The efficacy of mesenchymal stem cell treatment and colistin-fosfomycin combination on colistin-resistant Acinetobacter baumannii sepsis model.

INTRODUCTION: This study examines the role of mesenchymal stem cells (MSCs) in an experimental sepsis model developed with colistin-resistant Acinetobacter baumannii (CRAB). MATERIALS AND METHODS: BALB-c mice were divided into treatment groups (MSC, MSC + colistin (C)-fosfomycin (F), and C-F and control groups (positive and negative)). CRAB was administered to mice through intraperitoneal injection. Three hours later, C, F, and MSC were given intraperitoneally to the treatment groups. Colistin administration was repeated every 12 h, F administration was done every 4 h, and the second dose of MSC was administered after 48 h. Mice were sacrificed at 24 and 72 h. The bacterial load was determined as colony-forming units per gram (cfu/g). Histopathological examination was conducted on the left lung, liver, and both kidneys. IL-6 and C-reactive protein (CRP) levels in mouse sera were determined by enzyme-linked immunosorbent assay. RESULTS: Among the treatment groups, the C-F group had the lowest colony count in the lung (1.24 ± 1.66 cfu/g) and liver (1.03 ± 1.08 cfu/g). The highest bacterial clearance was observed at 72 h compared to 24 h in the MSC-treated groups (p = 0.008). The MSC + C-F group showed the lowest histopathological score in the liver and kidney (p = 0.009). In the negative control group, the IL-6 level at the 24th hour was the lowest (p < 0.001). Among the treatment groups, the CRP level was the lowest in the MSC + C-F group at 24 and 72 h. CONCLUSION: In a CRAB sepsis model, adding MSCs to a colistin-fosfomycin treatment may be beneficial in terms of reducing bacterial loads and preventing histopathological damage.

Genotypic Evolution of Klebsiella pneumoniae Sequence Type 512 during Ceftazidime/Avibactam, Meropenem/Vaborbactam, and Cefiderocol Treatment, Italy.

In February 2022, a critically ill patient colonized with a carbapenem-resistant K. pneumoniae producing KPC-3 and VIM-1 carbapenemases was hospitalized for SARS-CoV-2 in the intensive care unit of Policlinico Umberto I hospital in Rome, Italy. During 95 days of hospitalization, ceftazidime/avibactam, meropenem/vaborbactam, and cefiderocol were administered consecutively to treat 3 respiratory tract infections sustained by different bacterial agents. Those therapies altered the resistome of K. pneumoniae sequence type 512 colonizing or infecting the patient during the hospitalization period. In vivo evolution of the K. pneumoniae sequence type 512 resistome occurred through plasmid loss, outer membrane porin alteration, and a nonsense mutation in the cirA siderophore gene, resulting in high levels of cefiderocol resistance. Cross-selection can occur between K. pneumoniae and treatments prescribed for other infective agents. K. pneumoniae can stably colonize a patient, and antimicrobial-selective pressure can promote progressive K. pneumoniae resistome evolution, indicating a substantial public health threat.

Sensibilidad de Escherichia coli frente a fosfomicina, en infecciones urinarias provenientes de personas con discapacidad que acudieron a la Secretaría Nacional por los Derechos Humanos de las Personas con Discapacidad-SENADIS / Susceptibility of Escherichia coli against fosfomycin in urinary tract infections from people with disabilities who attended SENADIS

INTRODUCCIÓN: Fosfomicina es un antimicrobiano de amplio espectro utilizado para el tratamiento de las infecciones urinarias bajas; tiene actividad sobre bacilos gramnegativos y cocos grampositivos, así también sobre microorganismos multirresistentes, además de ofrecer una alternativa terapéutica de administración vía oral en dosis única, alcanzando una efectividad de 90%. OBJETIVO: Conocer la sensibilidad in vitro de Escherichia coli frente a fosfomicina, en infecciones urinarias provenientes de personas con discapacidad. MATERIAL Y MÉTODO: Estudio observacional, descriptivo, prospectivo, en el que se incluyó un total de 273 muestras de urocultivo, de pacientes de ambos sexos que acudieron a SENADIS, y que en el momento de la consulta presentaban síntomas de infección del tracto urinario, por lo que se les solicitó el análisis de orina simple y cultivo. De las muestras procesadas en el laboratorio de microbiología, que fueron positivas con crecimiento bacteriano significativo, se procedió a la identificación bacteriana y a la realización del antibiograma según las recomendaciones de CLSI. RESULTADOS: De estas 273 muestras, 91 fueron positivas para diferentes uropatógenos, 62/91 (68%) resultaron ser E. coli. De estas cepas de E. coli, 59/62 (95%) mostraron sensibilidad in vitro a fosfomicina. Comentario: Aunque el número de muestra obtenido es pequeño y no extrapolable ampliamente, pretendemos extender el trabajo por un tiempo más para compararlo más adelante. CONCLUSIONES: Se observa que fosfomicina presenta buena actividad in vitro frente a cepas de E. coli aisladas de urocultivo, pudiendo representar una buena alternativa terapéutica a ser utilizada en la población en estudio.

