Following the COVID-19 pandemic, our hospital found an increase in Stenotrophomonas maltophilia isolates. The risk factors identified as contributing to the emergence of this opportunistic pathogen include immunosuppression, prolonged hospital stay—especially in specialised units—and the use of broad-spectrum antibiotics, intravascular devices, or mechanical ventilation.1,2

During the pandemic period, our pharmacy service occasionally detected subtherapeutic doses of sulfamethoxazole-trimethoprim (SMX-TMP) (less than 9 mg/kg/day of trimethoprim) for the treatment of conditions associated with S. maltophilia.3–6

Given the association between SMX-TMP (also known as cotrimoxazole) and prescribing errors, a prospective study was proposed to review patients receiving active treatment in the hospital. Such errors are often caused by the variability in dosing across different indications and potential confusion about the correct dose for each active pharmaceutical ingredient.7,8

The objective of this study was to evaluate the impact of a pharmaceutical intervention on improving prescribing appropriateness based on the review and optimisation of SMX-TMP prescriptions.

A before-and-after intervention study was conducted at a tertiary hospital. The intervention period followed a prospective design and took place from September 2021 to January 2022. The post-intervention period was retrospective and ran from March to December 2022.

All patients over the age of 18 years who had received SMX-TMP treatment during the specified dates were included in both periods.

To establish the criteria for the appropriate dosage, recommended SMX-TMP doses were reviewed across several treatment guidelines3,4 and drug information databases.5,6 We also reviewed the Summary of Product Characteristics (SPC) of the drug.9 For the treatment of S. maltophilia infection, a trimethoprim dose of at least 9 mg/kg/day6 was considered appropriate, although the majority of the sources reviewed recommended 15 mg/kg/day (Table 1).

Patients were identified using the hospital prescription software system, and their data were obtained by reviewing each patient's electronic medical record.

The following variables were collected: patient characteristics (age, sex, and weight), prescribing service, treatment indication, and the causative microorganism when microbiological confirmation was available.

During the intervention period, if a discrepancy was identified between the indication and the prescribed dosage and the recommended dosage, a dosage recommendation was communicated by telephone to the responsible physician and the hospital's Antimicrobial Stewardship Programme (ASP) team. Finally, the level of implementation of these interventions was recorded.

During the post-intervention period, all patients treated with SMX-TMP were retrospectively reviewed to assess the appropriateness of the dosage. It was also checked whether any pharmaceutical intervention had been recorded in the electronic prescribing system. The data obtained were collected in an Excel spreadsheet.

A descriptive statistical analysis was performed. Categorical variables are expressed as frequencies and percentages, and quantitative variables are expressed as medians and interquartile ranges (IQRs).

The Chi-squared test was used to compare the populations and the results obtained in each period, using the SPSS V.24 software package. A P-value of ≤0.05 was used as a cutoff for statistical significance.

During the intervention period, we analysed 69 prescriptions from 65 patients (men 55%; median age, 66 years; range, 55–79 years). The admission units were as follows: infectious diseases (15), resuscitation (11), respiratory (10), cardiology (4), general surgery (4), gastroenterology (3), haematology (3), internal medicine (3), urology (3), otolaryngology (3), and other (10). The indications for treatment were as follows: 23 prophylactic treatments, 5 empirical treatments, and 41 targeted treatments. The microorganisms detected were as follows: 14 S. maltophilia, 6 Pneumocystis jirovecii, 6 methicillin-resistant Staphylococcus aureus (MRSA), 6 Escherichia coli, 3 Klebsiella pneumoniae, 2 Acinetobacter baumannii, 1 Toxoplasma gondii, and 3 others.

We identified 18 inappropriate prescriptions (26%). Of these, 12 prescriptions were subtherapeutic doses related to the microbiological diagnosis (10 corresponded to patients with S. maltophilia infection, 1 with K. pneumoniae, and 1 with MRSA); 1 prescription was related to empirical treatment; 2 were adjustments based on renal function for treatments targeting S. maltophilia, and 3 were reconciliation errors for prophylactic home treatment. In total, 17 interventions were accepted and implemented (94%).

During the retrospective analysis period, 129 prescriptions from 127 patients were reviewed (men 61%; median age 66 years; range 54–77). The admission units were as follows: resuscitation (28), infectious diseases (17), respiratory (16), internal medicine (10), emergency (9), nephrology (8), cardiology (8), haematology (6), otolaryngology (6), vascular surgery (5), medical oncology (3), urology (3), and other (10). The indications for treatment were as follows: 43 prophylactic treatments, 12 empirical treatments, 3 suppressive treatments, and 71 targeted treatments. Of the targeted treatments, the microorganisms were as follows: 14 S. maltophilia, 12 E. coli, 8 Klebsiella oxytoca, 6 Enterobacter cloacae, 5 P. jirovecii, 4 A. baumannii, 4 MRSA, 3 K. pneumoniae, 3 Nocardia spp., 2 methicillin-sensitive Staphylococcus aureus (MSSA), 2 T. gondii, and 8 others.

