Myelosuppression associated with co-trimoxazole as a prophylactic antibiotic in the maintenance phase of childhood acute lymphocytic leukemia

Design

Two-center, randomized, double-blind, placebo-controlled, crossover study

N= 53

Objective

To determine whether co-trimoxazole affected specific measurements, namely, hematologic values, the amount of maintenance medicines administered, especially 6-mercaptopurine and methotrexate, and the incidence of infection

Study Groups

Co-trimoxazole (n= 18)

Placebo (n= 19)

Inclusion Criteria

Pediatric patients with acute lymphocytic leukemia (ALL), a successful induction and central nervous system prophylaxis phase, and minimum of 6 months of continuous remission, during which time many of the patients received co-trimoxazole for P. carinii prophylaxis

Exclusion Criteria

Not receiving 6-mercaptopurine daily and methotrexate weekly, previous adverse reaction to co-trimoxazole use

Methods

Patients were randomized to receive co-trimoxazole for 6 months (or two 84-day maintenance cycles) followed by placebo for 6 months (treatment A) or placebo for 6 months followed by co-trimoxazole for 6 months (treatment B). Patients were given co-trimoxazole (sulfamethoxazole: 750 mg/m²/day; trimethoprim: 150 mg/m²/day) every 12 hours; dose was determined based on body surface area and were rounded to the neared half-tablet or teaspoon.

Placebos were identical to co-trimoxazole in taste and look. Co-trimoxazole and placebo were not modified for myelosuppression however protocol was provided to physicians for chemotherapy dosing to manage leukemic maintenance medications for hematologic suppression. Patients had monthly complete blood counts (CBC) and trimonthly bone marrow aspirations, documented infections, and kept calendars to record medication compliance. 

Duration

Recruitment/trial: 1980-1983

Intervention: 12 months

Treatment periods: 6 months each

Outcome Measures

Hematologic changes (white blood count [WBC], absolute neutrophil count [ANC], absolute lymphocyte count [ALC], platelet count, hemoglobin, bone marrow buffy coat, bone marrow cellularity); average number of infections during 6-month period; antibiotic use

Baseline Characteristics

Age at diagnosis of ALL, years

Female

Race

White

Other

35

2

WBC at ALL diagnosis, µL

24,050

Results

Endpoint

Co-trimoxazole (n= 18)

Placebo (n= 19)

p-value

WBC, µL

ANC*, µL

ALC, µL

Platelet count, µL

Hemoglobin, gm/dL

Bone marrow buffy coat, %

Bone marrow cellularity**

Infections

Bacteria

Viral

Fungal

1.6

0.2

1.3

0.1

2.5

0.4

2.0

0.1

0.008

0.020

0.030

0.80

Other antibiotic use

*44% decrease in mean ANC was observed while patients were receiving co-trimoxazole

**0-4 scale; 2 is normocellularity

Adverse Events

Study Author Conclusions

Based on our study, children with ALL receiving co-trimoxazole will have significant reductions in several hematologic measurements, including absolute neutrophil counts. This untoward effect could significantly hamper the administration of more maintenance cancer chemotherapy. However, it is unknown whether increasing maintenance dosages can reduce leukemia relapse rates. Future ALL studies should investigate current recommendations regarding antibiotic prophylaxis and their effect on the amount of maintenance medicines administered and on subsequent leukemia-free survival.

InpharmD Researcher Critique

Using ANC as a measured outcome is appropriate as this is critical criteria for determining the presence of myelosuppression. In addition, chemotherapy agents have a risk of causing myelosuppression, but the effects these drugs might have on the findings of this study was minimized by the crossover structure and study protocol, as chemotherapy was the same in all stages of the trial, for both placebo or co-trimoxazole treatment. However, this study was based on a small, non-diverse population. Due to the limited availability of children with ALL who would be eligible to participate, this limitation is understandable. As well, the extent of co-trimethoxazole-induced myelosuppression should be further reviewed to determine its effect on chemotherapy. This study is significantly dated.