BACKGROUND: Fosfomycin is a broad-spectrum antibiotic used for the treatment of lower urinary tract infections, it is active against gramnegative bacilli and grampositive cocci, as well as against multi-resistant microorganism, in addition to offering a therapeutic alternative for oral administration in a single dose, reaching an effectiveness of 90%. AIM: To study the susceptibility of Escherichia coli to fosfomycin in urinary tract infections, of isolated strains obtained from patients with disabilities. METHODS: It is an observational, descriptive, prospective study in which a total of 273 urine culture samples of patients of both sexes who attended the SENADIS were included, and who at the time of the consultation presented symptoms of urinary tract infection. The urine positive cultures with significant bacterial growth were performed to determine its bacterial identification and the antibiogram according to CLSI recommendations. RESULTS: Of these 273 samples, 91 samples were positive for different uropathogens, with 62/91 (68%) being positive for E. coli. Of these E. coli strains, 59/62 (95%) showed in vitro susceptibility to fosfomycin. Comment: Although the number of samples obtained is small and it cannot be extrapolated, we pretend to extend the work for a while longer to be able to compare it later. CONCLUSION: Fosfomycin has good activity in vitro against E. coli isolated from urine culture in our institution, representing a good alternative to be used in our study population

Emerging issues on Staphylococcus aureus endocarditis and the role in therapy of daptomycin plus fosfomycin.

INTRODUCTION: Methicillin-resistant and -susceptible Staphylococcus aureus (MRSA/MSSA) infections are a major global health-care problem. Bacteremia with S. aureus exhibits high rates of morbidity and mortality and can cause complicated infections such as infective endocarditis (IE). The emerging resistance profile of S. aureus is worrisome, and several international agencies have appealed for new treatment approaches to be developed. AREAS COVERED: Daptomycin presents a rapid bactericidal effect against MRSA and has been considered at least as effective as vancomycin in treating MRSA bacteremia. However, therapy failure is often related to deep-seated infections, e.g. endocarditis, with high bacterial inocula and daptomycin regimens <10 mg/kg/day. Current antibiotic options for treating invasive S. aureus infections have limitations in monotherapy. Daptomycin in combination with other antibiotics, e.g. fosfomycin, may be effective in improving clinical outcomes in patients with MRSA IE. EXPERT OPINION: Exploring therapeutic combinations has shown fosfomycin to have a unique mechanism of action and to be the most effective option in preventing the onset of resistance to and optimizing the efficacy of daptomycin, suggesting the synergistic combination of fosfomycin with daptomycin is a useful alternative treatment option for MSSA or MRSA IE.

Efficacy and safety of intravenous fosfomycin for the treatment of carbapenem-resistant Klebsiella pneumoniae.

The aim of the study was to evaluate clinical and microbiological efficacy and safety of intravenous fosfomycin for the treatment of carbapenem-resistant K. pneumoniae infections. All adult inpatients receiving 48 h of intravenous fosfomycin, alone or combined with other antibiotics were included in the study. Overall favorable clinical response rate was 75.3% among 94 patients. Clinical response rates were 92.3%, 72.2% and 56.0% for urinary tract infections, bacteremia and pneumonia, respectively. Microbiological eradication was achieved in 55 of 86 patients. 30-day mortality was 33.0%. Adverse events were generally mild. Common adverse events were hypokalemia (37.2%) and hypernatremia (22.3%). Intravenous fosfomycin is an effective antibiotic option with a good safety profile for the treatment of carbapenem-resistant K. pneumoniae infections. The most favorable clinical and microbiological responses are obtained in urinary tract infections. The efficacy of the drug in more severe infections, such as pneumonia and bacteremia, is comparable to the literature.

