Multicenter, randomized, pragmatic, open clinical trial

N= 143

Group A: IV fosfomycin disodium (n=70)
Group B: Comparator — IV ceftriaxone (n=31) or IV meropenem if ceftriaxone-resistant (n=42) (combined comparator group n=73)

Trial enrollment: June 2014 – December 2018

Follow-up per patient: 60 days

Treatment duration: 10–14 days (mean IV therapy ~5.4–5.5 days)

Primary: Clinical and microbiological cure (CMC) at test of cure (TOC), defined as 5–7 days after completion of treatment, in the MITT population. Clinical cure = resolution of all new signs/symptoms at TOC; microbiological cure = no isolation of causative E. coli in blood cultures from day 5 or urine culture at TOC.

Secondary: CMC in the clinically evaluable population (CEP) and microbiologically evaluable population (MEP); length of hospital stay after randomization; relapse rate; reinfection rate; 30-day mortality; adverse events (AEs)

Exploratory: Rate of resistant bacteria in follow-up cultures; rate of new ceftriaxone-resistant or carbapenem-resistant gram-negative bacteria acquisition in rectal swabs

Fosfomycin

(n= 70)

Comparator

(n= 73)

Fosfomycin

(n= 70)

Comparator

(n= 73)

Common Adverse Events: Hypokalemia (well-known AE of fosfomycin, noted as typically mild); overall AEs reported in 44 (62.9%) fosfomycin vs 41 (56.2%) comparator patients (p=0.41)

Serious Adverse Events: Reported in 13 (18.6%) fosfomycin vs 10 (13.7%) comparator patients (p=0.42); heart failure occurred in 6 fosfomycin patients (8.6%), all aged ≥81 years, most with preexisting cardiac or renal disease; among these, 5 events were classified as serious

Percentage that Discontinued due to Adverse Events: 6/70 (8.5%) in the fosfomycin group vs 0/73 (0%) in the comparator group (p=0.006); reasons included heart failure (n=4), alithiasic cholecystitis (n=1), and persistent fever (n=1)

Intravenous Fosfomycin as Adjunctive Therapy for Gram-Negative Bacteria Bloodstream Infections: A Propensity Score Adjusted Retrospective Cohort Study

Design

Retrospective, comparative, monocentric cohort study in Italy

N=363

Objective

To explore efficacy and safety of intravenous fosfomycin (iv-FOS)-containing regimens for the treatment of Gram-negative bacteria bloodstream infections (GNB-BSIs) when compared with other mono- or combination regimens not including iv-FOS. 

Study Groups

Monotherapy or combination therapy without FOS (n=265)

Combination including iv-FOS (n=98)

Inclusion Criteria

Adult patients aged ≥18 years hospitalized during the study period who developed a GNB-BSI (including polymicrobial BSIs) and had survived at least the first 72 hours from BSI onset and were treated with antibiotics for at least 48 hours. 

Exclusion Criteria

Infections caused by Acinetobacter baumannii complex at any site (given the reported intrinsic resistance of the pathogen), incomplete data, life expectancy <48 hours. 

Methods

Blood cultures were performed for all patients by collecting 15–20 mL of blood per culture set before starting empirical antimicrobial therapy. Two bottles (for aerobic and anaerobic bacteria culture) were collected for each set. Identification and antibacterial phenotypic susceptibility testing were performed on the automated VITEK 2 system or VITEK MS (Biomerieux) according to the manufacturer’s instructions. The interpretative breakpoints of MIC values were based on the criteria of the European Committee on Antimicrobial Susceptibility Testing (EUCAST). The fosfomycin MIC was determined using the agar dilution method in a medium supplemented with 25 mg/L glucose-6-phosphate; MICs were reported with no interpretation, given the absence of predefined EUCAST clinical breakpoints.

