Sulfisoxazole Elicits Robust Antitumour Immune Response Along with Immune Checkpoint Therapy by Inhibiting Exosomal PD-L1.

Despite their potent antitumor activity, clinical application of immune checkpoint inhibitors has been significantly limited by their poor response rates (<30%) in cancer patients, primarily due to immunosuppressive tumor microenvironments. As a representative immune escape mechanism, cancer-derived exosomes have recently been demonstrated to exhaust CD8+ cytotoxic T cells. Here, it is reported that sulfisoxazole, a sulfonamide antibacterial, significantly decreases the exosomal PD-L1 level in blood when orally administered to the tumor-bearing mice. Consequently, sulfisoxazole effectively reinvigorates exhausted T cells, thereby eliciting robust antitumor effects in combination with anti-PD-1 antibody. Overall, sulfisoxazole regulates immunosuppression through the inhibition of exosomal PD-L1, implying its potential to improve the response rate of anti-PD-1 antibodies.

Involvement of imidazoline and opioid receptors in the enhancement of clonidine-induced analgesia by sulfisoxazole.

Clonidine, an alpha2-adrenergic agonist, has been demonstrated to produce significant analgesia and potentiate morphine analgesia. Endothelin (ETA) receptor antagonists have also been found to potentiate the antinociceptive response to morphine. Clonidine and ET have been reported to have cardiovascular interactions involving the sympathetic nervous system, but it is not known whether ETA receptor antagonist affects clonidine analgesia. This study examined the influence of sulfisoxazole (ETA receptor antagonist) on clonidine analgesia. Male Swiss Webster mice were used to determine antinociceptive response of drugs by measuring tail-flick latency. The effect of clonidine (0.3, 1.0, and 3.0 mg/kg, i.p.) alone or in combination with sulfisoxazole (25, 75, and 225 mg/kg, p.o.) on analgesia and body temperature was determined. Clonidine produced a dose-dependent analgesia and hypothermia. Sulfisoxazole (25, 75, and 225 mg/kg), when administered with clonidine (0.3 mg/kg), significantly potentiated (31% increase in area under the curve (AUC)) the analgesic effect of clonidine. Yohimbine (alpha2-adrenergic receptor antagonist) did not affect analgesic effect of clonidine plus sulfisoxazole. Idazoxan (I1-imidazoline and alpha2-adrenergic receptor antagonist) reduced (47% decrease in AUC) the analgesic effect of clonidine plus sulfisoxazole. Treatment with naloxone reduced (46% decrease in AUC) the analgesic effect of clonidine plus sulfisoxazole. The effect of another ETA receptor antagonist, BMS-182874 (2, 10, and 50 microg, i.c.v.) was studied, and it was found that the dose of 10 microg significantly potentiated (26% increase in AUC) the analgesic effect of clonidine. These results indicate that sulfisoxazole, an ETA receptor antagonist, potentiates the analgesic effect of clonidine, which could be mediated through I1-imidazoline receptors and opioid receptors.

Human metapneumovirus: an emerging respiratory pathogen.

Human metapneumovirus (hMPV) is an important emerging respiratory pathogen, previously unreported in the Emergency Medicine literature. It is primarily associated with the clinical syndromes of bronchiolitis and pneumonia. hMPV may predispose to bacterial pneumonia; coinfection with respiratory syncytial virus may lead to increased severity of clinical disease, and complications include asthma and chronic obstructive pulmonary disease exacerbations. Given its high prevalence and potential clinical implications as these patients present to the Emergency Department with initial infection or subsequent complications, a better understanding of hMPV will aid in their care. We report the case of a 13-month old who developed lobar pneumonia 3 weeks after being diagnosed with hMPV. The epidemiology, clinical presentation, complications, and treatment of hMPV are then discussed.

Adenoidectomy versus chemoprophylaxis and placebo for recurrent acute otitis media in children aged under 2 years: randomised controlled trial.

