Sean Bullis, MD, is an infectious diseases physician at The University of Vermont Medical Center and assistant professor of medicine at Larner College of Medicine at The University of Vermont in Burlington.

Sean S. M. Bullis, MD

is a ubiquitous fungus that can cause severe respiratory infection in the immunocompromised host. Patients at risk for 

pneumonia (PJP) include those on immunosuppressive therapies or those living with HIV/AIDS, organ transplantation, or hematologic malignancy.

 In areas with a low prevalence of uncontrolled HIV/AIDS, patients with hematologic malignancies constitute the largest group at risk of PJP.

Trimethoprim-sulfamethoxazole (TMP-SMX) is recommended for PJP prophylaxis in many patients with hematologic malignancy.

 TMP-SMX is also the treatment of choice for mild, moderate, and severe PJP.

 The CDC guidelines recommend a standard dose of 15 to 20 mg/kg daily of the TMP component for adults with PJP, but this recommendation is based on weak data extrapolated from pediatric literature.

 Moreover, adverse events from TMP-SMX are dose dependent, thus the standard doses of TMP-SMX typically used in PJP are frequently associated with significant adverse effects.

A recent meta-analysis of more than 300 patients compared reduced dose (10 mg/kg/d or less of TMP) with the standard dose (15-20 mg/kg/d of TMP) of TMP-SMX in the treatment of mild to severe PJP and revealed no statistically significant difference in mortality (absolute risk difference, –9%; 95%, CI, –27% to 8%) but a significant reduction in adverse events with the reduced dose (absolute risk reduction of 18%; 95% CI, –31% to –5%).

 However, as this analysis included only 63 (14%) patients with hematologic malignancies, the results may not be generalizable to this population.

Thus, questions remain regarding the ideal dosing of TMP-SMX in the treatment of PJP among patients with hematologic malignancies.

Hammarström et al examined this issue in their recent manuscript “Treatment With Reduced Dose Trimethoprim- Sulfamethoxazole Is Effective in Mild to Moderate 

Pneumonia in Patients with Hematologic Malignancies.”

 The authors completed a retrospective study of adult patients with hematologic malignancies who were treated for probable or proven PJP with TMP-SMX at 6 Swedish university hospitals between 2013 and 2017. Patients were included if they had (1) a hematologic malignancy or prior allogeneic hematologic stem cell transplant, (2) positive immunofluorescence or polymerase chain reaction for 

in a sputum or bronchoalveolar lavage sample, (3) both typical radiograph findings (ie, diffuse interstitial infiltrates or ground glass opacity) and respiratory symptoms (ie dyspnea, cough, or hypoxia < 95% oxygen saturation of arterial blood without oxygen therapy), and (4) were treated with TMP-SMX, with an initial dose of 7.5 to 20 mg/kg/day of the TMP component. The reduced-dose cohort was defined as those who received 7.5 to 15 mg/kg/d of the TMP component, and the standard-dose cohort as those who received more than 15 to 20 mg/kg/d of the same, with doses adjusted for renal function. The primary outcome assessed a change in objective respiratory function, measured as the difference in partial pressure arterial oxygen and fraction of inspired oxygen ratio (PaO₂/FiO₂) between baseline and day 8 of TMP-SMX treatment. The secondary outcomes included clinical failure ( failure to improve or worsening respiratory status as determined by clinical judgement) or death at day 8, 30-day mortality, and the frequency of adverse events.

A total of 113 patients were included in the study, with 80 patients in the reduced-dose cohort and 33 patients in the standard-dose cohort. Of the 33 patients receiving standard-dose TMP-SMX, 19 (53%) were transitioned to reduced-dose therapy between days 3 and 7 of treatment. The study population was predominantly men (80/113, 71%), older (median age 68 years, range 22-88), had normal or mildly reduced renal function (106/113, 95%) with a creatinine clearance of greater than 50, and hypoalbuminemia less than 30 g/L (77/113, 83%). The 2 study groups were comparable, aside from the standard-dose group having an ECOG performance status of greater than 3 in 27% (9/33) compared with 10% (8/80) in the reduced-dose group (

For the primary outcome, the change in PaO₂/FiO₂ by day 8 was a mean (SD) of +70.2 (± 104.2) mm Hg in the reduced-dose group compared with a mean (SD) of +83.8 (± 107.5) mm Hg in the standard-dose group, which was not a statistically significant difference (

= .5). The secondary outcomes also did not reveal a statistically significant difference between the reduced-dose and standard-dose groups regarding clinical failure or death at day 8 (18% vs 21%, 

= .8), overall 30-day mortality (14% vs 15%, 

The study had several limitations, including a small sample size and its retrospective nature. Although there were no significant differences in mortality between the 2 treatment groups regarding severe PJP, the authors advise caution that a relevant difference cannot be ruled out. There is also concern for selection bias, as patients with a worse baseline prognosis were more likely to have standard-dose TMP-SMX.

