Assessment of three antibiotic combination regimens against Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries.

Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs. The five most prevalent bacterial isolates in the NeoOBS study (NCT03721302) are Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens and Enterobacter cloacae complex. Among these isolates, high levels of ESBL and carbapenemase encoding genes are detected along with resistance to ampicillin, gentamicin and cefotaxime, the current WHO recommended empiric regimens. The three new combinations show excellent in vitro activity against ESBL-producing K. pneumoniae and E. coli isolates. Our data should further inform and support the clinical evaluation of these three antibiotic combinations for the treatment of neonatal sepsis in areas with high rates of multidrug-resistant Gram-negative bacteria.

Pharmacokinetics/pharmacodynamics cut-off determination for fosfomycin using Monte Carlo simulation in healthy horses.

Fosfomycin (FOM) is an approved veterinary medicinal product for large animals in Japan, but Clinical breakpoint (CBP) for antimicrobial susceptibility test (AST) is not defined for animals. This study aimed at conducting a pharmacokinetics/pharmacodynamics (PK/PD) analysis to determine the PK/PD cutoff for the CBP in horses. Drug concentrations following single intravenous administration (IV) of 20 mg/kg body weight (BW) FOM in nine horses were measured using liquid chromatography/mass spectrometry. The data were modelled using a nonlinear mixed-effects model, followed by Monte Carlo simulations. A 90% probability of target attainment for a PK/PD target of the ratio of Area Under the free plasma concentration-time curve divided by the minimal inhibitory concentration (MIC) >24 hr was set as PK/PD cut-off. The PK/PD cutoff for FOM 20 mg/kg BW q12 hr IV was estimated with the MIC value of ≤16.0 mg/L, and this regimen was considered effective against E. coli (MIC90; 16.0 mg/L) in healthy horses based on the MIC90 values of the wild population. Owing to the relevance of FOM to human health, veterinarians should use q 12 hr FOM 20 mg /kg against E. coli infections with an MIC <16 µg/mL, as suggested by our PK/PD cutoff after AST.

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.

A cost-minimization analysis of treatment options for postmenopausal women with dysuria.

BACKGROUND: Empiric therapy for urinary tract infection is difficult in postmenopausal women because of the higher rates of confounding lower urinary tract symptoms and differential resistance profiles of uropathogens in this population. OBJECTIVE: The objective of the study was to determine the least costly strategy for treatment of postmenopausal women with the primary complaint of dysuria. STUDY DESIGN: We performed a cost minimization analysis modeling the following clinical options: (1) empiric antibiotic therapy followed by urine culture, (2) urinalysis with empiric antibiotic therapy only if positive nitrites and leukocyte esterase, or (3) waiting for culture prior to initiating antibiotics. For all strategies we included nitrofurantoin, trimethoprim/sulfamethoxazole, fosfomycin, ciprofloxacin, or cephalexin. Pathogens included Escherichia coli, Enterococcus faecalis, Klebsiella pneumonaie, or Proteus mirabalis. Pathogens, resistance, treatment success, and medication side effects were specific to postmenopausal women. RESULTS: Cost minimization modeling with TreeAge Pro assumed 73.4% of urinary tract infections were caused by Escherichia coli with 24.4% resistance to nitrofurantoin, trimethoprim/sulfamethoxazole. With our assumptions, empiric antibiotics with nitrofurantoin, trimethoprim/sulfamethoxazole was the least costly approach ($89.64/patient), followed by waiting for urine culture ($97.04/patient). Except for empiric antibiotics with fosfomcyin, empiric antibiotics was always less costly than using urinalysis to discriminate antibiotic use. This is due to the cost of urinalysis ($38.23), high rate of both urinary tract infection (91%), and positive urinalysis (69.3%) with dysuria in postmenopausal women and resultant high rate of antibiotic use with or without urinalysis. Options with fosfomycin were the most expensive because of the highest drug costs ($98/dose), and tornado analyses showed fosfomycin cost was the most impactful variable for model outcomes. Sensitivity analyses showed empiric fosfomycin became the least costly option if drug costs were $25.80, a price still more costly than almost all modeled baseline drug costs. This outcome was largely predicated on low resistance to fosfomycin. Conversely, ciprofloxacin was never the least costly option because of higher resistance and side effect cost, even if the drug cost was $0. We modeled 91% positive urine culture rate in postmenopausal women with dysuria; waiting for the urine culture prior to treatment would be the least costly strategy in a population with a predicted positive culture rate of <65%. CONCLUSION: The least costly strategy was empiric antibiotics with nitrofurantoin and trimethoprim/sulfamethoxazole, followed by waiting on culture results. Local resistance patterns will have an impact on cost minimization strategies. Empiric fosfomycin would be least costly with reduced drug costs, even at a level at which drug costs were higher than almost all other antibiotics. In a population with high posttest probability of positive urine culture, urinalysis adds unnecessary cost. Antibiotic stewardship programs should continue efforts to decrease fluoroquinolone use because of high resistance, side effects, and increased cost.

