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In the face of increasing antimicrobial tolerance and resistance there is a global obligation to optimise oral antimicrobial dosing strategies including narrow spectrum penicillins, such as penicillin-V. We conducted a randomised, crossover study in healthy volunteers to characterise the influence of probenecid on penicillin-V pharmacokinetics and estimate the pharmacodynamics against Streptococcus pneumoniae . Twenty participants took six doses of penicillin-V (250 mg, 500 mg or 750 mg four times daily) with and without probenecid. Total and free concentrations of penicillin-V and probenecid were measured at two timepoints. A pharmacokinetic model was developed, and the probability of target attainment (PTA) calculated. The mean difference (95% CI) between penicillin-V alone and in combination with probenecid for serum total and free penicillin-V concentrations was significantly different at both timepoints (total: 45 min 4.32 (3.20–5.32) mg/L p  <  0.001 , 180 min 2.2 (1.58–3.25) mg/L p  <  0.001 ; free: 45 min 1.15 (0.88–1.42) mg/L p  <  0.001 , 180 min 0.5 (0.35–0.76) mg/L p  <  0.001 ). There was no difference between the timepoints in probenecid concentrations. PTA analysis shows probenecid allows a fourfold increase in MIC cover. Addition of probenecid was safe and well tolerated. The data support further research into improved dosing structures for complex outpatient therapy and might also be used to address penicillin supply shortages.

Purpose:To study patterns and predictors of medication use and laboratory monitoring in gout.Methods:In a cohort of veterans with a diagnosis of gout prescribed allopurinol, colchicine or probenecid, quality of care was assessed by examining adherence to the following evidence-based recommendations: (1) whether patients starting a new allopurinol prescription (a) received continuous allopurinol, (b) received colchicine prophylaxis, (c) achieved the target uric acid level of ⩽6 mg/dl; and (2) whether doses were adjusted for renal insufficiency. The association of sociodemographic characteristics, healthcare utilisation and comorbidity with the recommendations was examined by logistic/Poisson regression.Results:Of the 643 patients with gout receiving a new allopurinol prescription, 297 (46%) received continuous allopurinol, 66 (10%) received colchicine prophylaxis and 126 (20%) reached the target uric acid level of ⩽6 mg/dl. During episodes of renal insufficiency, appropriate dose reduction/discontinuation of probenecid was done in 24/31 episodes (77%) and of colchicine in 36/52 episodes (69%). Multivariable regression showed that higher outpatient utilisation, more rheumatology care and lower comorbidity were associated with better quality of care; more rheumatology clinic or primary care visits were associated with less frequent allopurinol discontinuation; more total outpatient visit days or most frequent visits to a rheumatology clinic were associated with a higher likelihood of receiving colchicine prophylaxis; and a lower Charlson Comorbidity Index or more outpatient visit days were associated with higher odds of reaching the target uric acid level of ⩽6 mg/dl.Conclusions:Important variations were found in patterns of medication use and monitoring in patients with gout with suboptimal care. A concerted effort is needed to improve the overall care of gout.

ObjectiveThe purpose of our study was to determine if cephalexin 500 mg orally four times daily was non-inferior to cefazolin 2 g intravenously daily plus probenecid 1 g orally daily in the management of patients with uncomplicated mild–moderate skin and soft tissue infection (SSTI) presenting to the ED.MethodsThis was a prospective, multicentre, double dummy-blind, randomised controlled non-inferiority trial conducted at two tertiary care teaching hospitals in Canada. Patients were enrolled if they presented to the ED with an uncomplicated SSTI, and randomly assigned in a 1:1 fashion to oral cephalexin or intravenous cefazolin plus oral probenecid for up to 7 days. The primary outcome was failure of therapy at 72 hours. Clinical cure at 7 days, intravenous to oral medication transition admission to hospital and adverse events were also evaluated.Results206 patients were randomised with 104 patients in the cephalexin group and 102 in the cefazolin and probenecid group. The proportion of patients failing therapy at 72 hours was similar between the treatment groups (4.2% and 6.1%, risk difference 1.9%, 95% CI −3.7% to 7.6%). Clinical cure at 7 days was not significantly different (100% and 97.7%, risk difference −2.3%, 95% CI −6.7% to 0.8%).ConclusionCephalexin at appropriate doses appears to be a safe and effective alternative to outpatient parenteral cefazolin in the treatment of uncomplicated mild–moderate SSTIs who present to the ED.Trial registration number NCT01029782; Results.

