Penicillin Encephalopathy: An Unlikely Adversary in the Treatment of Neurosyphilis--Case Report and Review of the Literature.

UNLABELLED: Penicillin encephalopathy is a rare, potentially reversible phenomenon of drug-induced neurotoxicity. CASE: A 65-year-old female with a history of HIV was admitted with a three-day history of worsening headache, confusion, and lethargy. On examination she was awake but confused. Cerebrospinal fluid (CSF) and serum venereal disease research laboratory (VDRL) test returned positive and the patient was started on intravenous penicillin G with probenecid. On the second day of therapy, she developed myoclonic jerking, consistent with penicillin neurotoxicity. Repeat labs also showed new onset renal failure. Penicillin and probenecid therapy were stopped with a resolution of symptoms. Subsequently, therapy without probenecid was reinstituted uneventfully. DISCUSSION: Herein, we describe a female who developed penicillin neurotoxicity after initiation of intravenous penicillin therapy with probenecid for neurosyphilis. It is important that penicillin-induced toxicity be considered if characteristic myoclonic movements accompany encephalopathy. The presence of coexistent renal compromise should heighten the vigilance of clinicians.

High-dose oral amoxicillin plus probenecid is highly effective for syphilis in patients with HIV infection.

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.

A phase I clinical pharmacologic study of pralatrexate in combination with probenecid in adults with advanced solid tumors.

PURPOSE: The antifolate pralatrexate (10-propargyl-10-deazaaminopterin, PDX) demonstrates greater in vitro and in vivo antitumor efficacy than methotrexate. Preclinical models indicated that the efficacy of pralatrexate may be enhanced by coadministration with probenecid. The aim of this phase I study was to determine the maximum-tolerated dose of pralatrexate when combined with probenecid given every 2 weeks in humans. METHODS: The starting dose was pralatrexate 40 mg/m(2) intravenously and probenecid 70 mg/m(2) intravenously administered every 14 days, where one cycle of treatment was every 28 days. The pralatrexate dose was initially fixed while probenecid dose escalation was explored. The pralatrexate area under the curve (AUC), terminal-half life (t1/2), and maximum plasma concentration (Cmax) were determined in cycle 1. RESULTS: Seventeen patients with advanced solid tumors were treated with a median of two prior chemotherapy regimens. Stomatitis was dose-limiting with pralatrexate 40 mg/m(2) and probenecid 233 mg/m(2). Mean pralatrexate AUC and half life (t1/2) increased with increasing doses of probenecid. No objective responses were seen. CONCLUSION: For patients with advanced solid tumors, the maximum-tolerated dose of this drug combination was pralatrexate 40 mg/m(2) and probenecid 140 mg/m(2). Vitamin B(12) and folate supplementation may allow for further dose escalation of pralatrexate and probenecid. This is a suitable question for a future study.

Treatment of calcinosis in juvenile dermatomyositis with probenecid: the role of phosphorus metabolism in the development of calcifications.

OBJECTIVE: To report the efficacy of probenecid for calcinosis of juvenile dermatomyositis (JDM) and assess the changes in phosphorus metabolism during treatment. METHODS: Biochemical studies of calcium and phosphorus metabolism were performed in a 9-year-old girl with JDM and extensive calcifications before and during probenecid treatment. RESULTS: The calcifications resolved over 18 months of treatment. Probenecid was found to be effective in reducing calcifications by increasing renal phosphate clearance. CONCLUSIONS: The tendency for calcifications in some patients with JDM might be related to an increase in renal phosphate reclamation, and therefore, probenecid treatment may be effective in these patients.

Cefaclor, an alternative to third generation cephalosporins for the treatment of gonococcal urethritis in the developing world?

OBJECTIVE: To reassess the in vivo and in vitro efficacy of cefaclor for the treatment of uncomplicated gonococcal infection. DESIGN: Open clinical trail conducted in South Africa among consecutive male patients with symptoms and signs of uncomplicated urethritis and laboratory evidence of gonorrhoea. METHODS: Patients were treated with 3 g of cefaclor plus 1 g probenecid as a single dose. Urethral specimens were cultured for Neisseria gonorrhoeae at the initial visit and at follow up. Patients were considered cured if follow up cultures were negative. Treatment was considered to have failed in the patients infected with identical gonococcal strains at the initial and at the control visit. Those with evidence of infection at the follow up visit were administered 400 mg of ofloxacin and doxycycline 100 mg twice daily for 7 days. Minimal inhibitory concentrations (MICs) of cefaclor were determined by an agar dilution technique on the gonococcal isolates from the study subjects. The results were compared with those of isolates from three other African countries. RESULTS: Of 155 patients evaluated, 151 were cured (97%). Thirty per cent of the patients complained of adverse effects, mainly gastrointestinal. Even though MICs for the isolates from the three other African countries were significantly higher than those for the isolates from the study, none was considered resistant to cefaclor in vitro. MICs were markedly influenced by the type of test medium used. CONCLUSION: The trial demonstrated the efficacy of a single oral dose of cefaclor with probenecid for the treatment of uncomplicated gonococcal urethritis in South Africa. Its potential as an alternative therapy to third generation cephalosporins deserves to be further investigated.