Antibiotic susceptibility and fosfomycin resistance characterization in a cohort of children older than 6 years of age with urinary tract infection / Sensibilidad antibiótica y caracterización de la resistencia a fosfomicina en una cohorte de niños mayores de 6 años con infección urinaria

Fosfomycin tromethamol (FT) was reintroduced as an option for the treatment of low urinary tract infection (UTI) in children. In this study, we described the antibiotic sensitivity and mechanisms of resistance to fosfomycin in isolates from children older than 6 years with UTI. Urine culture and antibiotic susceptibility study were performed. In fosfomycin resistant strains, PCR for fos, blaCTX-M was performed followed by classification by phylogenetic group and sequencetyping. Escherichia coli was the most frequent etiological agent (89.2%). The susceptibility percentages were: fosfomycin 97.9%; amoxicillin-clavulanate 92.7%; cefuroxime and ceftriaxone 99%; nitrofurantoin 94.4%. An E. coli strain (ST69, phylogenetic group D) was resistant to fosfomycin (MIC 256mg/l) and carried the blaCTX-M-14 and fosA3 genes in a 45kb IncN-type plasmid.

La fosfomicina-trometamol (FT) se reintrodujo como una opción para el tratamiento de la infección del tracto urinario (ITU) baja en niños. En este estudio describimos la sensibilidad antibiótica y los mecanismos de resistencia a FT en aislamientos de niños mayores de 6 anos con ITU. Se realizaron urocultivos y estudios de sensibilidad antibiótica. En las cepas resistentes a fosfomicina se realizó la técnica de PCR para fos, blaCTX-M, y su identificación según su grupo filogenéticoy secuenciotipo. Escherichiacoli fue el agente etiológico más frecuente (89,2%). Los porcentajes de sensibilidad fueron: fosfomicina 97,9%; amoxicilina-clavulánico 92,7%; cefurox-ima y ceftriaxona 99%; nitrofurantoína 94,9%. Una cepa de E. coli (ST69, grupo filogenético D) fue resistente a fosfomicina (CIM 256mg/l) y portaba los genes blaCTX-M-14 y fosA3 en un plás-mido de 45 kb del tipo IncN. Este es el primer reporte de E. coli ST69 con blaCTX-M-14/fosA3 de origen humano.

Fosfomycin Vs Ciprofloxacin as Oral Step-Down Treatment for Escherichia coli Febrile Urinary Tract Infections in Women: A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial.

BACKGROUND: We aimed to determine the noninferiority of fosfomycin compared to ciprofloxacin as an oral step-down treatment for Escherichia coli febrile urinary tract infections (fUTIs) in women. METHODS: This was a double-blind, randomized, controlled trial in 15 Dutch hospitals. Adult women who were receiving 2-5 days of empirical intravenous antimicrobials for E. coli fUTI were assigned to step-down treatment with once-daily 3g fosfomycin or twice-daily 0.5g ciprofloxacin for 10 days of total antibiotic treatment. For the primary end point, clinical cure at days 6-10 post-end of treatment (PET), a noninferiority margin of 10% was chosen. The trial was registered on Trialregister.nl (NTR6449). RESULTS: After enrollment of 97 patients between 2017 and 2020, the trial ended prematurely because of the coronavirus disease 2019 pandemic. The primary end point was met in 36 of 48 patients (75.0%) assigned to fosfomycin and 30 of 46 patients (65.2%) assigned to ciprofloxacin (risk difference [RD], 9.6%; 95% confidence interval [CI]: -8.8% to 28.0%). In patients assigned to fosfomycin and ciprofloxacin, microbiological cure at days 6-10 PET occurred in 29 of 37 (78.4%) and 33 of 35 (94.3%; RD, -16.2%; 95% CI: -32.7 to -0.0%). Any gastrointestinal adverse event was reported in 25 of 48 (52.1%) and 14 of 46 (30.4%) patients (RD, 20.8%; 95% CI: 1.6% to 40.0%), respectively. CONCLUSIONS: Fosfomycin is noninferior to ciprofloxacin as oral step-down treatment for fUTI caused by E. coli in women. Fosfomycin use is associated with more gastrointestinal events. CLINICAL TRIAL REGISTRATION: Trial NL6275 (NTR6449).

Role of inorganic phosphate concentrations in in vitro activity of fosfomycin.