Despite the limitations, this study included a well-defined cohort of patients from numerous institutions and was the first of its kind to analyze reduced-dose TMP-SMX for treatment of PJP in patients with hematologic malignancies. The authors demonstrated that reduced-dose TMP-SMX can be effective in mild to moderate PJP within the study population. Ultimately, this important study revealed the need for prospective, randomized investigations to establish updated guidelines for the treatment of PJP.



Hammarström H, Krifors A, Athlin S, et al. Treatment with reduced dose trimethoprim-sulfamethoxazole is effective in mild to moderate Pneumocystis jirovecii pneumonia in patients with hematologic malignancies. 

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. Published online May 20, 2022. doi:10.1093/cid/ciac386

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Here is a review of using this therapy in this patient population. 

Reduced-Dose Trimethoprim-Sulfamethoxazole Effective in Treating Mild to Moderate Pneumocystis jirovecii Pneumonia

 is an aerobic, nonfermenting, gram-negative bacillus that is ubiquitously found in water, soil, and plants and is closely related to 

 is an opportunistic pathogen and typically causes hospital-acquired infections, particularly bacteremia and pneumonia, among patients with heavy health care exposures, malignancy, cystic fibrosis, neutropenia, mechanical ventilation, central venous catheters, recent surgery, trauma, or recent broad-spectrum antimicrobials.

 ranges from 7.1 to 37.7 cases per 10,000 discharges and has increased in recent years, suggesting it is an increasingly emergent iatrogenic threat.

 Prior iatrogenic outbreaks, felt to be related to tap water, have been well described in intensive care and inpatient hematologic malignancy and bone marrow transplant settings.

Because of high-level intrinsic resistance to multiple other antibiotic classes, traditionally trimethoprim-sulfamethoxazole (TMP-SMX) has been perceived as the antimicrobial treatment of choice. Duration of therapy is usually 7 to 14 days, depending on the site of infection and the host immune status.

 However, in recent years, the management of 

 infections has become more difficult as the organism becomes increasingly resistant to TMP-SMX.

 As such, it is of increasing importance to identify which antimicrobials, particularly those besides TMP-SMX, are available to treat 

The recent manuscript “Clinical outcomes of 

infection treated with trimethoprim/sulfamethoxazole, minocycline, or fluoroquinolone monotherapy” by Junco et al explored this issue by assessing clinical outcomes of 

infection treated with a variety of antimicrobials. The authors completed a retrospective study of adult patients at an 1882-bed multihospital health system in Orlando, Florida, who received monotherapy for 

infection from January 1, 2010, to January 31, 2016. The antimicrobial agents assessed included TMP-SMX, a fluoroquinolone, or minocycline. The primary outcome was clinical failure, which included isolation of 

from the same culture site after 48 hours of therapy, alteration of treatment after at least 48 hours of therapy due to an adverse event of concern for clinical failure, and 30-day in-hospital all-cause mortality. Patients were excluded if they had less than 48 hours of monotherapy, a 

resistant to initial monotherapy, cystic fibrosis, or been treated for 

The authors screened 490 patients, with 284 meeting inclusion criteria. Of those 284 patients, 217 (76.4%) were treated with TMP-SMX, 28 (9.9%) with a fluoroquinolone (either moxifloxacin, ciprofloxacin, or levofloxacin), and 39 (13.7%) with minocycline. Baseline characteristics were reflective of an older population (mean age [SD], 60 [18.0] years) that was severely ill, with an average Acute Physiologic Assessment and Chronic Health Evaluation II score of 19 (corresponding to an approximate in-hospital mortality rate of 25%)

; 56% of patients required mechanical ventilation, and 22% required vasopressor support.