OBJECTIVE: To evaluate the efficacy of adenoidectomy compared with long term chemoprophylaxis and placebo in the prevention of recurrent acute otitis media in children aged between 10 months and 2 years. DESIGN: Randomised, double blind, controlled trial. SETTING: Oulu University Hospital, a tertiary centre in Finland. PARTICIPANTS: 180 children aged 10 months to 2 years with recurrent acute otitis media. INTERVENTION: Adenoidectomy, sulfafurazole (sulphisoxazole) 50 mg/kg body weight, given once a day for six months or placebo. Follow up lasted for two years, during which time all symptoms and episodes of acute otitis media were recorded. MAIN OUTCOME MEASURES: Intervention failure (two episodes in two months or three in six months or persistent effusion) during follow up, number of episodes of acute otitis media, number of visits to a doctor because of any infection, and antibiotic prescriptions Number of prescriptions, and days with symptoms of respiratory infection. RESULTS: Compared with placebo, interventions failed during both the first six months and the rest of the follow up period of 24 months similarly in the adenoidectomy and chemoprophylaxis groups (at six months the differences in risk were 10% (95% confidence interval -9% to 29%) and 18% (-2% to 38%), respectively). No significant differences were observed between the groups in the numbers of episodes of acute otitis media, visits to a doctor, antibiotic prescriptions, and days with symptoms of respiratory infection. CONCLUSIONS: Adenoidectomy, as the first surgical treatment of children aged 10 to 24 months with recurrent acute otitis media, is not effective in preventing further episodes. It cannot be recommended as the primary method of prophylaxis.

Nocardiosis cutánea primaria / Primary cutaneous nocardiosis

Se presenta un paciente de 71 años, de sexo masculino, con nocardiosis cutánea primaria por Nocardia asteroides. Se describen las formas clínicas de nocardiosis cutánea, así como los tratamientos que pueden efectuarse

Urinary protein binding does not affect response to furosemide in patients with nephrotic syndrome.

Response to loop diuretics in patients with nephrotic syndrome (NS) is subnormal. Studies in animal models of NS have suggested that binding of diuretic to urinary albumin is one of the mechanisms that may be operative in this diuretic resistance. To explore this hypothesis, 12 patients with NS were studied to determine whether displacement from urinary protein binding with sulfisoxazole would restore response to 120 mg of furosemide. The study was stopped after treating seven patients because it was clear that sulfizoxazole had no effect. Sodium excretion (mean +/- SD) from furosemide alone was 239 +/- 90 versus 240 +/- 115 mEq/8 h with sulfisoxazole. Sulfisoxazole had modest effects on serum pharmacokinetics of furosemide but had no effect on either the time course of furosemide urinary excretion or overall amount excreted: 49 +/- 15 mg versus 54 +/- 12 mg for furosemide alone and furosemide plus sulfisoxazole, respectively. It is concluded that urinary protein binding of loop diuretics is not a major mechanism for the diuretic resistance of NS. In turn, strategies aimed at displacing such binding are unlikely to be clinically helpful.

Otitis media prevention: non-vaccine prophylaxis.

Preventing recurrent acute otitis media (AOM) is a goal of child health care. The objective is to reduce the frequency of pain and fever, shorten the duration of hearing loss, reduce the costs of physician visits, surgery and drugs, reduce parent anxiety, and prevent long term sequelae. Preventive approaches include understanding individual and familial risk factors, avoidance of environmental risk factors, antibiotic drug prophylaxis, polyvalent pneumococcal vaccination, myringotomy with tympanostomy tubes, and adenoidectomy. Earlier and more aggressive treatment can be provided to infants at increased risk. Antibiotic prophylaxis is challenged by a relatively small benefit and emerging resistant bacteria. Tympanostomy tubes are beneficial in chronic otitis media with effusion (OME), but of less value in recurrent AOM absent chronic OME. Adenoidectomy after tympanostomy tube failure is supported by at least one clinical trial.

Treatment of acute sinusitis in childhood with ceftibuten.

Acute sinusitis is a common childhood illness. If it is overlooked or undertreated, suppurative and intracranial complications may develop. Amoxicillin has traditionally been the antibiotic of choice for treatment of acute sinusitis. However, the efficacy of amoxicillin has been reduced because of the emergence of bacteria producing b-lactamase and altered penicillin-binding proteins. This study compares the effectiveness of 10, 15, and 20 days of ceftibuten therapy with 14 days of erythromycin-sulfisoxazole therapy in treating acute sinusitis. The results indicate that both treatment regimens are effective in treating acute sinusitis (96% clinical response for erythromycin-sulfisoxazole vs 92% for a 10- or 15-day course of ceftibuten vs 100% for a 20-day course of ceftibuten). Longer treatment periods may be more effective in resolving the acute illness.

Otitis media-related antibiotic prescribing patterns, outcomes, and expenditures in a pediatric medicaid population.