Hematologic Abnormalities After Oral Trimethoprim-Sulfamethoxazole Therapy in Children

Design

Multicenter, prospective, controlled study

N= 70

Objective

To assess the frequency and severity of hematologic abnormalities associated with oral trimethoprim-sulfamethoxazole (TMP-SMX) in children

Study Groups

TMP-SMX (n= 50)

Amoxicillin (n= 20)

Inclusion Criteria

Children with acute otitis media or uncomplicated urinary tract infection

Exclusion Criteria

Known glucose-6-phosphate dehydrogenase deficiency; history of allergy to trimethoprim or sulfonamides

Methods

Trimethoprim-sulfamethoxazole was given to 30 consecutive patients (4 mg/kg of the trimethoprim component) every 12 hours for ten days. Children who weighed ≥40 kg were given the adult recommended dose (160-mg trimethoprim component) twice daily. The next 40 consecutive patients were treated alternately with TMP-SMX as described previously or with amoxicillin trihydrate, 50 mg/kg/24 hr in three divided doses, not exceeding a maximum dose of 2 g/24 hr (control group). Of 50 children total treated with TMP-SMX, 25 children were given Bactrim, and the other 25 children were given Septra.

Duration

November 1979 through June 1980

Outcome Measures

Baseline Characteristics

TMP-SMX (n= 50)

Amoxicillin (n= 20)

Bactrim (n= 25)

Mean age, years

Male:Female ratio

Diagnosis, n

Otitis media

Urinary tract infection

23

2

23

2

19

1

Duration of treatment, days

Results

Endpoint

TMP-SMX (n= 50)

Amoxicillin (n= 20)

p-value

Neutropenia*

Frequency

Mean onset, days

Mean duration, days

34%

5.8

8.9

5%

10

-

< 0.001

-

-

Thrombocytopenia**

Frequency

Mean onset, days

Mean duration, days

12%

10.3

12.7

0

-

-

< 0.01

-

-

Eosinophilia

Frequency

Mean onset, days

Mean duration, days

14%

6.5

8.5

5%

6.2

6.3

Not significant

-

-

Anemia

Frequency

Mean onset, days

Mean duration, days

6%

13

-

0

-

-

Not significant

-

-

*Neutropenia occurred mostly during the first week of treatment and lasted a mean of 8.9 days.

**Thrombocytopenia was noted between the seventh and 16th day (mean, 10.3 days) and lasted a mean of 12.7 days.

Study Author Conclusions

The study indicates that hematologic abnormalities occur in children who are given a ten-day course of oral TMP-SMX. Children treated with oral TMP-SMX should be followed up with biweekly leukocyte and platelet counts, and treatment should be discontinued if severe neutropenia or thrombocytopenia develops.

InpharmD Researcher Critique

The data on hematologic abnormalities were not provided based on the brand used (Bactrim vs. Septra). Minimal data were available at baseline.

Does Trimethoprim-Sulfamethoxazole Prophylaxis Induce Myelosuppression in Primary Immune Deficiency Disease Patients; A Retrospective, 3 Groups Comparative Study

Design

Single-center, retrospective study

N= 122

Objective

To identify if primary immune deficiency (PID) patients are at higher risk of developing myelosuppression secondary to the use of trimethoprim-sulfamethoxazole (TMP-SMX) compared to immune-competent patients with urinary tract infections (UTI)

Study Groups

PID + TMP-SMX (n= 41)

PID (n= 45)

UTI + TMP-SMX (n= 36)

Inclusion Criteria

Received TMP-MSX at prophylactic dose (5 mg/kg/day for PID and 2 mg/kg/day for UTI, where dose based on trimethoprim component) for at least 1 week, available complete blood count (CBC) results at baseline and after start point (starting date of TMP-SMX prophylaxis for PID + TMP-SMX group and UTI + TMP-SMX group; date of PID diagnosis for PID group)

Exclusion Criteria

Concurrent use of other medications that could affect the result, underwent bone marrow transplantation, baseline myelosuppression, unavailability of CBC at baseline or thereafter

Methods

Data were extracted from patients' medical records including demographic data, TMP-SMX dosage, and CBC results. Patients in the PID + TMP-SMX group had PID and received prophylactic TMP-SMX, while patients in the PID group had PID and did not receive prophylactic TMP-SMX. Patients in the UTI + TMP-SMX group were immune-competent and received prophylactic TMP-SMX for UTI. First and maximum myelosuppression were defined as the first dropped and maximally dropped values, respectively. The results chosen for CBC were within the duration of TMP-SMX use or within 1 year, whichever was shorter. 