PEACH trial data were used to evaluate the relationship between subsequent sexually transmitted infection and recurrent pelvic inflammatory disease on infertility and chronic pelvic pain (CPP). Recurrent pelvic inflammatory disease was associated with an almost 2-fold increase in infertility and more than 4-fold increase in CPP. Subsequent sexually transmitted infection was associated with CPP, but not infertility.

Background: Ampicillin/probenecid is an antimicrobial formulation indicated for the treatment of respiratory, urinary tract, and gastrointestinal infections. Ampicillin sodium is the active antimicrobial ingredient that can act on the phase of bacterial breeding and inhibit the biosynthesis of bacterial mucopeptide in the cell wall. Probenecid acts synergistically by competitively inhibiting an organic anion transporter in renal tubules, increasing the plasma concentrations, and thus extending the plasma elimination t 1/2. Objective: The aim of this study was to assess and compare the pharmacokinetic (PK) properties, bioavailability, and bioequivalence of a newly developed dispersible tablet formulation (test) of ampicillin/ probenecid with those of an established branded capsule formulation (reference) in healthy Chinese male volunteers. Methods: A randomized-sequence, single-dose, open-label, 2-period crossover study was conducted in fasted healthy Chinese male volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive 6 dispersible tablets (test) or branded capsules (reference) (1500 mg total; 250 mg each containing ampicillin 194.5 mg and probenecid 55.5 mg), followed by a 7-day washout period and administration of the alternate formulation. Plasma samples were collected over a 24-hour period following administration and analyzed for ampicillin and probenecid content by HPLC. PK parameters such as C max, AUC 0–t, and AUC 0–∞ were also determined. The formulations were considered bioequivalent if the geometric mean ratios of the log-transformed C max and AUC values were within the equivalence range (80%–125%) predetermined by the State Food and Drug Administration (SFDA) of the People's Republic of China. Tolerability was based on the observation of adverse events (AEs), monitoring of vital signs (blood pressure, heart rate, temperature, electrocardiography) and laboratory tests (hematology, blood biochemistry, hepatic function, urinalysis), and subject's interview on AEs. Results: The study was performed in 20 healthy Chinese male volunteers (mean [SD] age, 21.4 [2.2] years; weight, 64.1 [5.5] kg; height, 173.7 [5.3] cm; and body mass index, 21.2 [1.6] kg/m 2). The mean (SD) C max, T max, AUC 0–24, and AUC 0–∞ after administration of the test and reference formulations, respectively, were as follows: ampicillin, C max, 13.45 (3.43) versus 15.04 (5.68) μg/mL, T max, 1.58 (0.49) versus 1.78 (0.55) hours, AUC 0–24, 50.78 (13.39) versus 57.44 (17.27) μ/mL/h, and AUC 0–∞, 51.95 (13.45) versus 58.74 (17.19) μg/mL/h; probenecid, C max, 15.56 (2.94) versus 16.01 (2.88) μg/mL, T max, 2.85 (0.78) versus 3.30 (1.51) hours, AUC 0–24, 129.23 (27.59) versus 127.29 (26.89) μg/mL/h, and AUC 0–∞ 133.85 (28.80) versus 131.21 (28.25) μg/mL/h. On ANOVA, neither period nor sequence effects were observed for any of the PK properties. The 90% CIs of ampicillin for the log-transformed ratios of C max, AUC 0–24, and AUC 0–∞) were 86.5% to 108.0%, 96.7% to 107.8%, and 83.3% to 100.7%, respectively, and the corresponding values for probenecid were 90.2% to 108.3%, 96.8% to 107.8%, and 97.2% to 108.5%. No AEs were observed or reported up to 1 week after study end. Conclusions: In this small study in healthy Chinese male volunteers, a single 1500-mg dose of the dispersible tablet formulation (test) of ampicillin/probenecid met the SFDA's regulatory criteria for bioequivalence to the reference capsule formulation based on the rate and extent of absorption. Both formulations were well tolerated.

