PEDIATRICS Vol. 120 No. 1 July 2007, pp. e47-e51 (doi:10.1542/peds.2006-1360)
ARTICLE |
Successful Intermittent Prophylaxis With Trimethoprim/Sulfamethoxazole 2 Days per Week for Pneumocystis carinii (jiroveci) Pneumonia in Pediatric Oncology Patients
Center for Cancer and Blood Disorders, University of Colorado Health Science Center, Children's Hospital, Denver, Colorado
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVE. This study was conducted to determine the efficacy of dosing trimethoprim/sulfamethoxazole on 2 consecutive days per week for the prevention of Pneumocystis carinii (jiroveci) pneumonia in a pediatric leukemia and lymphoma population and to determine whether trimethoprim/sulfamethoxazole contributes to neutropenia during maintenance therapy.
METHODS. Charts were reviewed for all pediatric patients with leukemia and lymphoma diagnosed between January 1, 1993, and December 31, 2002. Data were collected through April 1, 2004.
RESULTS. A total of 575 charts were reviewed; 529 patients were included in the analysis. A total of 482 (345 leukemia, 137 lymphoma) patients were evaluated on trimethoprim/sulfamethoxazole dosed 2 consecutive days per week for 268074 patient-days. No breakthrough cases were documented in compliant patients; 2 noncompliant patients developed P carinii pneumonia. A total of 238 patients who were on trimethoprim/sulfamethoxazole prophylaxis and 13 patients who were receiving an alternative medication prophylaxis were evaluated for neutropenia during maintenance therapy. The median number of maintenance days on trimethoprim/sulfamethoxazole was 605.5 days and on alternative drug was 617 days. The median number of neutropenic maintenance days on trimethoprim/sulfamethoxazole was 15.5 days and on the alternative drug was 16 days. The median proportion of neutropenic days per patient was 0.029 on trimethoprim/sulfamethoxazole and 0.022 on the alternative drug.
CONCLUSIONS. Intermittent dosing of trimethoprim/sulfamethoxazole on 2 consecutive days per week is an effective alternative prophylactic regimen for P carinii pneumonia in pediatric patients with leukemia and lymphoma. This analysis does not support a difference in neutropenia during maintenance therapy between patients who are treated with trimethoprim/sulfamethoxazole versus an alternative drug.
Key Words: Pneumocystis carinii (jiroveci) • chemoprophylaxis • trimethoprim/sulfamethoxazole • leukemia • lymphoma • pediatrics
Abbreviations: PCP—Pneumocystis carinii pneumonia • TMP/SMX—trimethoprim/sulfamethoxazole • ALL—acute lymphoblastic leukemia
Pneumocystis carinii (jiroveci) pneumonia (PCP) is a widely recognized opportunistic infection in immunocompromised patients, including pediatric oncology patients. Before the initiation of routine prophylaxis for PCP with trimethoprim/sulfamethoxazole (TMP/SMX), attack rates as high as 43% were reported in subsets of pediatric oncology patients.1 In 1977, Hughes et al1 published results of the first study to document successful prophylaxis with daily TMP/SMX in pediatric oncology patients. The success of daily and intermittent prophylactic dosing of TMP/SMX has subsequently been recognized by several authors.1–4 Current recommendations for TMP/SMX dosing for PCP prophylaxis in immunocompromised patients are based on either daily dosing or dosing 3 consecutive days per week.5
This study reports >10 years of experience with intermittent dosing of TMP/SMX based on a regimen of 2 consecutive days per week used routinely for PCP prophylaxis in pediatric patients with leukemia and lymphoma. This dosing regimen was adopted from dosing in bone marrow transplant patients who returned to our center from outside institutions.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Charts were reviewed for all pediatric oncology patients who received a diagnosis of leukemia or lymphoma between January 1, 1993, and December 31, 2002. Patients were identified through the tumor registry and oncology databases that are maintained at this institution. Data gathered included patient diagnosis; regimen for PCP prophylaxis; length of time on prophylaxis; alterations to the prophylaxis regimen; interruptions to prophylaxis (including duration and reason); reason for stopping prophylaxis; and, for patients with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma who underwent a maintenance phase of therapy, the number and the duration of neutropenic episodes during maintenance therapy. Data were collected through April 1, 2004. Data that were obtained from the medical charts regarding pathologic diagnoses and complete blood counts were confirmed against computerized laboratory reports when possible.
