Multidrug-resistant urethritis caused by Haemophilus parainfluenzae: susceptibility pattern and fosfomycin as an alternative treatment
======================================================================================================================================

* Berta Isabel Fidalgo
* Jordi Iglesies
* David García
* Andrea Vergara
* Irene Fuertes de Vega
* Laura Horvath
* Yuliya Zboromyrska
* Jordi Bosch
* Ana González
* José Riera-Monroig
* Ignasi Roca
* Marina Alguacil
* Climent Casals-Pascual
* Cristina Pitart
* Josep Mallolas
* José Luis Blanco
* Mateu Espasa

*   URETHRITIS
*   Disease Transmission, Infectious
*   Treatment Adherence and Compliance

Urethritis is a common symptom of sexually transmitted infections (STIs), with *Chlamydia trachomatis* being the most identified cause in non-gonococcal urethritis (NGU).1 2 However, a significant proportion of NGU cases have an unknown origin. The potential of *Haemophilus parainfluenzae* to act as an opportunistic pathogen causing respiratory tract infections or urogenital infections has been described, and the emergence of multidrug resistance in this species has been reported.3–5 The main objective of the study was to describe the susceptibility profile and evaluate the effectiveness of fosfomycin as an alternative therapeutic option in the management of multidrug-resistant (MDR), including CTX-M producing *H. parainfluenzae* strains.

This observational, retrospective study analysed *H. parainfluenzae* strains isolated from urethral swabs of symptomatic men who have sex with men at Hospital Clinic, Barcelona, from January 2015 to June 2023. Clinical data were obtained from patient’s hospital records (online supplemental table 1). Bacterial identification and antibiotic susceptibility were determined using MALDI-TOF MS and the gradient diffusion method. The detection of extended-spectrum beta-lactamase (ESBL) CTX-M type was carried out using the CTX-M NGbiotech lateral-flow test. Results were interpreted based on breakpoints provided by the EUCAST guidelines available at the time of diagnosis.### Supplementary data

[[sextrans-2024-056142supp001.pdf]](pending:yes) 

Owing to the absence of other oral treatment options for MDR *H. parainfluenzae*, sensitivity testing for fosfomycin started in 2020 based on previous data.6–8 Results were interpreted according to the EUCAST *Escherichia coli* breakpoint for fosfomycin (MIC: 8).

A total of 360 strains of *H. parainfluenzae* from 322 patients were analysed. These correspond to 8% of 4510 urethral samples processed from 2015 to 2023. The percentage of *H. parainfluenzae* positive samples increased from 6% in 2015 to 12% in 2023 (online supplemental figure 1).

Figure 1 shows the antibiotic resistance trend from 2015 to 2023, illustrating an increase in resistance to all antibiotics used for *H. parainfluenzae* treatment. Notably, 76 isolates were considered MDR showing resistance to multiple antibiotics:ampicillin, amoxicillin/clavulanic acid, cefotaxime and levofloxacin, yet remaining susceptible to ertapenem. Two strains recovered between May 2022 and May 2023 were ESBL positive, belonging to the CTX-M group.9 A total of 129 strains (47 of which were MDR, including the 2 CTX-M group) were tested for fosfomycin activity: 128 (99.2%) were susceptible and 1 (0.8%) was resistant (online supplemental table 2).

![Figure 1](http://sti.bmj.com/https://sti.bmj.com/content/sextrans/101/3/201/F1.medium.gif)

[Figure 1](http://sti.bmj.com/content/101/3/201/F1)

Figure 1 
Evolution of *H. parainfluenzae* antibiotic resistance from 2015 to 2023.

Fosfomycin (3 g/48 hours in two doses) was prescribed in 36 cases of monobacterial urethritis when the spectrum of empirical treatment did not show activity against MDR *H. parainfluenzae* isolates. Of these, 30 received fosfomycin as first-line treatment, while 6 received it second-line due to persistent symptoms and positive culture results after previous antibiotic treatment failed. A test of cure was conducted on 21 patients, all being negative and considered cured. The remaining 15 were lost to follow-up, but no relapse was registered in the following 6 months.

This study shows the emergence of antibiotic resistance among *H. parainfluenzae* isolates collected from urethral swabs over the past decade in Barcelona. To our knowledge, this is the first study to evaluate fosfomycin as a treatment for *H. parainfluenzae* urogenital infection.

The emergence of *H. parainfluenzae* isolates in NGU and the observed increase in antibiotic resistance in our study concur with the findings reported by Sierra *et al*,5 corresponding to the same geographic area.

