scholarly journals 1122. Effect of Aluminum Hydroxide/Magnesium Hydroxide/Simethicone and Omeprazole on the Pharmacokinetics of Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) in Healthy Adult Subjects

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S652-S653
Author(s):  
Vipul K Gupta ◽  
Gina Patel ◽  
Leanne Gasink ◽  
Floni Bajraktari ◽  
Yang Lei ◽  
...  
Keyword(s):  
Single Dose ◽  
Oral Dose ◽  
Single Oral Dose ◽  
Aluminum Hydroxide ◽  
Magnesium Hydroxide ◽  
Whole Blood ◽  
Drug Product ◽  
Geometric Mean ◽  
Tebipenem Pivoxil ◽  
Tract Infections

Abstract Background Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral prodrug that is converted to tebipenem (TBP), the active moiety being developed for treating complication urinary tract infections. Antacids and proton pump inhibitors are known to change gastric pH after administration, which could affect the absorption of oral medications. This study evaluated the effect of a single dose of aluminum hydroxide/magnesium hydroxide/simethicone and the effect of multiple doses of omeprazole on the PK of TBP, following a single dose of TBP-PI-HBr. Methods This was an open-label, 3-period, fixed sequence drug-drug interaction study. On Day 1, Period 1, subjects received a single oral dose of TBP-PI-HBr 600 mg (2 x 300 mg tablets) at Hour 0. On Day 1, Period 2, subjects received a single oral 20 mL dose of aluminum hydroxide 800 mg/magnesium hydroxide 800 mg/simethicone 80 mg suspension per 10 mL (Maalox® Advanced Maximum Strength oral suspension) with a single oral dose of TBP-PI-HBr 600 mg at Hour 0. In Period 3, on Days 1 through 5, subjects received a single oral dose of omeprazole 40 mg (Prilosec®) once daily (QD), at Hour -2. On Day 5, a single oral dose of 600 mg TBP-PI-HBr was administered at Hour 0. Whole blood sampling for TBP PK occurred pre-dose and up to 24 hours post dose. Whole blood samples were assayed for TBP by liquid chromatography-tandem mass spectrometry. Results Twenty subject were enrolled and completed the study. Geometric mean ratios for AUC indicated mean TBP exposure (AUC) was approximately 11% lower and mean Cmax was 22% lower for TBP-PI-HBr combined with aluminum hydroxide/magnesium hydroxide/simethicone vs. TBP-PI-HBr alone (Figure). Similarly, geometric mean ratios for AUC indicated mean TBP exposure (AUC) was approximately 11% lower and mean Cmax was 43% lower for TBP-PI-HBr in combination with omeprazole vs. TBP-PI-HBr alone. Because the PK/PD driver for TBP efficacy is AUC dependent, concomitant administration is not expected to impact the efficacy of oral TBP-PI-HBr. Figure 1. Arithmetic mean plasma TBP concentrations following a 600 mg dose of clinical study drug product (A1 and A2) and registrational drug product (B) – PK population. Conclusion Administration of TBP-PI-HBr combined with aluminum hydroxide/magnesium hydroxide/simethicone or omeprazole QD had no meaningful effect on plasma TBP exposure; Cmax decreased with both agents. Co-administration was generally safe and well tolerated. Disclosures Vipul K. Gupta, Ph.D., Spero Therapeutics (Employee, Shareholder) Gina Patel, PhD, Spero Therapeutics, Inc. (Consultant) Leanne Gasink, MD, Spero Therapeutics, Inc. (Consultant) Floni Bajraktari, MSc, Spero Therapeutics, Inc. (Employee) Yang Lei, PhD, Spero Therapeutics, Inc. (Employee) Akash Jain, PhD, Spero Therapeutics, Inc. (Employee) Praveen Srivastava, MS, BS, Spero Therapeutics, Inc. (Employee) Angela Talley, MD, Spero Therapeutics, Inc. (Employee)

scholarly journals 1120. Absorption, Metabolism, and Excretion of [14C]-Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) Following a Single Oral Dose in Healthy Male Subjects

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S652-S652
Author(s):  
Vipul K Gupta ◽  
Gary Maier ◽  
Leanne Gasink ◽  
Amanda Ek ◽  
Mary Fudeman ◽  
...  
Keyword(s):  
Oral Dose ◽  
Mass Balance ◽  
Single Oral Dose ◽  
Whole Blood ◽  
Metabolite Profiling ◽  
Geometric Mean ◽  
Total Radioactivity ◽  
Single Dose Study ◽  
Tebipenem Pivoxil ◽  
Tract Infections

