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.

Studies on the epidemiology of Escherichia coli infections. V. Factors influencing acquisition of specific serologic groups.

Stool carrier rates of Escherichia coli serogroups 4, 6, and 75 were determined on admission and discharge for 190 patients. Persons who were in the hospital 3 weeks or longer had an intestinal carrier rate of 46% compared to a rate of 28% in individuals who had no recent hospital contact. Treatment with broad spectrum antibiotics increased the susceptibility for acquisition of certain specific serologic groups. This was apparently not related to replacement of sensitive E. coli by drug-resistant forms. Studies were made to determine the environmental source for colonization of hospitalized patients and the risk of urinary infection in stool carriers of these strains. A survey of inanimate objects of medical and urological wards demonstrated infrequent isolation of 04, 06, and 075, indicating that extraintestinal foci were an unlikely source for hospital-acquired E. coli. Hemagglutination titers with determination of group-specific O antibody failed to demonstrate any deficiency in hospitalized patients who became colonized with certain coliforms. Similarly, no significant deficit in group-specific serum antibody was found in patients who were community carriers of E. coli 04, 06, or 075. Despite a high rate of acquisition of E. coli serogroups 4, 6, and 75 in the stools of hospitalized patients, only those patients undergoing urinary tract manipulation developed bacteriuria.

Etiology of nongonococcal urethritis. Evidence for Chlamydia trachomatis and Ureaplasma urealyticum.

Chlamydia trachomatis, Ureaplasma urealyticum (T-mycoplasma), and Hemophilus vaginalis have previously been considered possible etiological agents in nongonococcal urethritis (NGU). In this study, current C. trachomatis infection was confirmed by culture and (or) micro-immunofluorescence serology in 26 of 69 men experiencing afirst episode of NGU, and 1 of 39 with no urethritis. Serum IgM immunofluorescent antibody to chlamydia was demonstrated in 16 of 20 men with chlamydia culture positive NGU, and 3 of 39 with chlamydia culture negative NG, and none of 34 with no urethritis. 9 of 10 culture positive men with less than or equal to 10 days symptoms developed immunofluorescent antibody seroconversion in paired sera. U. realyticum was isolated significantly more often and in significantly higher concentration from first voided urine from chlamydia-negative cases of NGU than from chlamydia-positive NGU. Ureaplasmacidal antibody titers increased fourfold in six men, four of whom had negative cultures for for unreaplasma. H. vaginalis was isolated from c9 of 33 men with no urethritis and 2 of 69 with NGU. C. trachomatis is susceptible, and U. urealyticum is resistant to sulfonamides. A 10-day course of sulfisoxazole therapy produced improvement in 13 of 13 chlamydia-positive, unreaplasma-negative, and only 14 of 29 chlamydia-negative, unreaplasma-positive NGU cases (P less than 0.002). Thus, culture, serology, and response to therapy support the etiologic role of chlamydia in NGU. Quantitative culture and response to therapy suggest U. unrealyticum may cause many cases of chlamydia-netative NGU.

Sulfonamide-induced hemolytic anemia and hemoglobin Hasharon.

A patient with Hb Hasharon had severe hemolytic anemia after several days of daily ingestion of 2 gm of sulfisoxazole. After recovery, her erythrocytes were incubated with the drug, leading to preferential oxidation and precipitation of the abnormal hemoglobin. Since carboxyhemoglobin and cyanmethemoglobin Hasharon were as stable in the heat stability test as identically liganded Hb A, we conclude that the substitution of the hydrophilic aspartate residue by histidine on the surface of the molecule at alpha47 has led by a still unknown mechanism to an interaction of hemoglobin with the drug that labilized the heme-globin bond. Since Hb Hasharon has been found in several unrelated families, the risk of drug-induced hemolytic anemia in such carriers deserves emphasis.

Nonsurgical treatment of cerebral nocardiosis.

In previously healthy, 49-year-old man, CNS infection due to Nocardia asteroides was manifested initially as sterile meningitis and then as a single large brain abscess and was treated successfully with medical therapy alone. Resolution of the brain abscess was documented with serial computed tomographic scans. The strain of N asteroides was sensitive to both sulfisoxazole and ampicillin. Although surgical intervention must always be considered in the treatment of brain abscess caused by N asteroides, medical therapy is preferable if the patient responds initially.