Population pharmacokinetics and pharmacodynamics of fosfomycin in non-critically ill patients with bacteremic urinary infection caused by multidrug-resistant Escherichia coli.

OBJECTIVES: To describe the population pharmacokinetics of fosfomycin for patients with bacteraemic urinary tract infection (BUTI). The analysis identified optimal regimens on the basis of pharmacodynamic targets and assessed the adequacy of Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) susceptibility breakpoints for Escherichia coli. METHODS: Data of 16 patients with BUTI caused by multidrug-resistant E. coli (FOREST clinical trial) received intravenous fosfomycin (4 g every 6 hours) were analysed. A population pharmacokinetic analysis was performed, and Monte Carlo simulations were undertaken using 4 g every 6 hours and 8 g every 8 hours. The probability of pharmacodynamic target attainment was assessed using pharmacodynamic targets for E. coli for static effect, 1-log drop in bacterial burden and resistance suppression. RESULTS: Sixty-four plasma samples were collected over a single dosing interval (day 2 or 3 after starting fosfomycin treatment). Fosfomycin concentrations were highly variable. Pharmacodynamic target attainment analysis showed mild improvement by increasing fosfomycin dosing (4 g every 6 hours vs. every 8 hours). These dosages showed success for decreasing 1-log bacterial burden in 89% to 96% (EUCAST breakpoints) and 33% to 54% (CLSI breakpoints) of patients, but they were unable to reach bacterial resistance suppression targets. CONCLUSIONS: Fosfomycin concentrations are highly variable-a fact partially explained by renal impairment. The present work supports the use of 4 g every 6 hours as an effective regimen for the treatment of non-critically ill patients with BUTI caused by multidrug-resistant E. coli, as higher dosages might increase toxicity but may not significantly increase efficacy. The current information may suggest that fosfomycin susceptibility breakpoints need to be reappraised.

Evaluation of perioperative prophylaxis with fosfomycin tromethamine in ureteroscopic stone removal: an investigator-driven prospective, multicenter, randomized, controlled study.

PURPOSE: To compare efficacy, safety, and cost-effectiveness of fosfomycin tromethamine with other standard-of-care antibiotics in patients undergoing ureteroscopic lithotripsy. METHODS: This study was a prospective, multicenter, randomized, controlled trial. Eligible patients scheduled for ureteroscopic lithotripsy were randomly assigned to receive either fosfomycin (fosfomycin group, N = 101 patients) or standard-of-care antibiotic therapy as prophylaxis (control group, N = 115 patients). The incidence of infectious complications and adverse events was analyzed between the two groups, as well as the cost-benefit analysis. RESULTS: The incidence of infections following lithotripsy was 3.0% in the fosfomycin group and 6.1% in the control group (p > 0.05). Only asymptomatic bacteriuria was reported in fosfomycin group. In the control group was reported asymptomatic bacteriuria (3.5%), fever (0.9%), bacteremia (0.9%), and genitourinary infection (0.9%). The rate of adverse events was very low, with no adverse event reported in the fosfomycin group and only one in the control group (forearm phlebitis). The average cost per patient of antibiotic therapy with fosfomycin was 151.45 ± 8.62 yuan (22.7 ± 1.3 USD), significantly lower compared to the average cost per patient of antibiotics used in the control group 305.10 ± 245.95 yuan (45.7 ± 36.9 USD; p < 0.001). CONCLUSIONS: Two oral doses of 3 g fosfomycin tromethamine showed good efficacy and safety and low cost in perioperative prophylaxis of infections following ureteroscopic stone removal.