However, there were notable differences in demographics and baseline characteristics between groups, including 3.5 days to initiate effective antimicrobial therapy in the minocycline group versus 2.9 and 2.4 days in the TMP-SMX and fluoroquinolone groups, respectively (

=.005), as well as 131 (60.4%) patients requiring mechanical ventilation in the TMP-SMX group versus 8 (28.6%) and 19 (48.7%) in the fluoroquinolone and minocycline groups, respectively (

=.004). Additionally, 101 (46.5%) patients had an acute kidney injury at any point during treatment in the TMP-SMX group versus 21 (75.0%) and 29 (74.4%) patients in the fluoroquinolone and minocycline groups, respectively (

For the primary outcome, 97 (34.2%) patients met criteria for clinical failure, and after propensity score weighting was performed, clinical failure was similar at 77 (35.5%), 8 (28.6%), and 12 (30.8%) in the TMP-SMX, fluoroquinolone, and minocycline treatment groups, respectively (

 =.69). After performing inverse probability–weighted regression adjustment, 30-day mortality was significantly lower at 5.5% in the minocycline group versus 15.0% in the TMP-SMX group (

=.011), but not significantly lower at 9.9% in the fluoroquinolone group (

The study had several limitations. Notably, out of the initial 490 patients with 

on monotherapy, 206 (42.0%) were excluded, suggesting there may be uncontrolled bias in the study population. Also, the fluoroquinolone and minocycline groups were small at 28 (9.9%) and 39 (13.7%) patients respectively, so there is a significant risk of confounding. The study was retrospective and occurred over 5 years, introducing the possibility of confounders in treatment selection and outcome. Lastly, the antimicrobial treatment groups were not compared to β-lactam antimicrobials such as cefepime, which are often used in the treatment of 

, so the picture is not yet entirely complete.

However, this was the largest study to date comparing TMP-SMX with other antimicrobial monotherapies in the treatment of 

infections in a real-world setting. The investigators demonstrated that fluoroquinolones and minocycline displayed similar outcomes to TMP-SMX. Although 30-day mortality was lower in the minocycline arm, the low numbers and retrospective nature of the study preclude statements about superiority. This important study reveals the need for further, prospective, randomized investigations to determine optimal antimicrobial monotherapy and explore the role of combination therapy. Equally important would be further data to identify which patients with 

 in cultures need no treatment at all. In its role as a harbinger of the multidrug resistant iatrogenic infections that will become increasingly impactful in the decades ahead, 

 presents a clinical dilemma that demandsmore pragmatic clinical trial data.

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Is There a Better Choice Than TMP-SMX to Treat Stenotrophomonas maltophilia Infections?

New agents to combat multidrug-resistant gram-negative (MDRGN) organisms are sorely needed.

 A modicum of reassurance can be found in a number of new compounds that have been developed in recent years and incorporated into updated Infectious Diseases Society of America guidelines, including novel β lactam-β lactamase inhibitors (βL- βLIs), tetracyclines, and a first-in-class siderophore antimicrobial, cefiderocol.

 Although a precise niche for each remains to be determined, combination therapies continue to be employed for treatment infection from MDRGN organisms, based on a theoretical advantage of augmented bacterial killing and preservation of susceptibility to individual drug classes. Randomized trial data are limited and have shown improved microbiological eradication but similar clinical outcomes.

Carbapenem-resistant GN bacilli (CR-GNB), broadly including species within the order Enterobacterales and certain lactose nonfermenters (

), are among the most problematic and novel treatments that have been prioritized by the World Health Organization.

Scudeller and colleagues recently described in vitro data of bacterial killing and antibiotic synergism, part of the broader COHERENCE (COmbination tHErapy to treat sepsis due to carbapenem-Resistant bacteria in adult and paediatric populations: EvideNCE and common practice) Project, a global collaboration examining combination therapies for CR-GNB.

 The study included various antibiotic combinations and dosages against CR-GNB from time kill (TK) and pharmacokinetic/pharmacodynamic (PK/PD) studies, chosen for their standardized methods and reproducibility, and their ability to recapitulate drug exposure in vivo, respectively.

All articles published through 2018 within the PubMed and Scopus databases and the Web of Science platform were eligible. Reviews, editorials, and protocol papers were excluded, as were publications examining single bacterial strains. Two investigators reviewed relevant studies for eligibility, with a third acting as a tie-breaker. Study quality was assessed on a 0 to 18-point scale, and studies with more than 11 points were deemed high quality and warranting sensitivity analysis. Relevance was categorized as reliable without restrictions, reliable with restrictions, not reliable, or not assignable.