Predictors of 30-day mortality were determined using first a univariate Cox regression model for variables of interest and then a stepwise multivariable Cox regression to control for potential confounders and adjusting for significant variables associated (p <0.1). Finally, an inverse probability treatment-weighted (IPTW) adjusted analysis was applied to compare the impact of iv-FOS on risk of 30-day mortality after balancing the cohort for variables influencing treatment assignment. 

Duration

January 1, 2021 through April 1, 2023

Outcome Measures

Primary: Incidence and predictors of 30-day mortality from BSI onset

Secondary: Incidence of 14-day mortality from BSI onset; incidence of treatment failure defined as one of the following: infection-related mortality at day 7, persistence of signs and symptoms of BSI after 5 days of therapy, treatment discontinuation by the treating physi- cian for clinical inefficacy, clinical worsening leading to transfer to an intensive care unit (ICU) after at least 72 hours of therapy; incidence of severe (grades 3–5) adverse events to antibiotic therapy leading to therapy discontinuation; incidence of microbiological eradication in case of deep-site associated BSI (including lower respiratory tract, intra-abdominal abscesses, osteoarticular infections) or urinary tract-associated BSI, defined as negative culture from the site of infection for the causative pathogen(s) performed after at least 72 hours of therapy; median duration of antimicrobial therapy

Baseline Characteristics

Monotherapy or combinations without FOS 

(n=265)

Combinations with iv-FOS 

(n=98)

Median age, years

Male sex, n (%)

Comorbidities, n (%)

COPD*

Obesity*

44 (17)

17 (6)

28 (29)

14 (14)

Characteristics of infection, n (%)

Acute kidney failure*

81 (31)

41 (42)

Surgical ward, n (%)*

Median SOFA score*

Deep site-associated BSI, n (%)*

Site of infection, n (%)

Urinary tract*

125 (47)

25 (26)

Antimicrobial resistance pattern of GNB, n (%)

3GC and BL/BLI sensitive*

Pathogen(s) involved, n (%)

P. aeruginosa*

Other Gram-negative*

39 (15)

38 (14)

24 (25)

4 (4)

Definitive therapy for BSI, n (%)

Monotherapy*

Combination therapy

174 (66)

91 (34)

0 (0)

98 (100)

Antibiotics used in combination, n (%)

Aminoglycosides*

46 (51)

0 (0)

Media days from symptom onset to discharge or death from infection*

*Identified as having statistically significant between-group differences at baseline and entered into regression analysis.

Results

Significant variables identified on multivariable analysis

Adjusted HR

95% CI

p-Value

Chronic kidney diseases

Solid neoplasia

Hematologic neoplasia

Septic shock at presentation

Other Gram-negative causative pathogen

Time to appropriate antimicrobial therapy >72 hours from infection onset

Combination therapy including FOS

Significant predictors identified on final IPTW-adjusted multivariable analysis

Chronic kidney diseases

Solid neoplasia

Hematologic neoplasia

Septic shock at presentation

Other Gram-negative causative pathogen

Time to appropriate antimicrobial therapy >72 hours from infection onset

Combination therapy including FOS

Adverse Events

Use of iv-FOS was associated with an increased microbiological eradication (90% vs 79%, p=0.042) and an increased incidence of adverse events leading to treatment discontinuation (12% vs 5%, p=0.024), including 7 cases of fluid overload and hypernatremia and 5 cases of hypokalemia. 

Study Author Conclusions

Fosfomycin in combination therapy for GNB-BSI may have a role in improving survival. These results justify the development of further clinical trials.

Critique

 This study's methodology was robust for a retrospective cohort analysis, given the extensive propensity matching and IPTW analysis employed to ensure balanced groups. The potential protective effect of combination therapy with iv-FOS remained through the final phase of regression analysis; however, this comes at the cost of greater incidence of adverse events. Notably, use of iv-FOS was done at the clinical discretion of the treating physicians and not based on an approved protocol, so potential for variability and confounding exists.