Abstract Background Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral prodrug that is converted to tebipenem (TBP), the active moiety, with activity against multidrug-resistant gram-negative pathogens, including extended-spectrum-β-lactamase (ESBL)-producing Enterobacterales. TBP-PI-HBr is the first oral carbapenem intended for treating complicated urinary tract infections and acute pyelonephritis. This study evaluated the absorption, metabolism, and excretion (AME) of TBP-PI-HBr following a single oral dose of [14C]-TBP-PI-HBr to healthy males and characterized metabolites in plasma, urine, and feces. Methods This was a Phase 1, open-label, single-dose study in healthy subjects. Study drug was provided as radiolabeled and non-radiolabeled active pharmaceutical ingredient containing approximately 150 μCi of [14C]-TBP-PI-HBr. On Day 1, each subject received a 600 mg dose of TBP-PI-HBr. administered with 240 mL of water and fasted overnight for at least 10 hours. Blood samples were collected to determine TBP concentrations (whole blood), total radioactivity (whole blood and plasma), and metabolite profiling and identification were determined from plasma, urine, and feces. For mass balance, total radioactivity derived from urine and feces collections were determined. PK parameters were calculated using noncompartmental methods. Results Total radioactivity in plasma and whole blood decreased rapidly with geometric mean t½ values of 6.0 hours and 3.5 hours, respectively and Tmax of 1 hour. The cumulative mean recovery of radioactivity was 38.7% in urine and 44.6% in feces. Most of the administered radioactivity was recovered in the first 144 hours post dose in urine and feces (80.0%). Six of 8 subjects achieved a mass balance recovery ranging from 80.1% to 85.0%. The TBP plasma to total radioactivity ratio of 0.536 indicated that other metabolites contribute to the total radioactivity AUC in plasma. Metabolite profiling and identification results indicated that TBP was the major component in plasma and urine. The inactive ring open metabolite of TBP (LJC 11,562) was also found in plasma ( >10%), urine (5.27%), and feces ( >10%) as a secondary metabolite. Conclusion This study adequately characterized the AME of TBP-PI-HBr in humans. Disclosures Vipul K. Gupta, Ph.D., Spero Therapeutics (Employee, Shareholder) Gary Maier, PhD, Spero Therapeutics, Inc. (Consultant) Leanne Gasink, MD, Spero Therapeutics, Inc. (Consultant) Amanda Ek, MS, Spero Therapeutics, Inc. (Employee) Mary Fudeman, BA, MBA, Spero Therapeutics, Inc. (Employee) Praveen Srivastava, MS, BS, Spero Therapeutics, Inc. (Employee) Angela Talley, MD, Spero Therapeutics, Inc. (Employee)

scholarly journals Urinary Excretion and Bactericidal Activities of a Single Oral Dose of 400 Milligrams of Fleroxacin versus a Single Oral Dose of 800 Milligrams of Pefloxacin in Healthy Volunteers

1998 ◽  
Vol 42 (7) ◽  
pp. 1659-1665 ◽  
Author(s):  
Kurt G. Naber ◽  
Ursula Theuretzbacher ◽  
Martina Kinzig ◽  
Orlin Savov ◽  
Fritz Sörgel
Keyword(s):  
Oral Dose ◽  
Healthy Volunteers ◽  
Single Oral Dose ◽  
E Coli ◽  
Wide Range ◽  
The Mean ◽  
Bactericidal Activities ◽  
Tract Infections ◽  
Time Kill ◽  
Randomized Crossover Study