An open study of procaine penicillin G, clavulanate-potentiated amoxycillin and probenecid in the treatment of acute gonorrhoea.

In an open study 55 patients presenting with acute gonorrhoea were given 4.8 mega units procaine penicillin G, intramuscularly, and oral probenecid (1 g) plus one 375-mg tablet clavulanate-potentiated amoxycillin orally. Before this treatment, 53 patients (96.4%) had presented with a purulent discharge, and dysuria was present in 47 patients (85.5%). The presence of Neisseria gonorrhoeae was confirmed by bacterial culture in 54 patients (98.2%). The majority of pathogens (92.5%) were penicillin resistant. On day 3 after treatment, dysuria was absent in 53 patients (96.4%) and there was no discharge in 40 cases (72.7%). N. gonorrhoeae was eradicated in 53 patients (96.4%). Two further patients were bacteriologically cured, but were suffering from post-gonococcal urethritis. The patients in whom discharge was still apparent were further assessed on day 7; discharge was resolved or resolving in all but one patient. There was one treatment failure. No adverse reactions were reported.

Sulfate homeostasis. IV. Probenecid-induced alterations of inorganic sulfate in rats.

Homeostasis of inorganic sulfate is maintained by the capacity-limited renal reabsorption of sulfate in the proximal tubule. The purpose of the present investigation was to determine if probenecid, the classical inhibitor of renal organic anion secretion, may affect sulfate renal clearance. Two groups of rats were administered in a randomized crossover design, an i.v. bolus dose (20.6 or 92.4 mg/kg) and 4-hr infusion (0.28 or 0.59 mg/min/kg) of probenecid or vehicle, and blood and urine samples were collected. At a steady-state serum concentration of 0.45 mM, probenecid had no significant effect on the serum concentrations or renal clearance of inorganic sulfate, whereas at a serum concentration of 1.4 mM, probenecid treatment caused a significant decrease in serum sulfate concentrations (0.57 +/- 0.11 vs 0.96 +/- 0.19 mM in controls, mean +/- SD, n = 6, P less than 0.001) due to an increase in the renal clearance of sulfate (3.88 +/- 1.18 vs 2.13 +/- 0.84 ml/min/kg in controls, P less than 0.01). The fraction of the filtered sulfate that was reabsorbed was significantly decreased (0.38 +/- 0.23, vs 0.74 +/- 0.09 in controls, P less than 0.01). Therefore, probenecid treatment results in the inhibition of the renal reabsorption of inorganic sulfate in rats in vivo.

Penicillin resistant Neisseria gonorrhoeae in low prevalence areas: implications for cost-effective management.

Though ampicillin is no longer recommended as first-line therapy for infections caused by Neisseria gonorrhoeae, the cost and efficacy of this policy in low prevalence areas has not been investigated. The problem was highlighted by an outbreak of penicillin-resistant N. gonorrhoeae in an area where the proportion of resistance had previously been only 0.14%. A decision analysis was performed to determine the cost-effectiveness of beta-lactamase screening and alternative therapies for patients attending sexually transmitted diseases clinics. Empiric therapy with an inexpensive agent active against resistant strains, such as ciprofloxacin, was the most cost-effective approach and remained more cost-effective than alternative strategies whenever the proportion of resistant isolates exceeded 3%. Ceftriaxone was less cost-effective. In low prevalence areas, and in areas where the return rate of recalled patients is high, ampicillin therapy was cost-effective, but beta-lactamase screening should be performed routinely.

The use of probenecid to increase the serum amoxycillin levels in patients with bronchiectasis.

Amoxycillin 3 g twice daily is effective in treating patients with bronchiectasis who have daily purulent sputum. However, it is a relatively expensive treatment if used for prolonged periods. This pilot study in six patients with bronchiectasis showed that the concurrent administration of probenecid with a smaller dose of amoxycillin produced similar clinical responses and pharmacokinetic profiles to those found with high dose amoxycillin alone. The amount of amoxycillin used was reduced by two thirds, producing a potential saving of approximately pound 1000 per patient per annum in those taking long term treatment.