Duration

Diagnosis of PID: January 1, 1985, to October 12, 2015

Outcome Measures

Myelosuppression, neutropenia

Baseline Characteristics

PID + TMP-SMX (n= 41)

PID (n= 45)

Age, years

Female

Duration of TMP-SMX, years (range)

Type of PID

Innate immune defect neutrophil function

T cell defect

Humoral immunodeficiency

Ataxic telangiectasia

Immune dysregulation

Congenital malformation

43.9%

29.3%

9.8%

7.3%

4.9%

4.9%

17.8%

22.2%

35.6%

22.2%

2.2%

0

Results

Endpoint

PID + TMP-SMX (n= 41)

UTI + TMP-SMX (n= 36)

Clinical myelosuppression

Absolute neutrophil count (ANC)

Red blood cell count (RBC)

White blood cell count (WBC)

Platelets

39.0%

36.6%

41.5%

24.4%

8.9%

13.3%

13.3%

15.6%

16.7%

13.9%

13.9%

2.8%

0.002

0.014

0.003

0.028

Development of neutropenia, n

Grade 1

Grade 2

Grade 3

Grade 4

16

0

5

4

7

4

0

1

2

1

6

0

4

1

1

-

-

-

-

-

Results for suppression were presented in graphical figures without data points. A general trend of suppression was seen in all cell lines of the three groups. However, only hemoglobin was found to have a statistically significant difference between the three groups with the highest percentage seen in the PID group (p= 0.003).

Patients in the PID + TMP-SMX group were at a higher risk of having clinical suppression of WBC by 5.7 folds compared to the UTI + TMP-SMX group (confidence interval [CI] 1.775 to 18.547).

Adverse Events

Study Author Conclusions

The myelosuppressive effect of TMP-SMX is amplified in primary immunodeficiency patients (particularly ANC and platelet) resulting in possible serious complications with long-term prophylaxis. The potential myelosuppressive effect varies among different types of PIDs. When prescribing TMP-SMX to PID patients, risks and benefits must be weighed accordingly. Physicians must closely monitor the complete blood count at regular intervals and dose/ duration must be adjusted accordingly.

InpharmD Researcher Critique

A causal relationship between myelosuppression and TMP-SMX use cannot be established based on this study. The results are only representative of patients with primary immune deficiencies.

Impact of Prophylaxis Choice on Risk of Pneumocystitis Pneumonia in Children with Cancer: A Case-Control Study

Design

Single-center, retrospective, case-control study

N= 61

Objective

To assess the risk of pneumocystitis jirovecii pneumonia (PCP) in pediatric cancer patients receiving trimethoprim-sulfamethoxazole (TMP-SMX) versus second-line agents for PCP prophylaxis

Study Groups

Case (n= 11)

Control (n= 50)

Inclusion Criteria

PJP diagnosis (cases); Aged <19 years; oncology diagnosis

Exclusion Criteria

Hematopoietic stem cell transplant

Methods

Case group patients were identified using the institution's microbiology database. Controls were then matched to case group characteristics including age at PJP diagnosis, oncology diagnosis, treatment protocol, phase of treatment, and oncology diagnosis date within 5 years. For each case, up to 5 controls were randomly selected. Participants in the case group had to be diagnosed with PJP and a dummy PJP diagnosis date was chosen for control group participants. All participants in the cases and control groups had to be on PJP prophylaxis (TMP/SMX, dapsone, atovaquone, or pentamidine). The institutional standard for PJP prophylaxis was TMP-SMX on 3 consecutive days/ week, either as a single daily dose or divided twice daily.

Duration

Chart review period: 18 years (between 2000 to 2018)

Outcome Measures

Reasons for second-line agent therapy

Baseline Characteristics

Cases (n= 11)

Control (n= 50)

Age, years, n (%)

     <1

     1-9.99

     >10

1 (9.1%)

7 (64.6%)

3 (27.2%)

4 (8%)

29 (58%)

17 (34%) 

0.91

Male

Cancer

     B-ALL or lymphoma

Standard risk

High risk

B-ALL, relapse

      T-ALL

Standard risk

Intermediate/high-risk

Infant ALL, intermediate risk

Rhabdomyosarcoma

1 (9.1%)

4 (36.4%)

1 (9.1%)

2 (18.2%)

1 (9.1%)

1 (9.1%)

1 (9.1%) 

5 (10%)

20 (40%)

4 (8%)

10 (20%)

5 (10%)

4 (8%)

2 (4%) 

2.0

0.23

-

-

Prophylaxis 3 months before PJP actual or dummy diagnosis

     TMP-SMX

     Pentamidine, inhale every 4 weeks

     Dapsone, every week

     Atovaquone

6 (54.5%)

3 (27.3%)

2 (18.%2)

0 

42 (84.0%)

4 (8.0%)

3 (6.0%)

1 (2.0%)

B-ALL, B-cell acute lymphoblastic leukemia; T-ALL, T-cell acute lymphoblastic leukemia; ALL, acute lymphoblastic leukemia

Results

Case (n= 11)

Control (n= 50)

Reasons for second-line therapy

     Myelosuppression

     Nausea/vomiting

     Elevated liver enzymes

     Rash

     Not documented

1 (9.1%)

2 (18.2%)

1 (9.1%)

1 (9.1%)

0 

10 (0.2%) 

0

0 

0 

1 (2%)

Patients who developed PJP were statistically significantly less likely to have received TMP-SMX as PJP prophylaxis (as opposed to second-line agents) during the three previous months as compared with control patients without PJP (odds ratio 0.15, 95% confidence interval: 0.01 to 0.97; p= 0.02).