OBJECTIVES: The objective of this study was to evaluate the in vitro activity of fosfomycin under different physiological concentrations of inorganic phosphate (Pi). METHODS: The wild-type BW25113 strain, four isogenic mutants (ΔglpT, ΔuhpT, ΔglpT-uhpT, and ΔphoB) and six clinical isolates of Escherichia coli with different fosfomycin susceptibilities were used. EUCAST breakpoints were used. Susceptibility was evaluated by agar dilution using standard Mueller-Hinton agar (Pi concentration of 1 mM similar to human plasma concentration) and supplemented with Pi (13 and 42 mM, minimum and maximum urinary Pi concentrations) and/or glucose-6-phosphate (25 mg/L). Fosfomycin transporter promoter activity was assayed using PglpT::gfpmut2 or PuhpT::gfpmut2 promoter fusions in standard Mueller-Hinton Broth (MHB), supplemented with Pi (13 or 42 mM) ± glucose-6-phosphate. Fosfomycin activity was quantified, estimating fosfomycin EC50 under different Pi concentrations (1, 13 and 42 mM + glucose-6-phosphate) and in time-kill assays using fosfomycin concentrations of 307 (maximum plasma concentration (Cmax)), 1053 and 4415 mg/L (urine Cmax range), using MHB with 28 mM Pi (mean urine Pi concentration) + 25 mg/L glucose-6-phosphate. RESULTS: All the strains showed decreased susceptibility to fosfomycin linked to increased Pi concentrations: 1-4 log2 dilution differences from 1 to 13 mM, and 1-8 log2 dilution differences at 42 mM Pi. Changes in phosphate concentration did not affect the expression of fosfomycin transporters. By increasing Pi concentrations higher fosfomycin EC50 bacterial viability was observed, except against ΔglpT-uhpT. The increase in Pi reduced the bactericidal effect of fosfomycin. DISCUSSION: Pi variations in physiological fluids may reduce fosfomycin activity against E. coli. Elevated Pi concentrations in urine may explain oral fosfomycin failure in non-wild-type but fosfomycin-susceptible E. coli strains.

[The efficiency of combined regimens for the treatment of urinary tract infections in women using the herbal drug Canephron N].

INTRODUCTION: Currently, empiric antibiotic therapy is considered the standard for acute cystitis. However, additional treatment may be required to alleviate the patient's condition and shorten the time to subjective recovery. AIM: To evaluate the efficiency of the combined administration of fosfomycin trometamol and herbal drug Canephron N in comparison with a single oral dose of fosfomycin trometamol in women with uncomplicated bacterial cystitis. MATERIALS AND METHODS: A randomized, comparative, open-label study was carried put between January 2018 and June 2019. The study included 112 women with symptoms of acute uncomplicated cystitis, who were randomized between two groups in a 1:1 ratio. In the main group, patients received a single oral dose of fosfomycin in combination with Canephron N (2 tablets t.i.d. for 2 weeks), while in the control group patients received only a single dose of fosfomycin (3 g). Symptoms were assessed using the Russian version of the Acute Cystitis Symptom Score (ACSS), completed daily for a week. Also, all patients underwent urine analysis on the 1st, 3rd, 5th and 7th days of therapy. The mean time to complete recovery based on the ACSS questionnaire and the time to resolution of pyuria were compared using the Mann-Whitney U test. Comparison of the proportion of patients with complete cure, according to the questionnaire, or with the elimination of pyuria was carried out using the chi-square test. RESULTS: The final analysis included 46 patients who received fosfomycin in combination with Canephron and 47 patients who received fosfomycin as monotherapy. In the group of combination therapy, patient-reported complete recovery (assessed by the ACSS questionnaire) was seen on average after 1 day, while in patients treated with monotherapy, the median time to subjective recovery was 3 days (p=0.00012). A significant difference between the groups in the proportion of patients with complete resolution of symptoms of acute cystitis was observed on days 1, 2, and 3 (p<0.05). The therapy was well tolerated in both groups. The most frequent adverse events were dyspepsia (8.7% in the combination group compared to 6.4% in the control group) and headache (in 4.3% and 6.4% of patients, respectively). CONCLUSION: the combined use of fosfomycin trometamol and the herbal drug Canephron N allows to reduce the duration of symptoms in patients with acute cystitis, thereby accelerating return to their usual lifestyle patterns.

Efficacy and safety of intravenous fosfomycin for the treatment of difficult-to-treat Gram-negative bacterial infections.