BACKGROUND: Treatment of otitis media is the most frequent reason for administering antibiotics to children in the United States. However, only limited data are available on medical effectiveness of antibiotic prescribing patterns for otitis media and their associated expenditures or the factors that influence antibiotic prescribing. METHODS: The study population consisted of 131 169 children during 1991 and 157 065 children during 1992 who were

Hypercalcemia in a patient with hypoparathyroidism and Nocardia asteroides infection: a novel observation.

Hypercalcemia is associated with numerous chronic granulomatous processes and chronic infections. Increased production of 1,25-dihydroxyvitamin D by activated macrophages has been shown to be the cause in most cases. In this article, we describe a case of hypercalcemia related to infection with Nocardia asteroides. In a 34-year-old woman who previously had hypocalcemia, acute hypercalcemia developed coincident with Nocardia pericarditis. The hypercalcemia resolved after treatment of N. asteroides with sulfisoxazole. Parathyroid hormone and phosphorus levels were within normal limits, and total 25-hydroxyvitamin D levels were only mildly increased. After successful treatment of the Nocardia infection, the patient required supplemental calcium and vitamin D. Her hypercalcemia was temporally related to the duration of the N. asteroides infection. We believe this is the first reported case of hypercalcemia associated with N. asteroides infection.

Prophylaxis with amoxicillin or sulfisoxazole for otitis media: effect on the recovery of penicillin-resistant bacteria from children.

The rate of recovery of oropharyngeal penicillin-resistant Streptococcus pneumoniae and aerobic and anaerobic beta-lactamase-producing bacteria (BLPB) from children who received a 4- to 6-month course of prophylaxis with amoxicillin or sulfisoxazole for otitis media was investigated monthly over 9 months. The BLPB recovered were Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, pigmented Prevotella species, and Fusobacterium species. The recovery rate for all penicillin-resistant S. pneumoniae isolates and BLPB increased only after administration of amoxicillin. Before amoxicillin was administered, six BLPB isolates were recovered from four of the children who were to be given this drug (20%). The number of BLPB recovered increased gradually until all of these patients were found to be colonized with BLPB; five (25%) of these patients were found to be colonized with penicillin-resistant S. pneumoniae after 5 months of prophylaxis. Three to five months after amoxicillin prophylaxis was discontinued, the number of BLPB recovered gradually declined; only three children (15%) remained colonized with BLPB, and none remained colonized with penicillin-resistant S. pneumoniae. These data illustrate that amoxicillin prophylaxis induces an increase in the number of penicillin-resistant bacteria in the oropharynx.

[Treatment of acute otitis media]. / Traitement des otites moyennes aiguës.

The treatment of acute otitis media (AOM) has three main aims: to relieve pain, to control fever and in case of suppurative AOM, to overcome the bacterial infection. The two former aims are best managed with salicylates or paracetamol. The local instillation of drops of an anaesthetic-antiseptic solution in the external canal is a useful adjuvant in painful congestive viral otitis. Antibiotherapy is only indicated in suppurative AOM. The most common organisms being Haemophilus influenzae and Streptococcus pneumoniae, amoxicillin is the first line treatment. However, in children who were treated for suppurative AOM in the previous months, amoxicillin/clavulanic acid or a second generation cephalosporin is preferable. Erythromycin-sulfonamide may also be used, particularly in children who are allergic to beta-lactamines. In case of failure of the first choice antibiotic treatment, it is necessary to perform a bacteriological study of the effusion which will determine the appropriate antibiotic to be used in second hand. The duration of the antibiotic treatment must be of 8 days in the absence of spontaneous perforation, and of 10 days in case of perforation. An examination of the tympanum at 10 days is recommended in infants under 6 months of age and in children with repeated AOM. A myringostomy is only indicated when a bacteriological evaluation is needed, mainly in infants under 6 months of age, in immuno-compromised children, and in case of failure of a first line antibiotic treatment.

Urolithiasis as a hazard of sulfonamide therapy.

We identified 40 patients (25 men and 15 women) who developed calculi composed totally or partially of sulfonamides (acetylsulfamethoxazole, sulfadiazine, and acetylsulfisoxazole) between 1980 and 1987. The incidence of sulfonamide stones is less than 1% of stones. Patient characteristics were determined from questionnaires sent to the patients and attending physicians. The majority of patients developed symptoms 1 to 4 weeks after beginning sulfonamide therapy. The bladder was the most common stone location. Obstruction of the urinary system by the acetyl derivatives of the drug is the most serious consequence of sulfonamide therapy. Early recognition of drug-related stones is essential to protect patients from recurrences, reduce the risk of renal complications, and avoid continuing ineffective therapeutic regimens.