Study Author Conclusions

This study demonstrated that pediatric oncology patients diagnosed with PJP were significantly less likely to be receiving TMP-SMX prophylaxis and more likely to be receiving second-line prophylactic agents. The use of such second-line medications for PJP prophylaxis should be restricted to cases in which true contraindications to TMP-SMX exist or when children have failed rechallenges with TMP-SMX.

InpharmD Researcher Critique

The majority of patients received TMP-SMX for PJP prophylaxis and the most common reason for second-line prophylaxis was myelosuppression. However, this was a chart review at a single center in Canada and included only 11 pediatric patients in the case group; hence, a causal relationship between myelosuppression and TMP-SMX use cannot be established. The dosing regimen of TMP-SMX and other second-line agents used by participants in the study was not specified.

A Rare Cause of Drug-Induced Pancytopenia: Trimethoprim-Sulfamethoxazole-Induced Pancytopenia

Design

Case presentation

A 62-year-old female with a past medical history of bipolar depression and diabetes mellitus type II that was well controlled initially presented to the emergency department with nonspecific symptoms of overall lethargy, weakness, and fatigue. She had been recently hospitalized during a manic episode for which she was initiated on lithium in addition to her home quetiapine. Her complete blood count (CBC) was noted to be normal upon discharge, 12 days prior to the current admission.

The patient believed she had a urinary tract infection between admission for the manic episode and her current admission due to pain on urination and leakage of urine, for which she received trimethoprim-sulfamethoxazole (TMP-SMX). The patient was unsure of the dosage but had taken it for 5 days and finished it three days before admission. At admission, the patient was found to be febrile with a temperature of 101.2°F, white blood cell count (WBC) of 3,100/μL, hemoglobin 9.4 g/dL, and platelet 84,000/μL. Other workups were determined to be normal.

On day 1 of her admission, her temperature increased to 102.7°F, and she was eventually transferred to the intensive care unit. She was initiated on broad-spectrum antibiotics, and a norepinephrine infusion was started after her hypotension did not respond to intravenous bolus fluids. A computed tomography (CT) was performed due to the patient's worsening condition but was unremarkable. 

Since her blood counts had decreased at some point in time following the initiation of lithium and TMP-SMX, it was thought that either drug may have caused her current clinical state. Her hematopoietic cell lines trended upward on day 3 of admission and continued to trend upward thereafter. Due to her increasing counts, the antibiotics were stopped one at a time with vancomycin on day 4 and then meropenem on day 5. She completed a 10-day course of doxycycline for possible tick-borne illness since tick panels had not yet resulted by day 10. Her blood cultures remained negative with no bacterial or viral etiology identified.

Study Author Conclusions

History and physical examination should consider the severity and time course of pancytopenia and associated symptoms. When extensive workup yields no identifiable cause, iatrogenic causes should be further explored. While TMP-SMX is known to cause pancytopenia, it is not widely reported in the literature, and further evaluation should be sought to reveal more about the mechanism behind it.

Trimethoprim-Sulfamethoxazole Induced Pancytopenia: A Common Occurrence but A Rare Diagnosis

Design

Case presentation

A 70-year-old female presented to the emergency department with complaints of hematemesis, hemoptysis, melanic stools, and diffuse generalized body pain for four days. The patient denied any fever, chills, lightheadedness, dizziness, chest pain, shortness of breath, or abdominal pain. There was no history of inflammatory bowel disease or gastric ulcers. She was in mild distress, hypotensive, tachycardia, and breathing room air. She was noted to have multiple ulcers throughout her hard palate, soft palate, and lips. After initial stabilization, she was admitted for further evaluation and management. Computerized Tomography (CT) was unremarkable. Hemoglobin was 7.5 mg/dL, white blood cell (WBC) count was 700/mm³, platelet count was 9,000/mm³, and absolute neutrophil count was 100/mm³.