We reviewed the efficacy and safety of intravenous (IV) fosfomycin for the treatment of infections caused by Gram-negative bacteria (GNB) with difficult-to-treat resistance (DTR). Data were retrospectively retrieved for all hospitalized patients who received IV fosfomycin for ≥48 h for the treatment of a DTR GNB between September 27, 2017 and January 31, 2020. A total of 30 patients were included, of which 63.3% were males, and the median age was 63.5 years (IQR 46-73). The median Charlson Comorbidity Score was 6 (IQR 3.8-9). The urinary tract (56.7%) was the most frequent site of infection, and the most frequent target organisms were Klebsiella pneumoniae (56.7%), and Escherichia coli (23.3%). The majority (76.%) received IV fosfomycin in combination with other antibacterial agents. Clinical improvement was observed in 22 (73.3%), eradication of baseline pathogens in 20 (66.7%), 30-day all-cause mortality in 7 (23.3%), and documented emergent resistance to fosfomycin in 5 (16.7%) patients. Treatment-related adverse events were infrequent and generally mild or moderate in severity. In conclusion, IV fosfomycin is a potentially efficacious and safe treatment option for the treatment of DTR GNB infections. Randomized trials are urgently required to confirm the utility of IV fosfomycin as monotherapy and in combination with other agents.

Amikacin Combined with Fosfomycin for Treatment of Neonatal Sepsis in the Setting of Highly Prevalent Antimicrobial Resistance.

Antimicrobial resistance (particularly through extended-spectrum ß-lactamase and aminoglycoside-modifying enzyme production) in neonatal sepsis is a global problem, particularly in low- and middle-income countries, with significant mortality rates. High rates of resistance are reported for the current WHO-recommended first-line antibiotic regimen for neonatal sepsis, i.e., ampicillin and gentamicin. We assessed the utility of fosfomycin and amikacin as a potential alternative regimen to be used in settings of increasingly prevalent antimicrobial resistance. The combination was studied in a 16-arm dose-ranged hollow-fiber infection model (HFIM) experiment. The combination of amikacin and fosfomycin enhanced bactericidal activity and prevented the emergence of resistance, compared to monotherapy with either antibiotic. Modeling of the experimental quantitative outputs and data from checkerboard assays indicated synergy. We further assessed the combination regimen at clinically relevant doses in the HFIM with nine Enterobacterales strains with high fosfomycin and amikacin MICs and demonstrated successful kill to sterilization for 6/9 strains. From these data, we propose a novel combination breakpoint threshold for microbiological success for this antimicrobial combination against Enterobacterales strains, i.e., MICF × MICA < 256 (where MICF and MICA are the fosfomycin and amikacin MICs, respectively). Monte Carlo simulations predict that a standard fosfomycin-amikacin neonatal regimen would achieve >99% probability of pharmacodynamic success for strains with MICs below this threshold. We conclude that the combination of fosfomycin with amikacin is a viable regimen for the empirical treatment of neonatal sepsis and is suitable for further clinical assessment in a randomized controlled trial.

Fe2+/H2O2-Strengite method with the enhanced settlement for phosphorus removal and recovery from pharmaceutical effluents.

Phosphorus excessively discharged into the water body is a primary cause of eutrophication, but phosphorus resource is limited and non-renewable. If phosphorus could be recovered from wastewaters, it can not only prevent phosphorus pollution but also achieve the recycling of phosphorus resources. This work proposed a novel strategy, Fe2+/H2O2-strengite method with the enhanced settlement, for phosphorus removal and recovery from pharmaceutical wastewater containing organic phosphorus (OP). In this scheme, OP could be converted into inorganic phosphorus (IP) in the Fe2+/H2O2 oxidation system, and then IP was recovered in the strengite system. This approach possessed the advantages of simple operation, high efficiency and valuable recovery products, besides, reducing the consumption of reagents, and hardly resulting in secondary pollution. Sixty cycles of phosphorus removal and recovery experiments were conducted, in which pH value was 4 and the initial molar ratio of Fe/P was 1.5. This process achieved a satisfactory and steady phosphorus removal performance, with soluble phosphate and total phosphorus removal efficiencies of 95.3% ± 1.7% and 91.4% ± 2.5%, respectively, and phosphorus was recovered. Possible mechanisms involved: the formation of amorphous strengite (FePO4·2H2O) analogue, the adsorption of hydrous ferric oxide (HFO) to phosphorus, and the flocculation of ferric salts. Besides, the presence of quartz as carriers could enhance the settling efficiency of products. Also, via various characterizations, products included amorphous strengite analogue and goethite mixed with phosphorus. This work provided an effective method to reduce OP pollution and recover phosphorus, and supplied thoughts for the treatment of refractory pollutants and the recycling of limited resources.