Most strains exhibited a fosfomycin MIC ≤4 µg/mL, and there were no reported instances of therapeutic failure. This suggests that fosfomycin is a promising alternative for the treatment of MDR *H. parainfluenzae* infection. Effective treatment with fosfomycin in cases of persistent MDR *H. parainfluenzae* previously treated supports this theory. Unfortunately, data are only available regarding fosfomycin sensitivity in *Neisseria gonorrhoeae* but not in *H. parainfluenzae* or in urogenital or respiratory samples.6 7 

Oral administration of fosfomycin, coupled with its short dosing duration, may enhance compliance. Its good safety profile and low interaction with other potential concomitant drugs make fosfomycin a better drug choice for the management of *H. parainfluenzae* infections in groups with sexual practices at risk of acquiring STIs.10 

This study has limitations. Due to its retrospective design, crucial clinical data were unavailable. Additionally, the lack of fosfomycin breakpoints for the treatment of *H. parainfluenzae* poses a challenge. Consequently, *E. coli* breakpoints were used as a substitute to fulfil the aim of the study. Finally, resistance data for doxycycline and azithromycin were not available, hindering the calculation of the MDR strain rate.

This study suggests that fosfomycin could be an effective alternative for treating MDR *H. parainfluenzae* urogenital infections, addressing the urgent need for new treatment strategies against resistant pathogens. However, randomised clinical trials are required to confirm these results and establish specific treatment guidelines.

## Ethics statements

### Patient consent for publication

Not applicable.

### Ethics approval

This study involves human participants and was approved by The Hospital Clínic of Barcelona Ethical Research Committee (HCB/2024/0031).

## Footnotes

*   Handling editor Erica L Plummer

*   BIF and JI contributed equally.

*   Contributors BIF and JI designed the study and played a key role in interpreting the results and writing the manuscript. CP, JB, LH, YZ, AV, IR and MA conducted the bacterial identification and antibiotic susceptibility testing, contributed to the methods and results sections, and provided critical feedback on the manuscript. DG, IFdV, JR-M, JM and JLB collected and analysed clinical data from patient records, contributed to the manuscript’s data interpretation section and revised the manuscript critically for important intellectual content. CC-P and ME contributed to the final approval of the version to be published.

*   Funding This study was supported by the I+D+i grant PID2021-127402OB-I00, funded by MCIN/AEI/10.13039/501100011033, co-financed by the European Development Regional Fund 'A way to achieve Europe' and grant 2017 SGR 0809 from the Departament d’Universitats, Recerca i Societat de la Informació, of the Generalitat de Catalunya. We also acknowledge support from the Spanish Ministry of Science, Innovation and Universities through the 'Centro de Excelencia Severo Ochoa 2019–2023' Program (CEX2018-000806-S) and support from the Generalitat de Catalunya through the CERCA Program'.

*   Competing interests The authors declare that the research was conducted in the absence of any other commercial or financial relationships that could be construed as a potential conflict of interest.

*   Provenance and peer review Not commissioned; externally peer reviewed.

*   Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

[http://creativecommons.org/licenses/by-nc/4.0/](http://creativecommons.org/licenses/by-nc/4.0/)
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: [http://creativecommons.org/licenses/by-nc/4.0/](http://creativecommons.org/licenses/by-nc/4.0/).

## References

1.   Workowski KA , Bachmann LH , Chan PA , et al . Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep 2023;70:1–187. [doi:10.15585/mmwr.rr7004a1](http://dx.doi.org/10.15585/mmwr.rr7004a1) 
    
    

2.   Hamasuna R , Yasuda M , Takahashi S , et al . The JAID/JSC guidelines to Clinical Management of Infectious Disease 2017 concerning male urethritis and related disorders. J Infect Chemother 2021;27:546–54. [doi:10.1016/j.jiac.2019.12.001](http://dx.doi.org/10.1016/j.jiac.2019.12.001) 
    
    [CrossRef](http://sti.bmj.com/lookup/external-ref?access_num=10.1016/j.jiac.2019.12.001&link_type=DOI) 
    
    [PubMed](http://sti.bmj.com/lookup/external-ref?access_num=33516669&link_type=MED&atom=%2Fsextrans%2F101%2F3%2F201.atom) 

3.   Tinguely R , Seiffert SN , Furrer H , et al . Emergence of extensively drug-resistant Haemophilus parainfluenzae in Switzerland. Antimicrob Agents Chemother 2013;57:2867–9. [doi:10.1128/AAC.00221-13](http://dx.doi.org/10.1128/AAC.00221-13) 
    
    [Abstract/FREE Full Text](http://sti.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiYWFjIjtzOjU6InJlc2lkIjtzOjk6IjU3LzYvMjg2NyI7czo0OiJhdG9tIjtzOjI0OiIvc2V4dHJhbnMvMTAxLzMvMjAxLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