The primary outcome was in vitro synergy or antagonism (defined as a >2-log reduction or increase, respectively, in colony-forming unit [CFU]/mL vs most active single agent) and was stratified by effect size (high, moderate, low, or absent). Secondary outcomes included bactericidal rates (a >3-log reduction in CFU/mL from baseline) and regrowth rate (a ≥2-log CFU/mL decrease of initial colony count, followed by an increase of ≥1-log CFU/mL at 12 and 24 hours). Resistance was determined according to European Committee on Antimicrobial Susceptibility Testing 2019 break points.

From nearly 7000 publications, 797 were assessed for eligibility and 136 included in the meta-analysis. Of these, 31% (42/136) reported PK/PD data, 69% (94/136) reported TK data, and 7% (10/136) reported both. 182 antimicrobial combinations were tested in TK studies and 41 in PK/PD studies. The vast majority involved 2-drug regimens, most commonly colistin- and carbapenem-based. Of 136 studies, 73 (54%) were deemed high quality.

, high synergy was observed with meropenem plus polymyxin/colistin, tigecycline plus colistin, rifampicin plus colistin, and imipenem plus tobramycin. On sensitivity analysis, 4 high-quality TK studies confirmed synergy with carbapenem plus polymyxin, and high synergy was observed with imipenem plus tobramycin and TMP/SMX plus colistin. With respect to secondary outcomes, of 29 polymyxin- and doripenem-based combinations, the authors observed no significant differences in bactericidal activity or regrowth rates vs monotherapy.

, moderate synergy was seen with combinations of ceftolozane/tazobactam plus colistin, imipenem plus colistin, meropenem plus amikacin, meropenem plus colistin, imipenem plus tobramycin, and doripenem plus colistin; high synergy was seen with imipenem plus amikacin. Sensitivity analysis revealed moderate synergy with combinations involving doripenem/imipenem plus colistin from 2 PK/PD studies and 1 TK study. For secondary outcomes, 6 combinations showed significantly higher bactericidal rates with combinations of meropenem plus amikacin, or imipenem plus amikacin/tobramycin vs monotherapy, and significantly less regrowth at 24 hours with imipenem plus amikacin/tobramycin vs monotherapy.

, high synergy was observed with combinations of rifampicin plus colistin, imipenem/doripenem plus polymyxin B, imipenem/meropenem plus amikacin, ceftazidime/avibactam plus aztreonam, and fosfomycin plus polymixin B. Sensitivity analysis revealed moderate to high synergy for combinations of fosfomycin plus polymixin, rifampicin plus polymyxin, and a carbapenem plus polymyxin. In 39 combination regimens from TK and PK/PD studies that were examined for secondary outcomes, investigators found that polymyxin-based combinations (with rifampicin or gentamicin) had significantly higher bactericidal rates vs monotherapy, and significantly lower regrowth at 12 and 24 hours vs monotherapy.

This was the largest systematic review and meta-analysis to date of in vitro data of combination therapy vs monotherapy for CR-GNB that examined multiple pathogens and a prolific number of regimens (>180). Compared to monotherapy, the authors found high synergy and increased bactericidal activity for 

; high synergy, increased bactericidal activity, and lower regrowth for 

 with polymyxin-based regimens; and high synergy, high bactericidal activity, and lower regrowth for 

 with a carbapenem and an aminoglycoside. Limitations included scant high-quality data for combinations involving novel compounds, heterogeneity in the combinations studied, regrowth assessment limited to 24 hours, and limited generalizability due to the variability of bacterial strains and resistance patterns. Additionally, the lack of in vivo correlates limits one’s ability to translate these findings into clinical practice.

Although the results do not address who should be treated with combination therapy, the authors should be commended on their appraisal of the literature. Despite their findings, it is incumbent upon infectious diseases practitioners to exercise caution with polymyxin-based regimens, which is underscored by the updated Clinical and Laboratory Standards Institute breakpoints listing only “intermediate” and “resistant” categories for Enterobacterales.

 These data, though intriguing, perhaps best serve to stimulate subsequent human trials of the most promising regimens identified to combat the rising tide of MDRGN infections.

Sean S. M. Bullis, MD, is an infectious diseases fellow at the University of Vermont Medical Center in Burlington.

Andrew J. Hale, MD, is an infectious disease physician at the University of Vermont Medical Center and an assistant professor of medicine at Larner College of Medicine at the University of Vermont in Burlington.

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 with Difficult-to-Treat Resistance (DTR-

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Performance Standards for Antimicrobial Susceptibility Testing

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Sean S. M. Bullis, MD

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