Optimal empiric treatment for KPC-2-producing Klebsiella pneumoniae infections in critically ill patients with normal or decreased renal function using Monte Carlo simulation.

BACKGROUND: Limited clinical studies describe the pharmacodynamics of fosfomycin (FOS), tigecycline (TGC) and colistin methanesulfonate (CMS) in combination against KPC-producing Klebsiella pneumoniae (KPC-Kp). Population pharmacokinetic models were used in our study. Monte Carlo simulation was conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) of each agent alone and in combination against KPC-Kp in patients with normal or decreased renal function. RESULTS: The simulated regimen of FOS 6 g q8h reached ≥90% PTA against a MIC of 64 mg/L in patients with normal renal function. For patients with renal impairment, FOS 4 g q8h could provide sufficient antimicrobial coverage against a MIC of 128 mg/L. And increasing the daily dose could result to the cut-off value to 256 mg/L in decreased renal function. For TGC, conventional dosing regimens failed to reach 90% PTA against a MIC of 2 mg/L. Higher loading and daily doses (TGC 200/400 mg loading doses followed by 100 mg q12h/200 mg q24h) were needed. For CMS, none achieved 90% PTA against a MIC of 2 mg/L in normal renal function. Against KPC-Kp, the regimens of 200/400 mg loading dose followed by 100 q12h /200 mg q24h achieved > 80% CFRs regardless of renal function, followed by CMS 9 million IU loading dose followed by 4.5/3 million IU q12h in combination with FOS 8 g q8h (CFR 75-91%). CONCLUSIONS: The use of a loading dose and high daily dose of TGC and CMS in combination with FOS can provide sufficient antimicrobial coverage against critically ill patients infected with KPC-Kp.

Investigation of New Inhibitors of UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA) by Virtual Screening with Antibacterial Assessment.

BACKGROUND: Considering the interesting role in the peptidoglycan biosynthesis pathway, the enzyme UDP-N-acetylglucosamine enolpyruvyl transferase is an attractive target to develop new antibacterial agents. It catalyzes the first key step of this pathway and its inhibition leads to bacterial cell death. Fosfomycin is known as the natural inhibitor of MurA. OBJECTIVE: The study aimed to introduce new inhibitors of MurA by virtual screening of different chemical compounds libraries, and test the best scored "virtual hits" against three pathogenic bacteria: Escherichia coli, Bacillus subtilis and Staphylococcus aureus. METHODS: A virtual screening of the structural analogues of fosfomycin downloaded from the Pub- Chem database was performed. Moreover, French National Chemical Library and ZINC database were also utilized to identify new structures different from fosfomycin. FlexX was the software used for this study. The antibacterial testing was divided into two methods: disk diffusion and broth dilution. RESULTS: A set of virtual hits was found to have better energy score than that of fosfomycin, seven of them were tested in vitro. In addition, the disk diffusion method explored four compounds that exhibited antibacterial activity: CID-21680357 (fosfomycin analogue), AB-00005001, ZINC04658565, and ZINC901335. The testing was continued by broth dilution method for both compounds CID-21680357 and ZINC901335 to determine their minimum inhibitory concentrations, and ZINC901335 had the best value with 457µg/ml against Staphylococcus aureus. CONCLUSION: Four compounds were found and proven in silico and in vitro to have antibacterial activity, namely CID-21680357, AB-00005001, ZINC04658565, and ZINC901335.

Pharmacodynamic Analysis of Meropenem and Fosfomycin Combination Against Carbapenem-Resistant Acinetobacter baumannii in Patients with Normal Renal Clearance: Can It Be a Treatment Option?

Background and Objective: Combination therapy may be a treatment option against carbapenem-resistant Acinetobacter baumannii (CR-AB) infections. In this study, we explored the utility of fosfomycin in combination with meropenem (FOS/MEM) against CR-AB isolates. Materials and Methods: Screening of synergistic activity of FOS/MEM was performed using the checkerboard assay. A pharmacokinetic/pharmacodynamic analysis was performed for various FOS/MEM regimens using Monte Carlo simulations. Results: The minimum inhibitory concentration (MIC) required to inhibit the growth of 50% of the isolates (MIC50) and MIC required to inhibit the growth of 90% of the isolates (MIC90) of FOS and MEM were reduced fourfold and twofold, respectively. The combination was synergistic against 14/50 isolates. No antagonism was observed. Sixteen out of fifty isolates had MEM MICs of ≤8 mg/L when subjected to combination therapy, compared to none with monotherapy. Forty-one out of 50 isolates had FOS MICs of ≤128 mg/L when subjected to combination therapy, compared to 17/50 isolates with monotherapy. The cumulative fraction response for MEM and FOS improved from 0% to 40% and 40% to 80%, with combination therapy, respectively. Conclusions: Addition of MEM improved the in vitro activity of FOS against the CR-AB isolates. FOS/MEM could be a plausible option to treat CR-AB for a small fraction of isolates.