Ciprofloxacin versus amoxycillin and probenecid in the treatment of uncomplicated gonorrhoea.

In a randomized study 100 patients, 78 males and 22 females, with uncomplicated gonorrhoea were treated with either a single oral dose of 250 mg of ciprofloxacin or a single oral dose of 3 g of amoxycillin and 1 g of probenecid. Three of the gonococcal strains produced penicillinase and, in addition, nine strains had MIC-values of amoxycillin ranging between 0.6 and 1.2 mg/l and five other strains MIC-values higher than 1.2 mg/l. Twenty-two patients had a concomitant infection due to Chlamydia trachomatis. All patients treated with ciprofloxacin were cured, while two patients treated with amoxycillin had treatment failures. Neither treatment regimen had any effect on the chlamydial infections. No adverse effects were observed. It was concluded that ciprofloxacin is the drug of choice in the treatment of uncomplicated infections due to Neisseria gonorrhoeae.

A comparative study of aztreonam and procaine penicillin/probenecid in the treatment of uncomplicated gonorrhoea.

236 patients with uncomplicated gonorrhoea were randomly allocated to receive either aztreonam or procaine penicillin plus probenecid. 115 patients (50 men and 65 women) with uncomplicated gonorrhoea were treated with 1 g aztreonam as a single intramuscular injection. The success rate among those who attended at least one follow up examination after treatment was 99%. The antibiotic was well tolerated and there were no side effects. The observed minimum inhibitory concentrations (MICs) of aztreonam in vitro were very much lower than obtainable serum concentrations. The penicillin treated patients who were evaluable showed a failure rate of 12.8%. We conclude that aztreonam is effective against Neisseria gonorrhoeae, including penicillinase-producing strains, both in vivo and in vitro.

Clinical experience in the use of clavulanic acid/penicillin regimens in the treatment of uncomplicated gonorrhoea.

In an attempt to investigate the possibility of re-establishing the use of penicillins in the treatment of gonorrhoea in Singapore, a series of studies were conducted between 1981 and 1984, to evaluate the efficacy of a variety of penicillin-clavulanic acid combinations. A total of 6 different regimens were evaluated, and we concluded that 3 regimens consisting of 2 doses of Augmentin 3.25 g P.O., 4 hours apart (regimen C), aqueous procaine penicillin G (APPG) 4.5 mega units I.M. + Augmentin 375 mg + probenecid 1g P.O. (regimen E), and APPG 4.5 mega units I.M. + Augmentin 750 mg + probenecid 1g P.O. (regimen F) were very efficacious against infection due to PPNG and non PPNG. The cure rates obtained were 96.6% (regimens C and E), and 95% (regimen F) for infection due to PPNG and 95.6% (regimen C), and 100% (regimens E and F) for those due to non PPNG. Regimen E consisting of aqueous procaine penicillin G 4.5 meg units I.M. + Augmentin 375 mg + probenecid 1g P.O. was felt to be economical as well as effective against PPNG and non PPNG, and had the potential advantage of being effective against incubating syphillis. Regimen consisting 2 oral doses of Augmentin 3.25 g, 4 hours apart was an effective therapy for patients who preferred oral medication alone. However, this therapy was most costly. No serious side effects of treatment were observed with any of the regimens used.

Two regimens of sultamicillin in treating uncomplicated gonorrhoea.

Sultamicillin is a covalent union of ampicillin and the beta lactamase inhibitor, sulbactam (CP-45,899). Two studies were conducted to assess its efficacy in treating uncomplicated gonorrhoea. In the first study treatment comprised sultamicillin 1.5 g and probenecid 1 g; 124 (89.2%) of 139 patients responded including seven of 11 patients harbouring beta lactamase (penicillinase) producing strains of Neisseria gonorrhoeae (PPNG). In the second study sultamicillin 2.25 g and probenecid 1 g were given; 122 (93.8%) of 130 patients responded. Only two of seven pharyngeal infections resolved, and if pharyngeal infections are excluded the overall cure rate rose to 95.3%. Thirteen of 14 patients infected with PPNG strains were cured by the larger dose. Side effects were mild and transitory. It may be concluded that sultamicillin 2.25 g plus probenecid 1 g is an effective regimen to treat uncomplicated rectal and genital gonorrhoea and is useful for treating infections with PPNG strains. Most beta lactamase resistant antimicrobials must be given parenterally; sultamicillin is given by mouth.

Failure of a once-daily regimen of cefonicid for treatment of endocarditis due to Staphylococcus aureus.