4.   Saiz-Escobedo L , Cadenas-Jiménez I , Olmos R , et al . Detection of blaCTX-M-15 in an integrative and conjugative element in four extensively drug-resistant Haemophilus parainfluenzae strains causing urethritis. Int J Antimicrob Agents 2023;62:106991. [doi:10.1016/j.ijantimicag.2023.106991](http://dx.doi.org/10.1016/j.ijantimicag.2023.106991) 
    
    [CrossRef](http://sti.bmj.com/lookup/external-ref?access_num=10.1016/j.ijantimicag.2023.106991&link_type=DOI) 
    
    [PubMed](http://sti.bmj.com/lookup/external-ref?access_num=37774891&link_type=MED&atom=%2Fsextrans%2F101%2F3%2F201.atom) 

5.   Sierra Y , González-Díaz A , Carrera-Salinas A , et al . Genome-wide analysis of urogenital and respiratory multidrug-resistantHaemophilus parainfluenzae. J Antimicrob Chemother 2021;76:1741–51. [doi:10.1093/jac/dkab109](http://dx.doi.org/10.1093/jac/dkab109) 
    
    [CrossRef](http://sti.bmj.com/lookup/external-ref?access_num=10.1093/jac/dkab109&link_type=DOI) 
    
    [PubMed](http://sti.bmj.com/lookup/external-ref?access_num=33792695&link_type=MED&atom=%2Fsextrans%2F101%2F3%2F201.atom) 

6.   Zboromyrska Y , Guerrero-Torres MD , Benítez MÁ . Is fosfomycin a good alternative drug for gonorrhoea treatment in our setting? Enferm infec microbiol clin (Eng ed) 2020;38:38–9. [doi:10.1016/j.eimce.2018.12.016](http://dx.doi.org/10.1016/j.eimce.2018.12.016) 
    
    [CrossRef](http://sti.bmj.com/lookup/external-ref?access_num=10.1016/j.eimc.2018.12.010&link_type=DOI) 

7.   Tesh LD , Shaeer KM , Cho JC , et al . Neisseria gonorrhoeae and fosfomycin: past, present and future. Int J Antimicrob Agents 2015;46:290–6. [doi:10.1016/j.ijantimicag.2015.05.007](http://dx.doi.org/10.1016/j.ijantimicag.2015.05.007) 
    
    [CrossRef](http://sti.bmj.com/lookup/external-ref?access_num=10.1016/j.ijantimicag.2015.05.007&link_type=DOI) 
    
    [PubMed](http://sti.bmj.com/lookup/external-ref?access_num=26145201&link_type=MED&atom=%2Fsextrans%2F101%2F3%2F201.atom) 

8.   Yuan Z , He C , Yan S , et al . Randomized controlled clinical trial on the efficacy of fosfomycin trometamol for uncomplicated gonococcal urethritis in men. Clin Microbiol Infect 2016;22:507–12. [doi:10.1016/j.cmi.2016.03.031](http://dx.doi.org/10.1016/j.cmi.2016.03.031) 
    
    [CrossRef](http://sti.bmj.com/lookup/external-ref?access_num=10.1016/j.cmi.2016.03.031&link_type=DOI) 
    
    [PubMed](http://sti.bmj.com/lookup/external-ref?access_num=27064136&link_type=MED&atom=%2Fsextrans%2F101%2F3%2F201.atom) 

9.   Caméléna F , Merimèche M , Liberge M , et al . Detection of CTX-M-15 ESBL in XDR Haemophilus parainfluenzae from a urethral swab. J Antimicrob Chemother 2024;79:539–45. [doi:10.1093/jac/dkad408](http://dx.doi.org/10.1093/jac/dkad408) 
    
    [CrossRef](http://sti.bmj.com/lookup/external-ref?access_num=10.1093/jac/dkad408&link_type=DOI) 
    
    [PubMed](http://sti.bmj.com/lookup/external-ref?access_num=38197448&link_type=MED&atom=%2Fsextrans%2F101%2F3%2F201.atom) 

10.  Iarikov D , Wassel R , Farley J , et al . Adverse Events Associated with Fosfomycin Use: Review of the Literature and Analyses of the FDA Adverse Event Reporting System Database. Infect Dis Ther 2015;4:433–58. [doi:10.1007/s40121-015-0092-8](http://dx.doi.org/10.1007/s40121-015-0092-8) 
    
    [CrossRef](http://sti.bmj.com/lookup/external-ref?access_num=10.1007/s40121-015-0092-8&link_type=DOI) 
    
    [PubMed](http://sti.bmj.com/lookup/external-ref?access_num=26437630&link_type=MED&atom=%2Fsextrans%2F101%2F3%2F201.atom)