Two weeks prior to admission, the patient's hemoglobin was slightly decreased at 11.0 g/dL. Her WBC count and platelet count were both within normal limits. Trimethoprim-sulfamethoxazole (TMP-SMX) was the only medication taken from the time of onset of symptoms leading to her admission, which was being used for the treatment of right lower extremity cellulitis. Over the course of her admission, her TMP-SMX was stopped, and she received two units of platelets and three units of packed red blood cells. She was also treated with recombinant human granulocyte colony-stimulating factor. At a follow-up visit two months later, the patient's complete blood count had normalized.

Study Author Conclusions

The differential diagnoses in a patient with acute onset pancytopenia are very comprehensive. It is important to understand that TMP-SMX can cause an idiosyncratic allergic reaction leading to pancytopenia. However, due to inadequate reports regarding such reaction drug-related pancytopenia is not a leading differential diagnosis and can affect the management of patients. Therefore, detailed history along with thorough physical examination and judicious laboratory investigation becomes extremely essential in investigating the cause of pancytopenia to initiate appropriate treatment.

Severe Thrombocytopenia Possibly Associated with Trimethoprim/Sulfamethoxazole (TMP/SMX) Therapy

Design

Case presentation

A 54-year-old female received TMP/SMX 160/800 mg twice daily for 10 days to treat chronic sinusitis. One day after the completion of treatment, she presented with scattered petechiae on both hands and blood blisters in her mouth with a severely low platelet count of 2 × 10³/mm³.  Stool occult blood was negative, but urinalysis results showed a large amount of blood in the urine. Since TMP/SMX was the only drug that had been added to her medication regimen (10 days prior to hospital admission), TMP/SMX was considered the most likely causative agent to cause her significantly low platelet count. After two units of platelet transfusion and receiving oral prednisone 60 mg twice daily for presumed drug-induced immune-mediated thrombocytopenia, her platelet count continued to increase (110 × 10³/mm³ on day 5 of her hospital course), and the petechiae on her hands and blood blisters in her mouth gradually resolved over the hospital course. She was discharged from the hospital on day 5, and prednisone was tapered over 10 days. Upon her follow-up 2 weeks later, her platelet count was within the normal range, and the petechiae on her hands and blood blisters in her mouth were completely resolved.

Study Author Conclusions

Thrombocytopenia associated with TMP/SMX appears to be an immune-mediated process resulting in platelet destruction by drug-dependent platelet antibodies. Treatment of thrombocytopenia associated with TMP/SMX therapy includes discontinuation of the offending drug and the use of corticosteroids. Platelet transfusion and intravenous immunoglobulin may be required in some patients.

Thrombocytopenia associated with TMP/SMX therapy can be serious or life-threatening because it may result in significant bleeding complications. This hematologic adverse effect of TMP/SMX may occur even with the usual recommended dosage and duration of therapy. Careful monitoring of complete blood cell count, including platelet count, before and during TMP/SMX therapy is suggested.

Severe Bactrim-induced neutropenia with reversal of CD4+/CD8+ lymphocyte ratio: response to recombinant human granulocyte-colony stimulating factor (R-metHUG-CSF)

Design

Case presentation

A male patient (age not specified) presented with fever and profound neutropenia following a 5-day course of trimethoprim/sulfamethoxazole (TMP/SMX) therapy for urinary tract infection. The blood counts revealed a white cell count of 0.9×10⁹/L, absolute neutrophil count (ANC) of 0.1×10⁹/L, and platelet count of 148×10⁹/L. Upon bone marrow aspirate and biopsy, a granulocyte maturation arrest at the promyelocyte state was observed. Flow cytometry revealed a CD4+ lymphopenia and a reversed CD4+/CD8+ lymphocyte ratio (CD4+ lymphocytes, 180/µL and CD8+ lymphocytes, 330-1,500/µL). CD8 cells were HLA-Dr negative and not activated. Serological tests and anti-neutrophil antibody assay were also negative. Following receiving intravenous (IV) antibiotics and R-metHUG-colony-stimulating factor (CSF) at a dose of 300 mcg daily, his white cell count responded within 48 hours. Granulocyte-CSF (G-CSF) was discontinued after 2 weeks of treatment. Four weeks after the normalized blood counts were reported, repeat flow cytometry revealed improved CD4+ counts (CD4+ lymphocytes 360 μl) and decreased CD8+ counts (CD8+ lymphocytes 460 μl).

Study Author Conclusions

G-CSF is useful in life-threatening neutropenia induced by sulphonamides like Bactrim as evidenced by the dramatic and long-lasting response in this patient. It will be useful to perform a flow cytometric analysis of peripheral blood lymphocytes to assess the incidence of this abnormality in drug-induced agranulocytosis.