Assessment of Fosfomycin for Complicated or Multidrug-Resistant Urinary Tract Infections: Patient Characteristics and Outcomes.

BACKGROUND: Bacterial resistance among uropathogens is on the rise and has led to a decreased effectiveness of oral therapies. Fosfomycin tromethamine (fosfomycin) is indicated for uncomplicated urinary tract infections (UTIs) and displays in vitro activity against multidrug-resistant (MDR) isolates; however, clinical data assessing fosfomycin for the treatment of complicated or MDR UTIs are limited. METHODS: We conducted a retrospective evaluation of patients who received ≥1 dose of fosfomycin between January 2009 and September 2015 for treatment of a UTI. Patients were included if they had a positive urine culture and documented signs/symptoms of a UTI. RESULTS: Fifty-seven patients were included; 44 (77.2%) had complicated UTIs, 36 (63.2%) had MDR UTIs, and a total of 23 (40.4%) patients had a UTI that was both complicated and MDR. The majority of patients were female (66.7%) and elderly (median age, 79 years). Overall, the most common pathogens isolated were Escherichia coli (n = 28), Enterococcus spp. (n = 22), and Pseudomonas aeruginosa (n = 8). Twenty-eight patients (49.1%) were clinically evaluable; the preponderance achieved clinical success (96.4%). Fifteen out of 20 (75%) patients with repeat urine cultures had a microbiological cure. CONCLUSIONS: This retrospective study adds to the limited literature exploring alternative therapies for complicated and MDR UTIs with results providing additional evidence that fosfomycin may be an effective oral option.

Fosfomicina: tratamiento de enfermedades por enterobacterias multiresistentes / Fosfomycin: treatment of enterobacterial diseases multi-resistant

CONTEXTO: Eficacia: Existe abundante evidencia que sustenta la eficacia antimicrobiana de fosfomicina. Ha demostrado ser activa frente a cepas multi-resistentes tanto de E coli como de KPC,y, em mucha menor medida, de P aeruginosa. No existe evidencia suficiente de su eficacia clínica. SEGURIDAD: El tratamiento con fosfomicina se ha asociado a un riesgo bajo de efectos adversos, que habitualmente son bien tolerados. COSTO: Si bien el costo de la fosfomicina en pacientes con efermedades por enterobactérias multiresistentes es significativo($ 4704 / semana), estaria justificado por la complejidad de la enfermedad del paciente. PROPUESTA: Por todo lo expuesto, la propuesta de los autores de este informe es que se incorpore fosfomicina disódica (EV) al formulario terapéutico del hospital. Asimismo, proponemos que se restrinja su uso a los casos de infecciones por gérmenes multi-resistentes con sensibilidad documentada a fosfomicina. CONCLUSIONES: Actualmente hay un incremento de la incidencia de infecciones producidas por enterobactérias resistentes a los antibióticos a los que anteriormente eran susceptibles. Entre ellas encontramos Klebsiella pneumoniae productora de carbapenemeasas (KPC) y Escherichia coli y Pseudomona aeruginosa productoras de BLEE. Habitualmente estos microorganismos son aislados en pacientes con infecciones severas que se encuentran en salas de cuidados intensivos (UTI). Fosfomicina ha demostrado ser segura en pacientes adultos. Su eficácia antibacteriana ha sido demostrada. Hay consenso en que debe utilizarse siempre em combinación con otro antibiótico para evitar la emergencia de resistencia. Existen pocos datos con respecto a la eficacia clínica. Sin embargo, los datos epidemiológicos, el contexto de emergencia de cepas multirresistentes, y la penetración documentada en distintos tejidos, sugiere que fosfomicina es una buena alternativa en infecciones por gérmenes multi-resistentes, en especial KPC.