ABSTRACT Twelve healthy volunteers participated in this randomized crossover study to compare the concentrations and recovery levels of fleroxacin and pefloxacin in urine and to assess their bactericidal activities against 12 strains of urinary pathogens with different susceptibilities over a wide range of MICs. The volunteers received a single oral dose of 400 mg of fleroxacin or 800 mg of pefloxacin. The mean cumulative renal excretion of unchanged fleroxacin,N-demethyl-fleroxacin, and N-oxide-fleroxacin accounted for 67, 7, and 6% of the total dose, respectively. The total urinary recovery of pefloxacin and the active metabolite norfloxacin was 34%. In the time-kill and the urinary bactericidal titer (UBT) studies, only the subjects’ urine not supplemented with broth was used. With most tested organisms and both quinolones it took more than 8 h to achieve a reduction in CFU of 99.9% (3 log units). Overall, there was a good correlation between UBTs and MICs for the strains. Against Escherichia coli ATCC 25922 the median UBTs were similar for both antibiotics and at least 1:8 for 96 h; against the E. coli strain for which the MIC was 0.5 μg/ml the UBT was at least 1:4 for 48 h. The UBTs of both drugs against Klebsiella pneumoniae were at least 1:16 for 72 h. The UBTs for Staphylococcus aureus (the MIC for which was 16 μg/ml) of both antibiotics were low, and in some of the samples, no bactericidal titers were observed. UBTs for Proteus mirabilis of pefloxacin are significantly higher than those of fleroxacin. For Pseudomonas aeruginosa the median UBTs were present for the 24-to-48-h interval. The same is true forEnterococcus faecalis. Against Staphylococcus saprophyticus, UBTs were present for at least 48 h with both quinolones. Overall, a single oral dose of 400 mg of fleroxacin exhibits UBTs comparable to those of 800 mg of pefloxacin. Therefore, it may be expected that half of the dose of fleroxacin gives comparable results in the treatment of urinary tract infections; this should be substantiated in comparative clinical trials.

Pharmacokinetics of Cefixime in Children with Urinary Tract Infections after a Single Oral Dose

1996 ◽  
Vol 78 (6) ◽  
pp. 417-420 ◽  
Author(s):  
Katerina Mamzoridi ◽  
Nicoletta Kasteridou ◽  
Alexander Peonides ◽  
Ioannis Niopas
Keyword(s):  
Urinary Tract ◽  
Oral Dose ◽  
Single Oral Dose ◽  
Urinary Tract Infections ◽  
Tract Infections

Single-Dose Therapy of Anogenital and Pharyngeal Gonorrhoea with Ciprofloxacin

1992 ◽  
Vol 3 (1) ◽  
pp. 49-51 ◽  
Author(s):  
T Balachandran ◽  
A P Roberts ◽  
B A Evans ◽  
B S Azadian
Keyword(s):  
Adverse Reaction ◽  
Single Dose ◽  
Oral Dose ◽  
Neisseria Gonorrhoeae ◽  
Treatment Failure ◽  
Single Oral Dose ◽  
Open Study ◽  
Dose Therapy ◽  
Single Dose Therapy

A single dose of ciprofloxacin, 250 mg by mouth, was used in an open study to treat pharyngeal or rectal gonorrhoea or both in 64 patients (32 men and 32 women). The study also included 151 men with urethral gonorrhoea and 53 women with cervical or urethral gonorrhoea. Ciprofloxacin cured 63 (98%) patients with pharyngeal or rectal gonorrhoea (including 5 patients with penicillinase-producing Neisseria gonorrhoeae; PPNG), 147 (97%) men with urethral gonorrhoea (including 8 with PPNG) and 52 (98%) women with cervical or urethral gonorrhoea. All the isolates of N. gonorrhoeae were sensitive to 0.03 mg/l of ciprofloxacin. Five of the 6 patients with treatment failure were subsequently cured by a single oral dose of ciprofloxacin 250 mg. None of the patients reported an adverse reaction. Ciprofloxacin 250 mg as a single oral dose is effective and safe in treating patients with pharyngeal or rectal gonorrhoea, including those with PPNG strains.

scholarly journals The metabolism of 2,6-di-tert.-butyl-4-hydroxymethylphenol (Ionox 100) in the dog and rat

1965 ◽  
Vol 97 (1) ◽  
pp. 303-310 ◽  
Author(s):  
AS Wright ◽  
DAA Akintonwa ◽  
RS Crowne ◽  
DE Hathway
Keyword(s):  
Single Dose ◽  
Oral Dose ◽  
Oral Administration ◽  
Single Oral Dose ◽  
Individual Variation ◽  
Uronic Acid ◽  
Species Difference ◽  
Hydroxybenzoic Acid ◽  
Tert Butyl