Pneumonia caused by Nocardia nova and Aspergillus fumigatus after cardiac transplantation.

Nocardia nova, a newly established species of the Nocardia asteroides complex, has recently been characterized as a human pathogen. This report of a case of pneumonia caused by Nocardia nova and Aspergillus fumigatus in a patient after cardiac transplantation is the first reported infection caused by Nocardia nova following its detailed description. Accurate identification and susceptibility testing of the Nocardia nova isolate allowed successful oral therapy with clarithromycin when therapy with sulfisoxazole was not tolerated.

Comparative efficacy of erythromycin-sulfisoxazole, cefaclor, amoxicillin or placebo for otitis media with effusion in children.

We randomly assigned children with otitis media with effusion to receive either erythromycin-sulfisoxazole, cefaclor, amoxicillin or placebo for a 2-week period, primarily to determine whether either erythromycin-sulfisoxazole or cefaclor would have greater short term efficacy than that found previously for amoxicillin, and secondarily to supplement earlier data on outcomes in placebo-treated subjects. Interim analyses showed no statistically significant (P less than 0.05) differences between the three antimicrobial treatment groups in the primary outcome measures, i.e. the prevalence of middle-ear effusion 2 and 4 weeks after entry, and indicated that postulated differences favoring the erythromycin-sulfisoxazole and cefaclor groups over the amoxicillin group were unlikely to be found even if the originally calculated sample size were attained. Subject accrual was therefore terminated. Final analysis showed no significant between-group differences in other outcome measures as well. In antimicrobial vs. placebo comparisons neither erythromycin-sulfisoxazole nor cefaclor gave more favorable outcomes than placebo, whereas more children were effusion-free in the amoxicillin group than in the placebo group at 2 weeks (31.6% vs. 14.1%, P = 0.007), but not at 4 weeks. We conclude that when antimicrobial treatment for otitis media with effusion is deemed advisable, neither erythromycin-sulfisoxazole nor cefaclor should replace amoxicillin as first line treatment.

Randomized, controlled trial comparing long-term sulfonamide therapy to ventilation tubes for otitis media with effusion.

Several studies have indicated that either the surgical insertion of ventilation tubes (VTs) or long-term treatment with sulfonamide-based antibacterials is effective in the management of otitis media with effusion (OME; otherwise known as serous otitis media, secretory otitis media, and glue ear) when compared with a no-treatment control or placebo. This controlled trial is the first to compare directly the effectiveness of these two treatments for long-standing OME. Outcome variables are treatment success rates, hearing thresholds, recurrent acute otitis media episodes, and side effects of medication or complications of VT placement. One hundred twenty-five children (aged 2.5 to 7 years) who met the usual indications for surgery (long-standing [greater than 3 months] OME and conductive hearing loss) were randomly assigned to "medical" treatment (sulfisoxazole 75 mg/kg per day for 6 months) or "surgical" treatment (bilateral insertion of VTs). Subjects underwent pure-tone audiometry (500, 1000, 2000, 4000 Hz) and otomicroscopic examination at 2, 4, 6, 12, and 18 months. A significantly greater proportion of medical subjects (67%) than surgical subjects (48%) were treatment failures at 6, 12, or 18 months (P = .0208). Surgical subjects had significantly better hearing at 2 and 4 months (P values less than .01) but not at 6, 12, and 18 months (P values greater than .2). A significantly greater proportion of surgical subjects (50%) experienced complications of treatment than did medical subjects (9%) (P less than .001). Thirty-three percent of candidates for VT placement did not require surgery when treated with a 6-month course of sulfisoxazole.(ABSTRACT TRUNCATED AT 250 WORDS)

Nocardial brain abscesses in a pregnant woman.

We describe what we believe to be the second case in which a pregnancy was complicated by the formation of brain abscesses due to Nocardia asteroides; this case may be the first one in which no risk factor for the infection (other than the pregnancy itself) could be found. Craniotomy with surgical drainage of the abscesses, combined with prolonged antimicrobial therapy, led to clinical cure in the mother, and she gave birth to an unaffected infant. This case illustrates the difficulty in treating a nocardial infection of the brain during pregnancy as well as the importance of achieving adequate surgical drainage of the abscesses.