Carbapenem versus fosfomycin tromethanol in the treatment of extended-spectrum beta-lactamase-producing Escherichia coli-related complicated lower urinary tract infection.

The aim of this observational prospective study was to compare the effect of fosfomycin tromethanol (FT) and carbapenems (meropenem or imipenem cilastatin) in the treatment of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli-related complicated lower urinary tract infection (CLUTI). Inclusion criteria were: patients who were aged >18 yr with dysuria or problems with frequency or urgency in passing urine; those with >20 leukocytes/mm³ in urine microscopy and culture-proven ESBL-producing carbapenem or FT-sensitive E. coli in the urine (>105 cfu/mm³); no leukocytosis or fever; and who were treated with ft (oral 3 g sachet x 1 every other night, three times) or carbapenems between march 2005 and January 2006 in our outpatient clinic and hospital. A total of 47 CLUTI attacks in 47 patients (27 FT group, 20 carbapenem group) were observed prospectively. Clinical and microbiological success in the carbapenem and ft groups was similar (19/20 vs 21/27 and 16/20 vs 16/27 p>0.05). Drug acquisition costs were significantly lower in the FT group (p<0.001). Although it is not a randomized controlled study, these data show that ft may be a suitable, effective and cheap alternative in the treatment of ESBL-producing E. coli-related CLUTI.

Assessing the emergence of resistance: the absence of biological cost in vivo may compromise fosfomycin treatments for P. aeruginosa infections.

BACKGROUND: Fosfomycin is a cell wall inhibitor used efficiently to treat uncomplicated urinary tract and gastrointestinal infections. A very convenient feature of fosfomycin, among others, is that although the expected frequency of resistant mutants is high, the biological cost associated with mutation impedes an effective growth rate, and bacteria cannot offset the obstacles posed by host defenses or compete with sensitive bacteria. Due to the current scarcity of new antibiotics, fosfomycin has been proposed as an alternative treatment for other infections caused by a wide variety of bacteria, particularly Pseudomonas aeruginosa. However, whether fosfomycin resistance in P. aeruginosa provides a fitness cost still remains unknown. PRINCIPAL FINDINGS: We herein present experimental evidence to show that fosfomycin resistance cannot only emerge easily during treatment, but that it is also cost-free for P. aeruginosa. We also tested if, as has been reported for other species such as Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis, fosfomycin resistant strains are somewhat compromised in their virulence. As concerns colonization, persistence, lung damage, and lethality, we found no differences between the fosfomycin resistant mutant and its sensitive parental strain. The probability of acquisition in vitro of resistance to the combination of fosfomycin with other antibiotics (tobramycin and imipenem) has also been studied. While the combination of fosfomycin with tobramycin makes improbable the emergence of resistance to both antibiotics when administered together, the combination of fosfomycin plus imipenem does not avoid the appearance of mutants resistant to both antibiotics. CONCLUSIONS: We have reached the conclusion that the use of fosfomycin for P. aeruginosa infections, even in combined therapy, might not be as promising as expected. This study should encourage the scientific community to assess the in vivo cost of resistance for specific antibiotic-bacterial species combinations, and therefore avoid reaching universal conclusions from single model organisms.

[Impact of regional guidelines on the management of urinary tract infections with antibiotics]. / Impact d'un guide régional pour la prise en charge des infections urinaires sur les pratiques d'antibiothérapies.