1. A single oral dose of [(14)C]Ionox 100 to rats is almost entirely eliminated in 11 days: 89.1-107.2% of the (14)C is excreted and 0.29+/-0.02% of the dose is present in the carcass plus viscera after removal of the gut. Rats exhibit an individual variation in the elimination pattern, 15.6-70.8% of (14)C being excreted in the urine and 75.2-27.0% in the faeces during 11 days. 2. After the oral administration of [(14)C]Ionox 100 to dogs, 87.1-90.3% of the (14)C is excreted in the faeces and urine during 4 days. 3. Dogs and rats do not show a species difference in this pattern of elimination. 4. The rate of elimination from dogs and rats given a single dose of Ionox 100 is not affected by the size of the dose and the presence of triglyceride fat in the diet. 5. Ionox 100 is completely metabolized in dogs and rats: unchanged Ionox 100 is absent from the urine and faeces, and from the carcass when elimination is complete. In rats, 3,5-di-tert.-butyl-4-hydroxybenzoic acid accounts for 50-85% of a dose of Ionox 100 and (3,5-di-tert.-butyl-4-hydroxybenzoyl beta-d-glucopyranosid)uronic acid for 47-10%; in dogs, the unconjugated acid accounts for 85% and the ester glucuronide for 10-12%. 3,5-Di-tert.-butyl-4-hydroxyhippuric acid is not formed. Other metabolites, which have been detected in small quantity in the faeces and urine of animals dosed with Ionox 100, have not been identified. 6. 3,5-Di-tert.-butyl-4-hydroxybenzoic acid and (3,5-di-tert.-butyl-4-hydroxybenzoyl beta-d-glucopyranosid)uronic acid are also the major metabolites of Ionol (2,6-di-tert.-butyl-p-cresol) in rats. 7. The elimination of Ionox 100 metabolites from rats is faster than that of Ionol and its metabolites. Unlike Ionol, unchanged Ionox 100 could not be detected in the bodies of these animals.

scholarly journals Pharmacodynamic Evaluation of Dosing, Bacterial Kill, and Resistance Suppression for Zoliflodacin Against Neisseria gonorrhoeae in a Dynamic Hollow Fiber Infection Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Susanne Jacobsson ◽  
Daniel Golparian ◽  
Joakim Oxelbark ◽  
Emilie Alirol ◽  
Francois Franceschi ◽  
...  
Keyword(s):  
Single Dose ◽  
Oral Dose ◽  
Neisseria Gonorrhoeae ◽  
Single Oral Dose ◽  
Hollow Fiber ◽  
Dose Range ◽  
World Health ◽  
Dose Fractionation ◽  
Infection Model ◽  
Pharmacokinetic Data

Antimicrobial resistance in Neisseria gonorrhoeae is threatening the treatment and control of gonorrhea globally, and new treatment options are imperative. Utilizing our dynamic in vitro hollow fiber infection model (HFIM), we examined the pharmacodynamics of the first-in-class spiropyrimidinetrione (DNA gyrase B inhibitors), zoliflodacin, against the N. gonorrhoeae reference strains World Health Organization F (susceptible to all relevant antimicrobials) and WHO X (extensively drug resistant, including resistance to ceftriaxone) over 7 days. Dose-range experiments with both strains, simulating zoliflodacin single oral dose regimens of 0.5–8 g, and dose-fractionation experiments with WHO X, simulating zoliflodacin oral dose therapy with 1–4 g administered as q12 h and q8 h for 24 h, were performed. A kill-rate constant that reflected a rapid bacterial kill during the first 6.5 h for both strains and all zoliflodacin doses was identified. In the dose-range experiments, the zoliflodacin 2–8 g single-dose treatments successfully eradicated both WHO strains, and resistance to zoliflodacin was not observed. However, zoliflodacin as a single 0.5 g dose failed to eradicate both WHO strains, and a 1 g single dose failed to eradicate WHO X in one of two experiments. The zoliflodacin 1 g/day regimen also failed to eradicate WHO X when administered as two and three divided doses given at q12 h and q8 h in the dose-fractionation studies, respectively. All failed regimens selected for zoliflodacin-resistant mutants. In conclusion, these data demonstrate that zoliflodacin should be administered at >2 g as a single oral dose to provide effective killing and resistance suppression of N. gonorrhoeae. Future studies providing pharmacokinetic data for zoliflodacin (and other gonorrhea therapeutic antimicrobials) in urogenital and extragenital infection sites, particularly in the pharynx, and evaluation of gonococcal strains with different gyrB mutations would be important.