Daptomycin Plus Fosfomycin Versus Daptomycin Alone for Methicillin-resistant Staphylococcus aureus Bacteremia and Endocarditis: A Randomized Clinical Trial (BACSARM)

Design

Randomized, multicenter, phase 3, superiority, open-label and parallel-group clinical trial in Spain

N=167 randomized (155 included in primary analysis)

Objective

To determine whether daptomycin plus fosfomycin provides higher treatment success than daptomycin alone for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and endocarditis. 

Study Groups

Daptomycin 10 mg/kg intravenously (IV) daily plus fosfomycin 2 g IV every 6 hours (n=74)

Daptomycin 10 mg/kg of IV daily (n=81)

Inclusion Criteria

Patients aged ≥18 years with MRSA bacteremia indicated by 1 or more positive blood cultures within the last 72 hours before randomization and with symptoms and signs of infection

Exclusion Criteria

Life expectancy ≤24 hours, polymicrobial bacteremia, pneumonia as a source of bacteremia, prosthetic valve endocarditis, severe end-stage liver disease (Child-Pugh class C), New York Heart Association functional classification III/IV, prior history of eosinophilic pneumonia, any clinical condition that required additional antibiotic therapy active against MRSA, or allergy to daptomycin or fosfomycin

Methods

Patients were randomly assigned to receive either daptomycin 10 mg/kg IV daily plus fosfomycin 2 g IV every 6 hours or daptomycin 10 mg/kg IV daily, between 10 and 14 days for uncomplicated bacteremia and between 28 and 42 days for complicated bacteremia.

Daptomycin was administered IV via 30-minute infusion once a day, and fosfomycin was administered IV by at least one 60-minute infusion every 6 hours. Antibiotic dosage was adjusted according to creatinine clearance. Patients were evaluated by researchers at inclusion, day 3, day 7, and end of therapy (EOT), and at the test of cure (TOC) visit 6 weeks after EOT. Blood cultures were obtained at day 3, day 7 (when positive at day 3), EOT, and TOC. Blood cultures and biochemistry analyses were  also performed whenever considered necessary by the attending physicians and/ or researchers. Echocardiograms were performed at the discretion of the attending physicians. 

Treatment success was considered when patient was alive and had resolution of clinical manifestations of infection and negative blood cultures at TOC after completion of therapy. Treatment failure was considered in any of the following situations: lack of clinical improvement at day 3 or later after the start of therapy, persistent MRSA bacteremia at day 7 or later, premature discontinuation of therapy due to adverse events (AEs) or based on clinical judgment, recurrent MRSA bacteremia before or at TOC, additional antimicrobial therapy active against MRSA administered before TOC, lack of blood cultures obtained at TOC, and/or death due to any cause before TOC. Only patients without treatment failure could have treatment success. For analysis purposes, patients lost to follow-up (with missing TOC data) were classified as treatment failure. Microbiological failure was considered in the case of persistent bacteremia, recurrent bacteremia, and the emergence of resistance to study drugs during treatment.

Duration

December 2013 through November 2017

Outcome Measures

Primary: Treatment success at TOC 

Secondary: MRSA bacteremia at day 3, day 7, and/or at TOC; microbiological failure; complicated bacteremia; AEs leading to treatment discontinuation; mortality due to any cause at day 7 and at TOC

Baseline Characteristics

Daptomycin plus fosfomycin

(n=74)

Daptomycin monotherapy

(n=81)

Median age, years

Male sex, n (%)

Median Charlson Comorbidity Index

Diabetes mellitus with end organ damage, n (%)

Mean Pitt score

Implants, n (%)

Orthopedic

Pacemaker

11 (14.9)

8 (10.8)

13 (16)

4 (4.9)

Previous antibiotic therapy, n (%)

Acquisition, n (%)

Community

Nosocomial

Healthcare-associated

7 (9.4)

36 (48.6)

31 (41.8)

4 (4.9)

35 (43.2)

42 (51.8)

Main source of infection, n (%)

Intravascular catheter

Skin and soft tissue

Surgical site

Urinary tract

Unknown

Other

31 (41.9)

10 (13.5)

7 (9.5)