For uniformity in data collection, the following terms were defined: neutropenia denotes an absolute neutrophil count 
500 cells per mm3; the prophylaxis start date is either the date of oncologic diagnosis or, when the diagnosis was made at another institution, the date on which the child was first seen at the Children's Hospital and prophylaxis was documented; and the prophylaxis end date was the off-therapy date for the treatment protocol, the end review date of April 1, 2004, the date on which the patient went to bone marrow transplant, the date on which the patient was last seen in the clinic if care was transferred, or the date of death.
Nonparametric tests were used in the comparison of neutropenia during maintenance therapy between patients who were treated with TMP/SMX and alternative drug regimens. A Fisher's exact test was used to compare the groups with regard to the proportion of patients with no neutropenic days observed. A Wilcoxon 2-sample test and an analysis of covariance were used to compare the proportion of neutropenic days per patient between the groups. A 
2 analysis was performed to compare the total proportion of neutropenic days for the groups as a whole.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Patient Characteristics and Prophylaxis Regimens
Between January 1, 1993, and December 31, 2002, 575 patients received a diagnosis of leukemia or lymphoma (409 leukemia, 166 lymphoma). The distribution of diagnoses is shown in Table 1.
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Forty-six patients (33 leukemia, 13 lymphoma) were excluded from additional analysis. Reasons for exclusion were inability to locate a chart in 12 (10 leukemia, 2 lymphoma), treatment with bone marrow transplant only in 11 (all leukemia), poor documentation of the prophylaxis regimen in 15 (8 leukemia, 7 lymphoma), and death before initiation of treatment/prophylaxis in 8 (4 leukemia, 4 lymphoma). After exclusions, 529 patients remained for analysis: 376 with leukemia and 153 with lymphoma.
A total of 482 patients (345 leukemia, 137 lymphoma) received TMP/SMX prophylaxis on 2 consecutive days per week. TMP/SMX was dosed 5 mg/kg per day of TMP divided into 2 doses on 2 consecutive days per week up to a maximum dosage equivalent of 1 double-strength TMP/SMX tablet twice daily. TMP/SMX dosages were adjusted for growth throughout the course of prophylaxis.
Forty-seven patients (31 leukemia, 16 lymphoma) received PCP prophylaxis with either an alternative drug or an alternative dosing regimen of TMP/SMX. Thirty-four (25 leukemia, 9 lymphoma) received pentamidine or dapsone. Alternative drugs were used when a patient had a preexisting sulfa allergy or when the adverse effect profile of TMP/SMX was of concern. The acute myeloid leukemia subgroup had the largest percentage of patients receiving alternative drugs secondary to provider bias regarding concern for myelosuppression with TMP/SMX. Thirteen (6 leukemia, 7 lymphoma) received TMP/SMX as PCP prophylaxis dosed on 3 consecutive days per week. Alternative dosing of TMP/SMX was most commonly found in patients who transferred care from another institution, and dosing was not adjusted.
Attack Rate of PCP With TMP/SMX 2 Consecutive Days per Week
A total of 482 patients who were receiving prophylaxis with TMP/SMX 2 consecutive days per week were evaluated for a total of 268074 patient-days (233716 leukemia, 34358 lymphoma). Two (0.41%) patients developed PCP during the study period. Both patients admitted noncompliance with prophylaxis before infection. There were no (0%) cases of PCP in patients who were compliant with their prophylactic regimen. Given our level of communication with our patients as well as outside institutions, it is highly unlikely that any PCP diagnoses were missed. Because there is no control group in this retrospective review, comparison can be made only with historical data. Hughes et al1,2 published a PCP attack rate of 21% in a placebo group that was observed for 27138 patient-days, 0% in a treatment group that received daily TMP/SMX prophylaxis and was observed for 30602 patient-days, and 0% in a treatment group that received TMP/SMX prophylaxis 3 days per week and was observed for 29329 patient-days.