Cefonicid, a new long-acting cephalosporin, was evaluated for treatment of endocarditis due to Staphylococcus aureus. Four patients, all with infection of the tricuspid valve, were treated with a single daily injection. By the fifth day of therapy, three of the four patients continued to have spiking fevers and positive blood cultures, and treatment with cefonicid was discontinued. Even though peak concentrations of antibiotic in serum were greater than 20-40 times the minimum inhibitory concentration of the antibiotic for the infecting organism, serum bactericidal titers were less than 1:8 in three patients. Susceptibility testing of 52 clinical isolates in broth confirmed a marked difference between inhibitory and bactericidal concentrations for 40% of these strains. In addition, susceptibility testing performed in serum rather than broth resulted in a sixfold increase in the minimum inhibitory concentration, a result suggesting that protein binding may be in part responsible for these failures of treatment. Cefonicid administered as a single daily dose is inadequate for treatment of endocarditis due to S. aureus and should not be used for treatment of bacteremia or life-threatening infections known or suspected to be caused by this organism.

[Treatment of gonorrhea with spectinomycin and penicillin]. / Die Behandlung der Gonorrhoe mit Spectinomycin und Penicillin.

In an open clinical trial, spectinomycin and penicillin G were compared with regard to clinical efficacy, side effects, as well as bacteriological sensitivity in patients suffering from acute gonorrhea. The study was concerned with 176 female patients of a harbor medical practice who were frequently changing partners. 87 out of these patients were treated with spectinomycin, 89 of them with penicillin G. Smear specimens of all patients were tested microscopically; in addition, we performed bacteriological tests (as agar diffusion test, tube dilution test, beta-lactamase test). Both spectinomycin and penicillin showed a good clinical efficacy, except for one case of resistance against penicillin. Afterwards, this patient was successfully treated with spectinomycin. Apart from intermittent pain in the injection area, no side effects have been reported in either group of patients.

Organic acid transport to the blood from the corpus striatum, the thalamus and the cerebellum of the rat.

Conscious rats were given intracerebral injections by preplaced microsyringes. The injectates were 0.3-0.5 microliters of 125I- and 131I-o-iodohippurate. One hour after injection the isotopes present in the unopened cranial cavity were measured by gamma spectrometry. Some animals received 200 mg/kg probenecid intraperitoneally and this reduced the rate of absorption from injectates into the corpus striatum to 65.7 +/- 12.6% of control; from injectates into the cerebellum to 57.1 +/- 9.8% of control. Dye injections showed that injections into the cerebellum did not remain in the parenchyma, in contrast to injections into the corpus striatum or thalamus. Probenecid was also given as 2.9% solution, pH 7, mixed with the iodohippurate in the microsyringe. It had no effect on injections into the cerebellum, reduced the rate of absorption from the corpus striatum to 80.9 +/- 3.2% of controls and that from the thalamus to 88.3 +/- 2.2%. The results indicate parenchymal probenecid-sensitive transport of iodohippurate from the corpus striatum and thalamus but failed to settle the matter for the cerebellum.

A controlled study of mezlocillin in uncomplicated acute gonorrhoea.

In a randomized trial, 149 patients with uncomplicated gonorrhoea were treated with a single intramuscular dose of 1.0 g mezlocillin, 150 with 2.0 g ampicillin plus 1.0 g probenecid orally and 150 with a single dose of 1.8 mega units of procaine penicillin. Cure rates at 3, 10 and 17 days after treatment were 97%, 99% and 96% for mezlocillin, 95%, 99% and 95% for ampicillin, and 97%, 98% and 98% for procaine penicillin, respectively. The incidence of post-gonococcal urethritis was 11.3% for ampicillin plus probenecid, 10.9% for procaine penicillin and 10.5% for mezlocillin. Side-effects after all three regimens were minimal.

Regional distribution and production rate of 3-methoxy-4-hydroxyphenylethyleneglycol sulphate (MHPG-SO4) in rat brain.

The levels of noradrenaline (NA) and 3-methoxy-4-hydroxyphenylethyleneglycol sulphate (MHPG-SO4) in 15 brain regions showed a parallel distribution in male Wistar rats. The differences in regional distribution of MHPG-SO4 were similar to those in the rate of NA turnover reported by other investigators. The accumulation rates of MHPG-SO4 during 45 and 90 min after probenecid injection significantly correlated to the steady state levels of MHPG-SO4 in nine regions studied. With the results, the regional levels of MHPG-SO4 either in untreated or in probenecid-treated rats, are considered to be a useful index of NA turnover.