6 (8.1)

14 (18.9)

6 (7.4)

39 (48.1)

19 (23.5)

4 (4.9)

3 (3.7)

8 (9.9)

8 (9.9)

Endocarditis, n (%)

Median days of therapy

Results

Endpoint

Daptomycin plus fosfomycin

(n=74)

Daptomycin monotherapy

(n=81)

Relative risk (95% CI)

Treatment success at TOC, n (%)

Positive blood cultures at day 3

Positive blood cultures at day 7

Positive blood cultures at TOC

Microbiological failure at TOC

Number of episodes of complicated bacteremia at TOC

Overall mortality at day 7

Overall mortality at TOC

Significant cause for treatment failure included microbiological failure: 0% daptomycin plus fosfomycin vs 11.1% daptomycin monotherapy (p=0.003).

Adverse Events

Any AE leading to treatment discontinuation: 13/74 (17.6%) daptomycin plus fosfomycin vs 4/81 (4.9%) daptomycin monotherapy; RR 3.56 (95% CI 1.21 to 10.44)

Study Author Conclusions

Daptomycin plus fosfomycin provided 12% higher rate of treatment success than daptomycin alone, but this difference did not reach statistical significance. This antibiotic combination prevented microbiological failure and complicated bacte remia, but it was more often associated with adverse events.

Critique

This study did not find statistically significant clinical efficacy with fosfomycin IV added onto daptomycin IV for MRSA bacteremia; however, the combination treatment was not associated with microbiological failure or clinical failure at the expense of higher AE rates. It was noted that daptomycin plus fosfomycin could be more effective than daptomycin alone in younger patients and in those with more severe disease, but this needs to be confirmed after further study.

Cloxacillin Plus Fosfomycin versus Cloxacillin Alone for Methicillin-Susceptible Staphylococcus aureus Bacteremia: A Randomized Trial (SAFO)

Design

Multicenter, open-label, phase III-IV, superiority, randomized clinical trial in Spain

N=215

Objective

To assess whether cloxacillin plus fosfomycin achieves better treatment success than cloxacillin alone in hospitalized adults with methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. 

Study Groups

Cloxacillin 2 g IV every 4 hours (n=110)

Cloxacillin 2 g IV every 4 hours plus fosfomycin 3 g IV every 6 hours (n=105)

Inclusion Criteria

Adults aged ≥18 years with at least one blood culture positive for MSSA ≤72 hours before inclusion and evidence of active infection

Exclusion Criteria

Severe clinical status with expected death; severe hepatic cirrhosis (Child- Pugh C); moderate-to-severe cardiac chronic failure (New York Heath Association class III–IV; prosthetic endocarditis; history of significant allergy to β-lactams or fosfomycin; known S. aureus fosfomycin non-susceptibility; polymicrobial bacteremia with >1 micro-organism in blood cultures; positive pregnancy test or pregnancy or lactation at the time of inclusion; myasthenia gravis; participation in another clinical trial or previous participation in the present clinical trial; social problems, cognitive or psychiatric impairment which might be expected to affect adherence to the protocol; acute SARS- CoV-2 infection

Methods

Patients were randomly assigned to IV cloxacillin 2 g every 4 hours plus fosfomycin 3 g every 6 hours, or to IV cloxacillin 2 g every 4 hours for the duration of 7 days. Cloxacillin was adusted to 2 g IV every 6 hours if creatinine clearance <30 mL/min. Fosfomycin was also renally adjusted. After the first week, the choice of antibiotic strategy and the duration of overall antibiotic treatment will be determined according to clinical criteria by the attending physician, based on current guidelines and including need for source control of infection.