There is no established incidence rate for PCP infection at the Children's Hospital. During the study period, 31 cases of pathologically proven PCP pneumonia were diagnosed. Currently, the Children's Hospital laboratory uses a monoclonal antibody that is specific for P carinii and immunofluorescence techniques to detect the organism (BioRad, Hercules, CA). Three cases occurred in pediatric oncology patients: the 2 patients who had leukemia and were noncompliant with prophylaxis and 1 patient who had a relapsed solid tumor and had had an autologous bone marrow transplant and was not on prophylaxis. Four cases occurred in patients who had had a bone marrow transplant, all of whom were receiving intravenous pentamidine as their prophylaxis regimen. The other 24 patients received a diagnosis of either a defined immunodeficiency syndrome or were immunocompromised secondary to treatment for disorders such as rheumatologic illness, nephrotic syndrome, solid-organ transplant, or chronic pulmonary conditions.
Alterations to Prophylaxis Regimen
Changes were made to the TMP/SMX prophylaxis regimen of 2 consecutive days per week at the discretion of the primary oncologist. Eighty-nine medication changes were made in 82 patients (17.0%). The reasons for alteration are listed in Table 2. Neutropenia accounted for the majority of changes in the leukemia group (41.3%). Inability to take the medication as a result of nausea, anorexia, or mucositis accounted for the majority of alterations in the lymphoma group (64.3%). Eleven (2.3%) patients were considered to have developed a new allergy to TMP/SMX with the report of rash and had their prophylaxis drug changed. Very few changes were required secondary to noncompliance. In some instances, the prophylaxis regimen was altered but the reason was not clearly documented in the chart; these were categorized "physician choice."
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Some patients had brief interruptions to their TMP/SMX prophylaxis without actual medication change. Forty-four patients (41 leukemia, 3 lymphoma) had 57 interruptions documented. The median length of interruption was 7 days. Fifty-four (94.7%) of 57 interruptions occurred secondary to neutropenia.
Neutropenia During Maintenance Therapy
Patients who had a diagnosis of ALL or lymphoblastic lymphoma and were on TMP/SMX and underwent a maintenance phase of therapy were evaluated for neutropenia and compared with patients who were receiving other medications (pentamidine, dapsone) for prophylaxis. Of the 299 patients with ALL and 14 patients with lymphoblastic lymphoma, 272 underwent a maintenance phase of therapy. Patients were included in this analysis only when they remained on either TMP/SMX or an alternative medication throughout the entire course of maintenance therapy. Twenty-one were excluded because of medication changes during maintenance therapy, leaving 238 patients on TMP/SMX and 13 on alternative medications to be evaluated for neutropenia.
A total of 175 (73.5%) of 238 patients who were receiving TMP/SMX had at least 1 documented episode of neutropenia during maintenance. The median number of maintenance days on TMP/SMX was 605.5 (range: 13–1232 days), and the median number of neutropenic days was 15.5 (range: 0–171 days). Nine (69.2%) of 13 patients who were receiving an alternative medication had at least 1 documented episode of neutropenia during maintenance. The median number of maintenance days on alternative medication was 617 (range: 273–977 days), and the median number of neutropenic days was 16 (range: 0–37 days).
Patients who were on TMP/SMX experienced neutropenia on 4.11% of maintenance days compared with 2.17% on alternative drugs (P < .001, 2 test). Although previous studies2 reported neutropenia data using neutropenic days as a proportion of total maintenance days for all patients, given the small number of patients in the alternative drug group for this study, the 2 groups were additionally compared using the proportion of neutropenic days per patient.