Abstract Background Grape-induced acute kidney injury (AKI) is caused by tartaric acid and may lead to death in dogs. Probenecid, an organic anion transporter-1 inhibitor, recently has been shown to block the uptake of tartaric acid in Madin–Darby canine kidney cells and has been suggested as a possible target for prevention of AKI after grape ingestion. Hypothesis/Aims Assess the safety and pharmacokinetics (PK) of PO probenecid in dogs. We hypothesized that probenecid would result in mild, self-limiting gastrointestinal (GI) adverse effects and would be safe in healthy dogs. Additionally, we hypothesized that PO probenecid (50 mg/kg) would have adequate bioavailability and achieve pharmacologically active plasma drug concentrations. Animals Six healthy beagle dogs. Methods Pharmacokinetic (PK) study. Dogs were given 50 mg/kg of probenecid PO, with PK data collected for 48 h after administration. Complete blood count, serum biochemistry profile, urinalysis, and clinical monitoring were performed throughout a 21-day study period to assess safety. Plasma concentration versus time data was analyzed using non-compartmental and two-compartmental modeling. Results Orally administered probenecid had excellent estimated bioavailability (82.6%) and rapid absorption, with a mean maximal plasma concentration of 589.3 μM (range: 368.0–830.5 μM) within 1.5 h. The mean volume of distribution was 0.71 L/kg, with mean systemic clearance of 0.022 L/h/kg and mean half-life of 24.1 h. Probenecid was well tolerated by all six dogs, with no clinically relevant adverse effects noted. Conclusions and Clinical Importance Orally administered probenecid is safe and bioavailable in healthy dogs. Future clinical trials assessing PO probenecid in dogs with known tartaric acid ingestion are warranted.

Carbamazepine (CBZ) undergoes biotransformation by CYP3A4 and CYP2C8, and glucuronide conjugation. There has been no clear demonstration to reveal the role of glucuronidation in the disposition of CBZ. We evaluated the effect of probenecid, a UDP-glucuronosyltransferase inhibitor, on the pharmacokinetics of CBZ in humans. In a randomized, open-label, two-way crossover study, ten healthy male subjects were treated twice daily for 10 days with 500 mg probenecid or with a matched placebo. On day 6, a single dose of 200 mg CBZ was administered orally. Concentrations of CBZ and CBZ 10,11-epoxide (CBZ-E) in plasma and urine were measured. Probenecid decreased the area under the plasma concentration-time curve (AUC) of CBZ from 1253.9 micromol h/l to 1020.7 micromol h/l (P < 0.001) while increasing that of CBZ-E from 137.6 micromol h/l to 183.5 micromol h/l (P = 0.033). The oral clearance of CBZ was increased by probenecid by 26% (90% confidence interval, 17-34%; P < 0.001). Probenecid increased the AUC ratio of CBZ-E/CBZ from 0.11 to 0.16 (P < 0.001). However, probenecid had minimal effect on the recovery of the conjugated and free forms of CBZ and CBZ-E in urine. Although probenecid showed a minimal effect on the glucuronidation of CBZ and CBZ-E, it increased CBZ biotransformation to CBZ-E, most likely reflecting the induction of CYP3A4 and CYP2C8 activities, in humans. These results demonstrate that glucuronide conjugation plays a minor role in the metabolism of CBZ and CBZ-E in humans, and that probenecid has an inducing effect on the disposition of CBZ.