Evaluation of Drugs with Therapeutic Potential for Susceptibility of Neisseria Gonorrhoeae Isolates from 8 Provinces in China from 2018.

PURPOSE: The study aimed to evaluate meropenem, fosfomycin, berberine hydrochloride, and doxycycline minimum inhibitory concentrations (MICs) of Neisseria gonorrhoeae collected from eight provinces in China in 2018. METHODS: The MICs of 540 Neisseria gonorrhoeae isolates (451 isolates selected randomly and 89 isolates selected with preference) were determined to meropenem, fosfomycin, berberine hydrochloride, and doxycycline using the agar dilution method, and the MICs of ceftriaxone and azithromycin were detected for comparison. RESULTS: Among 451 randomly selected isolates, the MIC90 was 0.06 mg/L for meropenem, 64 mg/L for fosfomycin, 64 mg/L for berberine hydrochloride, and 16 mg/L for doxycycline. All isolates showed the MIC ≤ 0.125 mg/L to meropenem, 13 isolates (2.9%) showed MIC > 64 mg/L to fosfomycin, 8 isolates (1.8%) demonstrated MIC > 64 mg/L to berberine hydrochloride, and 271 isolates (60.1%) demonstrated MIC > 1 mg/L to doxycycline. Comparing all 540 tested isolates, a correlation of r = 0.50 (P < 0.001) between meropenem and ceftriaxone MIC was observed. In 24 ceftriaxone-decreased susceptibility isolates, all isolates showed an MIC ≤ 0.125 mg/L for meropenem, 1 isolate (4.2%) showed an MIC > 64 mg/L for fosfomycin, 1 isolate (4.2%) showed an MIC > 64 mg/L for berberine hydrochloride, and 13 isolates (54.2%) showed an MIC > 1 mg/L for doxycycline. In 87 azithromycin resistant isolates, all isolates showed an MIC ≤ 0.125 mg/L for meropenem, 2 isolates (2.3%) showed an MIC > 64 mg/L for fosfomycin, 4 isolates (4.6%) showed an MIC > 64 mg/L for berberine hydrochloride, and 64 isolates (73.6%) showed an MIC > 1 mg/L for doxycycline. CONCLUSION: The in vitro results suggest that meropenem might be a promising treatment option for resistant gonococcal infections, while the effects of fosfomycin and berberine hydrochloride should be further evaluated as potential therapeutic agents. The effectiveness of these drugs in animal experiments and clinical use may need further study.

Imipenem plus Fosfomycin as Salvage Therapy for Vertebral Osteomyelitis.

We applied combination antibiotic therapy to treat vertebral osteomyelitis and a psoas abscess caused by glycopeptide-intermediate (MIC, 2 µg/ml) and daptomycin-nonsusceptible (>2 µg/ml) methicillin-resistant Staphylococcus aureus The Etest synergy test showed the largest synergistic effects for imipenem/cilastatin and fosfomycin. Whole-gene sequencing showed amino acid changes in SA0802, SA1193 (mprF), and SA1531 (ald). Four weeks of combination treatment using imipenem/cilastatin (1.5 g per day) and fosfomycin (4.0 g per day) resulted in clinical improvement.

Acute Cystitis Symptom Score questionnaire for measuring patient-reported outcomes in women with acute uncomplicated cystitis: Clinical validation as part of a phase III trial comparing antibiotic and nonantibiotic therapy.