Effects of Child-Pugh B Cirrhosis on Pharmacokinetics of Tofogliflozin, a New Sodium-Glucose Co-Transporter (SGLT2) Inhibitor

Drug Research ◽  
2020 ◽  
Vol 70 (09) ◽  
pp. 401-409
Author(s):  
Haruki Yamada ◽  
Hiromasa Ohira ◽  
Fumiaki Ikegami ◽  
Koichi Nakamura ◽  
Atsushi Takahashi ◽  
...  
Keyword(s):  
Adverse Events ◽  
Oral Dose ◽  
Laboratory Test ◽  
Single Oral Dose ◽  
Hepatic Impairment ◽  
Geometric Mean ◽  
Sglt2 Inhibitor ◽  
Mean Value ◽  
Moderate Hepatic Impairment ◽  
Urinary Glucose

Abstract Background Tofogliflozin is a highly selective sodium-glucose co-transporter 2 (SGLT2) inhibitor. A mass balance study with combinations of microdoses revealed that tofogliflozin has high oral bioavailability (97.5%) and that tofogliflozin in circulation is eliminated primarily by metabolic pathways, with the liver playing a prominent role in elimination. Objectives This study aimed to evaluate the effect of moderate hepatic impairment on the pharmacokinetics of tofogliflozin and on the pharmacodynamics (urinary glucose excretion [UGE]). Methods In an open-label, parallel-group study, 17 subjects (9 with moderate hepatic impairment [Child-Pugh Class B, score 7–9] and 8 healthy) received a single oral dose of 40 mg tofogliflozin. Plasma and urine concentrations of tofogliflozin were determined. Accumulated UGE, adverse events, and physiological and laboratory test data were monitored. Results Geometric mean ratio (GMR; geometric mean value for subjects with moderate hepatic impairment / geometric mean value for healthy subjects) of Cmax was 1.47 and GMR of AUCinf was 1.70. Moderate hepatic impairment had only a little effect on tmax and CLR but it prolonged MRT. The levels of cumulative UGE were similar between the 2 groups. No clinically significant adverse events, laboratory test values, or physiological test values were observed in any subject. Conclusions Moderate hepatic impairment increased Cmax and AUCinf of tofogliflozin by 47% and 70%, respectively. This increase in tofogliflozin exposure did not increase UGE in hepatically impaired subjects. A single oral dose of 40 mg tofogliflozin was well tolerated, supporting dose adjustment is unnecessary even in moderately hepatically impaired subjects.

scholarly journals Milk iodine concentration in cows treated orally or intramuscularly with a single dose of iodinated fatty acid esters

2012 ◽  
Vol 48 (No. 6) ◽  
pp. 155-162 ◽  
Author(s):  
I. Herzig ◽  
J. Poul ◽  
B. Písaíková ◽  
E. Göpfert
Keyword(s):  
Single Dose ◽  
Fatty Acid ◽  
Oral Dose ◽  
Dairy Cows ◽  
Single Oral Dose ◽  
Experimental Period ◽  
Iodine Concentration ◽  
Fatty Acid Esters ◽  
Oral Application ◽  
Acid Esters

The effect of a single oral dose of iodinated fatty acid esters (IFAE) on iodine levels in colostrum and milk of goats was tested. In experimental goats that received a single oral dose of IFAE before delivery, significantly higher iodine levels in milk were recorded 60 days after the delivery. In the following period since day 75 after the delivery iodine levels decreased, however, remained higher compared to the control, e.g. on day 152 the levels were twice as high as in the controls. Based on these results, the effect of a single oral and parenteral application of IFAE was tested on dairy cows. The results of the experiment showed that a single oral application of IFAE increases milk iodine levels for a shorter period. Intramuscular application resulted in a significantly higher milk iodine levels during the whole experimental period compared to both untreated controls and cows with oral application of IFAE.

scholarly journals Comparison of single-dose cefuroxime axetil with ciprofloxacin in treatment of uncomplicated gonorrhea caused by penicillinase-producing and non-penicillinase-producing Neisseria gonorrhoeae strains.

1996 ◽  
Vol 40 (12) ◽  
pp. 2775-2780 ◽  
Author(s):  
E M Thorpe ◽  
J R Schwebke ◽  
E W Hook ◽  
A Rompalo ◽  
W M McCormack ◽  
...  
Keyword(s):  
Single Dose ◽  
Oral Dose ◽  
Confidence Interval ◽  
Neisseria Gonorrhoeae ◽  
Single Oral Dose ◽  
Cefuroxime Axetil ◽  
Female Patients ◽  
Male Patients ◽  
Males And Females ◽  
Uncomplicated Gonorrhea