Background. Intramuscular benzathine penicillin G (BPG) is widely used for the treatment of syphilis. However, BPG is not available in some countries. This study examined the effectiveness and safety of high-dose oral amoxicillin plus probenecid for the treatment of syphilis in patients with human immunodeficiency virus type 1 (HIV-1). Methods. This retrospective observational study included 286 HIV-infected male patients with syphilis (median age, 36 years; median CD4 count, 389 cells/μL) who were treated with oral amoxicillin 3 g plus probenecid. Syphilis was diagnosed by both serum rapid plasma reagin (RPR) titers ≥8 and positive Treponema pallidum hemagglutination test. Patients with neurosyphilis diagnosed by cerebrospinal fluid examination were excluded. Successful treatment was defined as a at least 4-fold decrement in RPR titer. Results. The overall treatment efficacy was 95.5% (95% confidence interval [CI], 92.4%–97.7%; 273/286 patients), and efficacy for primary, secondary, early latent, late latent, and unknown duration syphilis was 93.8% (95% CI, 68.1%–99.8%; 15/16), 97.3% (95% CI, 92.9%–99.2%; 142/146), 100% (95% CI, 90.5%–100%; 37/37), 85.7% (95% CI, 58.6%–96.4%; 18/21), and 92.4% (95% CI, 81.9%–97.3%; 61/66), respectively. Treatment duration was mostly 14–16 days (49.7%) or 28–30 days (34.3%), with efficacy of 94.4% (134/142) and 95.9% (94/98), respectively; 96.3% of successfully treated patients achieved a ≥4-fold decrement in RPR titer within 12 months. Adverse events were noted in 28 (9.8%) patients, and 25 of these (89.3%) were successfully treated. Only 6% of patients underwent lumbar puncture. Conclusions. The combination of oral amoxicillin 3 g plus probenecid was highly effective and tolerable for the treatment of syphilis in patients with HIV-1 infection.

Cidofovir, (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine, is a novel antiviral nucleotide analogue with potent in vitro and in vivo activity against cytomegalovirus (CMV) and other herpesviruses. Thirty-one human immunodeficiency virus-seropositive patients with asymptomatic CMV excretion were evaluated in a phase Ijll study with 2 regimens of cidofovir: cidofovir alone at doses of 0.5, 1.0, 3.0, or 10.0 mg/kg/week (20 patients) and cidofovir at 3.0, 5.0, or 7.5 mg/kg with concomitant oral probenecid, saline prehydration, extended dosing intervals, and drug interruption for proteinuria (19 patients). Prolonged and dose-dependent anti-CMV effect was observed with all cidofovir regimens ⩾3.0 mg/kg. The dose-limiting toxicity of cidofovir was dose- and schedule-dependent nephrotoxicity. Four of20 patients had serum creatinine levels ⩾2.0 mg/dL after a mean cumulative exposure of 14.8 mg/kg cidofovir alone; however, none of 19 patients receiving the modified regimen had elevated creatinine (mean cidofovir exposure, 32.2 rug/kg). The clinical efficacyof cidofovir and its potential for cumulative nephrotoxicity needs further study in patients with end-organ CMV disease.

Rheumatoid arthritis patients can be prescribed a combination of immunosuppressive drug leflunomide (LEF) and the antiviral drug acyclovir to reduce the high risk of infection. Acyclovir is a substrate of organic anion transporter (OAT) 1/3 and multidrug resistance-associated protein (MRP) 2. Considering the extraordinarily long half-life of LEF’s active metabolite teriflunomide (TER) and the kidney injury risk of acyclovir, it is necessary to elucidate the potential impact of LEF on the disposition of acyclovir. Here we used a specific MRP inhibitor MK571 and probenecid (OAT1/3 and MRP2 inhibitor) to assess the effects of MRP2 and OAT1/3 on the pharmacokinetics and tissue distribution of acyclovir in rats. We showed that LEF and probenecid, but not MK571 significantly increased the plasma concentration of acyclovir. However, kidney and liver exposures of acyclovir were increased when coadministered with LEF, probenecid or MK571. The kidney/plasma ratio of acyclovir was increased to approximately 2-fold by LEF or probenecid, whereas it was increased to as much as 14.5-fold by MK571. Consistently, these drugs markedly decreased the urinary excretion of acyclovir. TER (0.5−100 μmol/L) dose-dependently increased the accumulation of acyclovir in MRP2-MDCK cells with an IC 50 value of 4.91 μmol/L. TER (5 μmol/L) significantly inhibited the uptake of acyclovir in hOAT1/3-HEK293 cells. These results suggest that LEF/TER increased the kidney accumulation of acyclovir by inhibiting the efflux transporter MRP2, which increased its kidney/plasma ratio and renal injury risk. However, the inhibitory effects of LEF/TER on OAT1/3 reduced the tubular cells’ uptake of acyclovir and increased the plasma concentration.