Duration

May 31, 2019 through February 24, 2022

Outcome Measures

Primary: Treatment success at day 7 (defined as a composite of patient being alive, stable or with improved quick SOFA score, afebrile and with negative blood cultures for MSSA)

Secondary: mortality, adverse events

Baseline Characteristics

Cloxacillin plus fosfosmycin

(n=104)

Cloxacillin monotherapy

(n=110)

Median age, years

Female sex, n (%)

Acquisition, n (%)

Community

Nosocomial

Healthcare-associated

42 (40)

36 (35)

26 (25)

36 (33)

48 (44)

26 (24)

Median time from index blood culture to randomization

Mean Charlson Comobordity Index score

Mean qSOFA score

Mean Pitt bacteremia score

Implants, n (%)

Orthopedic

Pacemaker or indwelling prosthetic valve

Other

14 (13.4) 

2 (1.9)

4 (3.8)

16 (14.5)

6 (5.5)

9 (8.2)

Source of infection at time of index blood culture, n (%)

Intravascular catheter

Bone/joint

Skin/soft tissue

Not established

Urinary

Endocarditis

Surgical site

Pneumonia

Other

32 (31)

21 (20)

12 (11.5)

14 (13)

5 (5)

3 (3)

6 (6)

2 (2)

9 (9)

36 (33)

11 (10)

15 (14)

19 (17)

8 (7)

2 (2)

6 (5)

2 (2)

11 (10)

Any anti-staphylococcal antibiotic in 72 hours prior to randomization, n (%)

Results

(ITT population)

Endpoint

Cloxacillin plus fosfosmycin

(n=104)

Cloxacillin monotherapy

(n=110)

Risk difference (95% CI), p-Value

Treatment success at day 7, n (%)

All-cause mortality at day 7, n (%)

All-cause mortality at end of therapy, n (%)

Adverse Events

Serious adverse events leading to discontinuation of therapy: 11 (10.6%) cloxacillin plus fosfomycin vs 9 (8.2%) 2.40 cloxacillin monotherapy, risk difference 2.40 (95% CI −5.43 to 10.22), p=0.547

Study Author Conclusions

Cloxacillin plus fosfomycin did not achieve better treatment success at day 7 of therapy than cloxacillin alone in MSSA bacteremia. Further trials should consider the intrinsic heterogeneity of the infection by using a more personalized approach.

Critique

This study included only monomicrobial bacteremias; as such, its external validity to complicated polymicrobial bacteremias with multiple drug-resistant pathogens is limited. Unlike prior studies, rates of adverse events were comparable between the fosfomycin group and comparator group in this study. These findings may have been affected by the numerically higher incidence of age, chronic comorbidity index score, prosthetic implants, and high-risk infectious sources (including endocarditis) in the cloxacillin monotherapy group. 

Post hoc pooled analysis of individual participant data from 2 multicenter, randomized, controlled trials (BACSARM and SAFO)

N= 369

Fosfomycin combination therapy (n=178)

Monotherapy (n=191)

Patients in BACSARM received daptomycin 10 mg/kg IV once daily plus fosfomycin 2 g IV every 6 hours or daptomycin IV alone. In BACSARM, fosfomycin was administered as a 1-hour IV infusion.

In SAFO, patients received cloxacillin 2 g IV every 4 hours plus fosfomycin 3 g IV every 6 hours or cloxacillin IV alone. In SAFO, fosfomycin was administered as a 4-hour IV infusion.

Fosfomycin was administered for the entire duration of treatment in BACSARM and for the first 7 days in SAFO. Treatment duration varied based on SAB complexity.

Primary: Treatment success at 8 weeks

Secondary: Persistent bacteremia at days 3 and 7; all-cause mortality at days 14, 30, and 60; adverse events leading to treatment discontinuation

Fosfomycin combination therapy

(n=178)

Fosfomycin monotherapy

(n=91)

Fosfomycin combination therapy

(n=178)

Adverse events leading to treatment discontinuation were more frequent in the fosfomycin combination therapy group (13.5% vs 6.8%, respectively, median RR 1.97 (95% CrI 1.04 to 3.92), posterior probability of benefit 2.0% (posterior probability of harm 98.0%).

Common adverse events included gastrointestinal disturbances, acute heart failure, hypokalemia, and acute liver injury.