A randomized, multicenter, investigator-blind trial was conducted to compare the efficacies of cefuroxime axetil and ciprofloxacin for treatment of patients with uncomplicated gonorrhea caused by penicillinase-producing Neisseria gonorrhoeae (PPNG). A total of 832 patients (434 females and 398 males) received a single oral dose of cefuroxime axetil (1,000 mg [417 patients]) or ciprofloxacin (500 mg [415 patients]). N. gonorrhoeae was eradicated from the cervix in 114 of 118 (97%) and 118 of 119 (99%) bacteriologically evaluable females treated with cefuroxime axetil and ciprofloxacin, respectively (P = 0.213; difference, -2%; 95% confidence interval, -6 to 1%), and from the urethra in 154 of 166 (93%) and 171 of 171 (100%) bacteriologically evaluable male patients treated with cefuroxime axetil and ciprofloxacin, respectively (P < 0.001; difference, -7%; 95% confidence interval, -11 to -3%). Both treatments were effective in eradicating N. gonorrhoeae in females with rectal infections (cefuroxime axetil, 29 of 30 [97%]; ciprofloxacin, 25 of 25 [100%]; P = 1.00). In small numbers of patients, cefuroxime axetil was less effective than ciprofloxacin in treating males with pharyngeal infections (eradication in 4 of 10 and in 8 of 8 patients, respectively; P = 0.013). PPNG was eradicated from the cervix in 22 of 23 (96%) and 32 of 32 (100%) bacteriologically evaluable female patients treated with cefuroxime axetil and ciprofloxacin, respectively (P = 0.418; difference, -4%; 95% confidence interval, -13 to 4%), and from the urethra in 35 of 36 (97%) and 34 of 34 (100%) bacteriologically evaluable male patients treated with cefuroxime axetil and ciprofloxacin, respectively (P = 1.00; difference, -3%; 95% confidence interval, -8 to 3%). The incidences of drug-related adverse events were similar for the two study drugs. In summary, treatment with a single oral dose of cefuroxime axetil is as effective as treatment with a single oral dose of ciprofloxacin in eradicating PPNG from males and females with uncomplicated gonorrhea (urethral and endocervical), and both regimens are well-tolerated. However, in the present study, cefuroxime axetil was less effective than ciprofloxacin in treating urethral gonococcal infections in male patients, although both study drugs were highly effective in treating cervical gonococcal infections in female patients.

scholarly journals Pharmacodynamic Evaluation of Fosfomycin against Escherichia coli and Klebsiella spp. from Urinary Tract Infections and the Influence of pH on Fosfomycin Activities

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Nayara Helisandra Fedrigo ◽  
Josmar Mazucheli ◽  
James Albiero ◽  
Danielle Rosani Shinohara ◽  
Fernanda Gomes Lodi ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Urinary Tract ◽  
Oral Dose ◽  
Single Oral Dose ◽  
Urinary Tract Infections ◽  
Bacterial Isolates ◽  
Gram Negative ◽  
Content Type ◽  
E Coli ◽  
Tract Infections

ABSTRACT Fosfomycin is widely used for the treatment of uncomplicated urinary tract infection (UTI), and it has recently been recommended that fosfomycin be used to treat infections caused by multidrug-resistant (MDR) Gram-negative bacilli. Whether urine acidification can improve bacterial susceptibility to fosfomycin oral dosing regimens has not been analyzed. The MIC of fosfomycin for 245 Gram-negative bacterial isolates, consisting of 158 Escherichia coli isolates and 87 Klebsiella isolates which were collected from patients with urinary tract infections, were determined at pH 6.0 and 7.0 using the agar dilution method. Monte Carlo simulation of the urinary fosfomycin area under the concentration-time curve (AUC) after a single oral dose of 3,000 mg fosfomycin and the MIC distribution were used to determine the probability of target attainment (PTA). Fosfomycin was effective against E. coli (MIC90 ≤ 16 μg/ml) but not against Klebsiella spp. (MIC90 > 512 μg/ml). Acidification of the environment increased the susceptibility of 71% of the bacterial isolates and resulted in a statistically significant decrease in bacterial survival. The use of a regimen consisting of a single oral dose of fosfomycin against an E. coli isolate with an MIC of ≤64 mg/liter was able to achieve a PTA of ≥90% for a target pharmacodynamic index (AUC/MIC) of 23 in urine; PTA was not achieved when the MIC was higher than 64 mg/liter. The cumulative fractions of the bacterial responses (CFR) were 99% and 55% against E. coli and Klebsiella spp., respectively, based on simulated drug exposure in urine with an acidic pH of 6.0. A decrease of the pH from 7.0 to 6.0 improved the PTA and CFR of the target pharmacodynamic index in both E. coli and Klebsiella isolates.

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