagues note, successful outcomes depend on the integrity of the immune response of the host, a crucial issue given multiple reports of neurological relapses occurring after recommended penicillin treatment in individuals with HIV. These reports, however, surfaced before the advent of effective antiretroviral therapy. Patients with HIV have been shown to have lower rates of neurosyphilis when their HIV infection is treated,6 and the availability of effective antiretroviral therapy has helped alleviate concerns regarding HIV-induced immunosuppression. Given the advantages of single-dose therapy for earlystage syphilis and the relatively low rate of posttreatment clinical neurosyphilis in the contemporary era, we believe that improved outcomes overall will result from investment in better surveillance systems for early-stage syphilis, increased adherence to therapy, close follow-up of all infected patients, and expanded access to effective antiretroviral therapy for those with HIV infection. Meredith E. Clement, MD N. Lance Okeke, MD Charles B. Hicks, MD Author Affiliations: Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina (Clement, Okeke); Division of Infectious Diseases, University of California, San Diego (Hicks). Corresponding Author: Charles B. Hicks, MD, Divisions of General Internal Medicine/Infectious Diseases, University of California, San Diego, 200 W Arbor Dr, San Diego, CA 92103 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
In a preliminary study, Liangos et al2 found rapid increases in the levels of several chemokines and adhesion molecules after cardiopulmonary bypass in patients developing AKI, suggesting a strong interaction between hemodynamic and inflammatory mechanisms. The therapeutic intervention was performed a median of 32 hours (interquartile range, 26-52 hours) after initiation of the surgery. This late initiation of treatment might have contributed to the negative findings of the study. Although inclusion of patients at development of AKI might be perceived as early recognition and the performed intervention as timely, the authors’ definition of AKI required an increase in serum creatinine level of at least 50%. The trends in serum creatinine level reported in Figure 2 in the article suggest that patients experienced their initial renal insult during rather than after surgery. Furthermore, at intensive care unit admission an increase in serum creatinine level was already observed despite expected positive fluid balance during surgery, showing that a substantial drop in glomerular filtration rate (GFR) had already occurrred.3 The early increase in renal tubule injury biomarkers compared with the later elevation in serum creatinine level after cardiopulmonary bypass has been found in several studies. 4 By the second postoperative day, when fenoldopam was initiated, patients already had wellestablished AKI, and dopamine agonists would be expected to lack effectiveness in reversing renal hypoperfusion and may even have worsened renal perfusion.5 Although the study adds important information, the success of a therapeutic intervention may depend on early inclusion of patients after renal insult. In future interventional trials, treatment should be based on biomarkers allowing early detection of kidney injury and not on late detection of loss of function.
1. Morrison RE, Harrison SM, Tramont EC. Oral amoxycillin, an alternative treatment for neurosyphilis. Genitourin Med. 1985;61(6):359-362. 2. Rolfs RT, Joesoef MR, Hendershot EF, et al; Syphilis and HIV Study Group. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. N Engl J Med. 1997;337(5): 307-314. 3. Ghanem KG. Neurosyphilis: a historical perspective and review. CNS Neurosci Ther. 2010;16(5):e157-e168. 4. Perdrup A, Jørgensen BB, Pedersen NS. The profile of neurosyphilis in Denmark: a clinical and serological study of all patients in Denmark with neurosyphilis disclosed in the years 1971-1979 incl by Wassermann reaction (CWRM) in the cerebrospinal fluid. Acta Derm Venereol Suppl (Stockh). 1981;96: 1-14. 5. Jaffe HW, Kabins SA. Examination of cerebrospinal fluid in patients with syphilis. Rev Infect Dis. 1982;4:S842-S847. 6. Ghanem KG, Moore RD, Rompalo AM, Erbelding EJ, Zenilman JM, Gebo KA. Neurosyphilis in a clinical cohort of HIV-1-infected patients. AIDS. 2008;22(10): 1145-1151.
Fenoldopam and Acute Kidney Injury To the Editor The trial by Dr Bove and colleagues1 found that the renal vasodilator fenoldopam did not reverse acute kidney injury (AKI) after cardiac surgery, in contrast to previous trials and meta-analyses. The failure of this selective renal vasodilator to prevent further deterioration of AKI supports current concepts that several pathophysiological mechanisms besides renal hypoperfusion are involved in AKI associated with on-pump cardiac surgery. 970
Matthieu Legrand, MD, PhD Michael Darmon, MD, PhD Michael Joannidis, MD, PhD Author Affiliations: Department of Anesthesiology and Critical Care and Burn Unit, AP-HP, St Louis Lariboisière, Paris, France (Legrand); Medical-Surgical ICU, Hôpital Nord, St Priest en Jarez, Saint-Etienne, France (Darmon); Division of Intensive Care and Emergency Medicine, Medical University of Innsbruck, Innsbruck, Austria (Joannidis). Corresponding Author: Matthieu Legrand, MD, PhD, Department of Anesthesiology and Critical Care and Burn Unit, St Louis Hospital, Université Paris Diderot–Paris 7, 1 Rue Claude Vellefaux, 75010 Paris, France (matthieu.m [email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Legrand reported receiving lecture fees from Alere and Gilead and consulting fees from Astellas. Dr Darmon reported receiving logistical research support from Astutos Medical; receiving a grant and logistical research support from Saint-Etienne University Hospital; and being a moderator at a symposium for Hospal. Dr Joannidis reported receiving speaking fees from Baxter, Gambro, Fresenius, CLS Behring, Braun, and Astute and consulting fees from AM Pharma. 1. Bove T, Zangrillo A, Guarracino F, et al. Effect of fenoldopam on use of renal replacement therapy among patients with acute kidney injury after cardiac surgery: a randomized clinical trial. JAMA. 2014;312(21):2244-2253. 2. Liangos O, Addabbo F, Tighiouart H, Goligorsky M, Jaber BL. Exploration of disease mechanism in acute kidney injury using a multiplex bead array assay: a nested case-control pilot study. Biomarkers. 2010;15(5):436-445. 3. Waikar SS, Bonventre JV. Creatinine kinetics and the definition of acute kidney injury. J Am Soc Nephrol. 2009;20(3):672-679.
JAMA March 3, 2015 Volume 313, Number 9 (Reprinted)
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