Of the 129 prescriptions retrospectively analysed, 12 were considered inappropriate (9%). Pharmaceutical interventions were recorded for 7 prescriptions (5%), and 6 of them (86%) were accepted.

The reasons for the prescriptions being considered inappropriate were as follows: 10 used subtherapeutic doses (5 related to S. maltophilia, 2 to Nocardia spp., 1 to P. jirovecii, 1 to E. cloacae, and 1 was an empirical treatment); 1 used a dosage higher than the recommended dose for prophylaxis; and 1 was an adjustment based on renal function for treatment targeting S. maltophilia. Table 2 shows the results obtained.

The results of the Chi-squared test were significantly different (p = 0.0082) for the periods analysed (18/69 and 12/129).

Using the same statistical test, it was determined that there were no statistically significant differences between the populations regarding age, sex, and treatment indication, indicating their similarity.

Only microorganisms requiring high doses were analysed, and no differences were found (p = 0.0504).

During the first stage of the appropriateness study, the pharmacy service confirmed that a significant percentage of SMX-TMP prescriptions did not comply with the usual recommended dosage, particularly in the case of S. maltophilia infection. This high percentage was also found in a previous study assessing dosage appropriateness, where the percentage of inappropriate dosing for S. maltophilia was 74.3%.7 We identified 2 potential causes of underdosing in these treatments. One was related to the information included in the S. maltophilia antibiograms, which listed the following EUCAST recommended dose: high dose: 0.24 g trimethoprim +1.2 g sulfamethoxazole/12 h oral or IV,14 which was insufficient for patients weighing more than 53 kg. The other was related to the standard reference guide.3 In the monograph on cotrimoxazole, the dosage section originally listed the standard dose as 160/800 mg/8–12 h. A small note in the comment section mentioned the need for higher doses for some microorganisms, but this could have been easily overlooked. From 2023, this information has been included in the main dosage section, making it easier to consult and reducing the risk of errors.10

The pharmacy service recommended changing the information included in the antibiograms. This change, together with the work conducted through individualised interventions by the pharmacy service, may have contributed to the improvement observed in the appropriateness of the doses prescribed in the post-intervention period, especially in the treatment of S. maltophilia. Nevertheless, in the post-intervention period, we detected underdosing errors in prescriptions related to Nocardia spp. The recommended dosage information provided in the antibiogram was incorrect, and the pharmacy service recommended changing this information.

As observed in previous studies with antibiotics,15 reviewing and optimising prescriptions through pharmaceutical intervention with SMX-TMP improves antibiotic use.

Given the wide range of potential dosages depending on the indication and the continuous updating of treatment guidelines, we believe it is essential to review SMX-TMP dosing practices to reduce the high rate of inappropriate prescriptions—particularly in cases involving microorganisms that require high-dose regimens.

The results obtained highlight the importance of pharmaceutical review of these prescriptions, supporting its potential implementation in other hospitals and its inclusion as a strategic objective within Antimicrobial Stewardship Programmes.

The first part of the study (initial phase) was presented in poster format at the 67th conference of the Spanish Society of Hospital Pharmacy (Barcelona, November 24–26, 2022).

Maialen Inclán-Conde: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Clara Vila-Gallego: Writing – review & editing, Visualization, Validation, Supervision, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Maite Vara-Urruchua: Writing – review & editing, Visualization, Validation, Methodology, Formal analysis, Data curation, Conceptualization. Ana Victoria Aguirrezabal-Arredondo: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Formal analysis. Oscar Luis Ferreiro-Beneitez: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Formal analysis. Matxalen Vidal-García: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Formal analysis. Pamela Ruiz-Rodríguez: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Formal analysis. José Antonio Domínguez Menéndez: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.

Maialen Inclán-Conde and José Antonio Domínguez-Menéndez participated in the conception and design of the work, data collection, data analysis and interpretation, writing, critical review, and approval of the final version. Clara Vila-Gallego and Maite Vara-Urruchua participated in the design, data collection, analysis, critical review, and approval of the final version. Ana Victoria Aguirrezabal-Arredondo, Oscar Luis Ferreiro-Beneitez, Matxalen Vidal-García, and Pamela Ruiz-Rodríguez participated in data analysis and interpretation, critical review, and approval of the final version for publication.

None declared.