AIM AND METHOD: We assessed the impact of a committed guideline at the end of the first quarter 2008 on the management of urinary tract infection (UTI) with antibiotic prescription (fluoroquinolone, fosfomycin, and nitrofurantoin), by analysing reimbursement data for ambulatory care provided by the regional health insurance agency. RESULTS: During the survey, we observed a 13.2% decrease of norfloxacin prescriptions between the first quarter 2008 and the first quarter 2009. The (fosfomycin+nitrofurantoin)/norfloxacin ratio increased between the third quarter 2007 and the first quarter 2009 from 0.55 to 0.72 and from 0.82 to 1.13 for general practitioners and hospital physicians respectively. The global number of patients treated with these antibiotics remained stable during the period. The number of fluoroquinolone prescription was stable between the first quarter 2008 and the first quarter 2009 with 28,427 DDD and 28,363 DDD, respectively; while the number of single dose rise in the same time from 151 DDD to 427.5 DDD, respectively. DISCUSSION: The three messages which seem to be essential for an optimal use of fluoroquinolones in UTIs are: no treatment for bacterial colonisation (asymptomatic bacteriuria) except for specific cases, no indication for fluoroquinolones in non-complicated acute cystitis and for elderly women, UTI is complicated only if it occurs in women with co-morbidities regardless of age. CONCLUSION: Our indicators suggest that our guideline had an impact on the prescription of fluoroquinolones for uncomplicated acute cystitis.

Single-dose treatment of acute cystitis with fosfomycin tromethamine.

OBJECTIVE: To review the clinical pharmacology of fosfomycin tromethamine, a new antimicrobial agent for the treatment of uncomplicated lower urinary tract infections (UTIs). DATA SOURCE: Publications in English on fosfomycin, fosfomycin tromethamine, and fosfomycin trometamol (MEDLINE, 1970-1997), as well as unpublished studies submitted to the Food and Drug Administration (FDA), were reviewed. STUDY SELECTION: Comparative, randomized, controlled studies were used to analyze the efficacy and safety of fosfomycin tromethamine. DATA SYNTHESIS: Fosfomycin tromethamine is an oral antimicrobial indicated for the treatment of uncomplicated lower UTIs. This agent is active in the urine against common uropathogens that are associated with cystitis in women, including organisms resistant to other antibiotics. A single dose of fosfomycin tromethamine is well absorbed and produces therapeutic concentrations in the urine for 2-4 days. Comparative clinical trials suggest that a single dose of fosfomycin tromethamine 3.0 g is as clinically effective as 7- to 10-day treatment regimens of standard agents used to treat UTIs, such as nitrofurantoin, norfloxacin, and trimethoprim/sulfamethoxazole. Fosfomycin tromethamine is well tolerated and appears safe to use during pregnancy. CONCLUSIONS: Fosfomycin tromethamine is the only antimicrobial to be approved by the FDA for single-dose therapy in women with acute cystitis. It is as effective and safe as multidose comparators and appears safe to use during pregnancy. The acquisition cost of this new drug will need to be weighed against the improved compliance and convenience associated with its use in the treatment of uncomplicated UTIs.

Single dose fosfomycin trometamol versus multiple dose norfloxacin over three days for uncomplicated UTI in general practice.

The aim of this study was to carry out a small-scale bacteriological comparison between a standard therapy with norfloxacin 400 mg twice daily, and fosfomycin trometamol (3 g) in single dose in uncomplicated urinary tract infections (UTI) in women. Only patients with UTI with cultures showing a bacterial count of 10(5) or more bacteria/ml were included in the study (n = 32; ages 16-75 years). After one week sterile cultures were obtained in 14 of 16 cases in the fosfomycin trometamol group, and in 14 of 16 cases in the norfloxacin group. After one month eradication was confirmed in 13 of 16 patients in the fosfomycin trometamol group, and in nine of 16 patients in the norfloxacin group. Recurrence was seen in one case in the fosfomycin trometamol group, and in five cases in the norfloxacin group. The reinfection and persistence rates were identical (1/16) in both groups. The main clinical symptoms disappeared very rapidly after initiating treatment, and the correlation with the bacteriological data after one week was excellent. Both drugs were well tolerated and the compliance for fosfomycin trometamol was 100%.