The distribution of neutropenic days per patient was highly skewed as a result of the large number of patients with 0 neutropenic days (63 of 238 TMP/SMX, 5 of 13 alternative medication). This proportion of patients with 0 neutropenic days was not significantly different between the 2 groups (P = .26, Fisher's exact test). The median proportion of neutropenic days was 0.029 in patients who were receiving TMP/SMX and 0.022 in those who were receiving an alternative drug. The groups were compared using a Wilcoxon 2-sample test and were not significantly different (P = .20). The days of neutropenia were also compared using analysis of covariance with total days on drug and drug group as covariates. This was also nonsignificant for drug group (P = .11).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Pneumocystis organisms were first identified in the early 20th century by Carlos Chagas6 while studying a model of trypanosome infection and by Antonio Carini in infected rat lung.7 The organism was initially thought to be a protozoan and was named Pneumocystis carinii.8 In the late 1980s, analysis of small ribosomal RNA subunits established that the organism was a fungus.9 The organism that causes infection in humans has been found to be different from the organism that causes infection in animals, and a change in the name to Pneumocystis jiroveci was proposed in the late 1990s.10 The name change remains controversial.11,12
PCP was reported as an epidemic problem for children who receive treatment for malignancy in a report of 19 patients who had malignancy and were treated at St Jude Children's Research Hospital in 1968 and 1969.13 In the early 1970s, PCP was described as an opportunistic infection in pediatric patients with malignancy.14 In 1977, Hughes established the efficacy of daily TMP/SMX in the prevention of P carinii–associated pneumonia in pediatric oncology patients. He followed this in 1987 by establishing the efficacy of intermittent prophylaxis with TMP/SMX given 3 consecutive days per week.1,2 PCP prophylaxis with TMP/SMX given 2 consecutive days per week has been found effective in heart transplant patients15 and bone marrow transplant patients.16
This study establishes the efficacy of an intermittent PCP prophylaxis regimen of 2 consecutive days per week with TMP/SMX in pediatric patients with leukemia and lymphoma. Although the study is not a prospective comparison, the large number of patients and the long study period in this study support the efficacy of this practice. Our analysis documents the treatment of 482 pediatric patients with leukemia and lymphoma over 
268000 patient-days with no breakthrough infections observed in patients who were compliant with the prophylactic regimen.
Hematologic abnormalities such as granulocytopenia and thrombocytopenia are known adverse reactions associated with use of TMP/SMX in children.17 These effects may be of importance in recovery after intensive chemotherapy as well as bone marrow transplant but are of particular concern in the maintenance phase of ALL therapy.18 In a crossover study of children with ALL in maintenance phase, patients had significant reductions in total white blood count, absolute neutrophil count, absolute lymphocyte count, and platelet count while taking daily TMP/SMX compared with placebo.19 Although the amount of maintenance chemotherapy in the 2 arms of this small study was similar, there remains concern that myelosuppression as a result of TMP/SMX will compromise delivery of maintenance chemotherapy.
This study compared patients who were receiving prophylaxis with TMP/SMX on 2 consecutive days per week with patients who were receiving alternative medications for prophylaxis during maintenance therapy for ALL and lymphoblastic lymphoma. Although there seemed to be a higher proportion of total days of neutropenia on TMP/SMX (4.11%) compared with alternative drug (2.17%) across all patients disregarding the exposure time for each patient, there was not a significant difference in the proportion of neutropenic days per patient. This analysis is complicated by several factors. First, the retrospective study design does not allow for uniformity in the interval at which blood counts were rechecked when found to be low. Second, although patients were evaluated only when they underwent a maintenance phase of therapy, the study period crossed multiple treatment protocols and therapy before the maintenance phase may have confounded the analysis. Finally, the size of the group that received an alternative drug compared with the group that received TMP/SMX was very small. The delivery of chemotherapy during these periods of neutropenia is likely a more important issue than the neutropenia alone. Given recommendations included in most of the treatment protocols during the study period, it is likely that patients with neutropenia as defined would have had their oral chemotherapy held; however, the retrospective nature of the study does not allow an accurate assessment of how long chemotherapy was withheld as the neutropenia resolved.
This study was not designed to address whether a reduction to 2 days per week from 3 days per week would reduce neutropenia. However, our findings that patients had neutropenia on only 4.11% of maintenance days compares favorably with the Hughes study in which neutropenia was noted on 8.6% of maintenance days in patients who received daily prophylaxis and 5.8% of maintenance days in the 3-day intermittent prophylaxis group.2 Additional study is needed to compare TMP/SMX dosing on a 3 consecutive days versus 2 consecutive days versus an alternative drug regimen to explore efficacy as well as important secondary outcomes, such as the contribution to neutropenia, the impact on the delivery of chemotherapy and treatment outcomes, and the development of resistance.
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ACKNOWLEDGMENTS |
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This work was supported by the Ruth L Kirschstein National Research Services Award for Fellowship Training in Pediatric Hematology/Oncology/Bone Marrow Transplant.
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FOOTNOTES |
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Accepted Dec 12, 2006.
Address correspondence to Susan Lindemulder, MD, Children's Hospital, Center for Cancer and Blood Disorders, 1056 E 19th Ave, B115, Denver, CO 80218. E-mail: lindemulder.susan{at}tchden.org
The authors have indicated they have no financial relationships relevant to this article to disclose.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
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