PURPOSE: The Acute Cystitis Symptom Score (ACSS) used in a clinical trial comparing the phytodrug Canephron®N (BNO 1045) with an antibacterial agent (fosfomycin trometamol [FT]) in the treatment of acute uncomplicated cystitis (AC) in women was evaluated as a patient-reported outcome measure in a post hoc analysis. MATERIALS AND METHODS: This double-blind, randomized, multicenter, phase III noninferiority trial was performed in 51 centers in Europe. The ACSS questionnaire was used to assess severity and course of symptoms. RESULTS: The post hoc analysis included 325 patients treated with BNO 1045 and 332 patients treated with FT (total of 657 patients). The mean sum-scores of the ACSS-typical domain were comparable between groups on day 1 (BNO 1045: 10.2; FT: 10.1), and then decreased on day 4 (BNO 1045: 5.1; FT: 4.5), at end of treatment on day 8 (BNO 1045: 2.1; FT: 2.1), and at late follow-up on day 38 (BNO 1045: 0.8; FT: 0.9). Predefined thresholds using the scoring system of the ACSS could be established and validated to define "clinical cure." CONCLUSIONS: Evaluating not only antibacterial but also nonantibacterial agents indicated for the treatment of AC in women, clinical criteria for diagnostics, and measures of patient-reported outcomes are more important as main objectives than microbiological criteria. In this post hoc evaluation, we showed that the ACSS questionnaire, validated in several languages, has the potential to be used as a suitable instrument for diagnostics and patient-reported outcomes in well-designed, international, clinical studies investigating different treatment modalities of uncomplicated urinary tract infections.

Synergistic Effects from Combination of Cryptotanshinone and Fosfomycin Against Fosfomycin-Susceptible and Fosfomycin-Resistant Staphylococcus aureus.

PURPOSE: Fosfomycin is now widely used to treat methicillin-resistant S. aureus due to its unique antibacterial activity. However, fosfomycin-resistant S. aureus has rapidly emerged, it is urgent to find new treatments to eliminate fosfomycin-resistant S. aureus infection. The purpose of this study was to analyze the activity of cryptanshinone, a traditional Chinese medicine monomer, in combination with fosfomycin against fosfomycin-sensitive S. aureus (FSSA) and fosfomycin-resistant S. aureus (FRSA). METHODS: The MICs of fosfomycin and/or cryptanshinone were determined by agar dilution assay and checkerboard microdilution assay. Furthermore, synergistic effects from fosfomycin and/or cryptanshinone were analyzed by the time-kill assay in vitro. RESULTS: The combination of fosfomycin and cryptotanshinone had a synergistic effect on most (71.43%) of the FRSA and had a partial (28.57%) synergistic effect on a small part. In addition, time sterilization curve verified synergistic activity between cryptanshinone and fosfomycin against FSSA and FRSA, especially when fosfomycin was added for a second time. CONCLUSION: These data suggest that cryptanshinone combined with fosfomycin could be a novel treatment for FRSA and provide a new direction for the treatment of bacterial infections in the future.

Impact of reflex fosfomycin susceptibility testing on the utilization of carbapenems for definitive extended-spectrum ß-lactamase Escherichia coli urinary tract infection treatment.

PURPOSE: A protocol was started within a large health system to automatically test all confirmed extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli urine isolates for susceptibility to fosfomycin, an antibiotic not routinely included in such testing in most institutions. This study assessed the effectiveness of the protocol at reducing carbapenem use for the definitive treatment of ESBL E. coli urinary tract infection (UTI) through several endpoints. METHODS: Eighty and 99 patients were compared pre- and postintervention, respectively. The primary outcome was the proportion of patients who received definitive carbapenem therapy. Key secondary outcomes included median total carbapenem days of therapy (DOT), discharge on intravenous UTI antibiotics, and median total antibiotic DOT. RESULTS: Preprotocol vs postprotocol definitive carbapenem use was seen in 59 of 80 patients (73.8%) and 71 of 99 patients (71.7%) (95% confidence interval [CI] for difference, -11.1% to 15.1%; P = 0.76). The rates of step-down to oral agents pre- and postintervention were 15 of 59 (25.4%) and 35 of 71 (49.3%) (P = 0.004). Median carbapenem DOT in those receiving carbapenems decreased from 8 to 4 days (95% CI, -5 to -1 days; P = 0.001). Median total DOT decreased from 10 to 8 days (95% CI, -3 to -1 days; P = 0.002). CONCLUSION: Implementation of a laboratory policy to automatically test ESBL positive E. coli for fosfomycin susceptibility did not reduce the percentage of patients receiving at least 1 dose of carbapenem treatment. It did result in a larger percentage reduction in step-down use of intravenous antibiotics for UTI prior to discharge, reduction in carbapenem DOT, and reduction in total antibiotic DOT.