Synergistic anti-Pneumocystis carinii effects of erythromycin and sulfisoxazole.

Pneumocystis carinii pneumonitis was effectively prevented in 90% of immunosuppressed rats by the administration of 100 mg of erythromycin and 300 mg/kg/day of sulfisoxazole. All of the untreated control and erythromycin-treated animals developed the infection and 80% of rats given sulfisoxazole alone had the pneumonitis. A similar pattern of response occurred when the drugs were used therapeutically for rats with established P. carinii pneumonitis. The erythromycin and sulfisoxazole ratio of 1:3 was the most effective of several dose combinations tested. The established safety record from three decades of clinical use of this drug combination plus the broad spectrum of coverage for other causes of diffuse pneumonitis such as Chlamydia, Mycoplasma, and Legionella warrant further study of erythromycin-sulfisoxazole in AIDS patients.

IgM and IgG antibody response in two immunosuppressed patients with Legionnaires' disease. Evidence of reactivation of latent infection.

Two patients in whom pneumonia due to Legionella pneumophila developed while they were receiving immunosuppressive therapy had serologic evidence of prior infection with the same serogroup of L. pneumophila two and eight months prior to their clinical pneumonia. This suggests that the pneumonia in these patients may have been due to the reactivation of a latent infection, possibly due to their immunosuppressed state. A new enzyme-linked immunosorbent assay (ELISA) was developed to detect IgG and IgM antibodies to L. pneumophila, and the kinetics of these antibody responses were useful diagnostically.

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)

Purulent ocular discharge in neonates: significance of Chlamydia trachomatis.

We obtained cultures for bacteria and chlamydiae from 100 infants with conjunctivitis that began during the first month of life. Sixty-nine infants were evaluated during well-child visits (group A); 31 were seen specifically for the ocular discharge (group B). Potentially pathogenic bacteria, predominantly Staphylococcus aureus, were cultured from one third of the infants in each group. Chlamydia trachomatis was recovered from three infants (4%) in group A and from ten (32%) in group B. Three infants with chlamydial conjunctivitis (two in group A, one in group B) had only mild inflammation. Initial treatment with topical antibiotics was unsuccessful in eliminating the organism from seven of 11 infants.

Sulfisoxazole chemoprophylaxis for frequent otitis media.

Sulfisoxazole, 75 mg/kg/d in two divided doses for 3 months, was administered in a double-blind placebo crossover study to 35 children aged 6 months to 5 years who had frequent recurring episodes of otitis media. There was a 40% reduction in the rate of otitis media among patients receiving sulfisoxazole compared with those receiving placebo (0.25 v 0.42 episode per patient-month) which did not depend on age, sex, season, or several other factors. Using a randomized order, among patients who received placebo first, there was a 64% reduction on sulfisoxazole therapy compared with placebo (0.20 v 0.56 episode per patient-month). In this subgroup, there was significant improvement in eustachian tube function according to serial tympanograms. In the patients who received sulfisoxazole first, the rate of acute otitis remained low on placebo (0.28 v 0.30 episode per patient-month), and tympanogram patterns continued to improve after discontinuation of the active drug. These differences suggest a carry-over effect from the benefits of chemoprophylaxis. There was no significant difference in the species or sensitivity patterns of bacteria isolated from patients receiving sulisoxazole or placebo. Sulfisoxazole chemoprophylaxis appears to be safe and effective in significantly reducing episodes of otitis media and improving tympanogram patterns.

Treatment of chlamydial pneumonia of infancy.

Infants with untreated chlamydial pneumonia shed Chlamydia trachomatis and are symptomatic for may weeks. We used sulfisoxazole, 150 mg/kg/day, or erythromycin ethyl succinate, 40 mg/kg/day, for approximately 14 days to treat 32 patients with chlamydial pneumonia of infancy, and observed them for nasopharyngeal shedding of C trachomatis and changing clinical status. All infants stopped shedding chlamydiae soon after treatment was started. After treatment, three of the 25 infants tested again became culture positive (but did not have clinical relapse). All infants improved clinically. In 24 (83%) of 29 infants, where the onset of improvement could be times, improvement began within seven days of starting treatment. Progression to complete recovery was observed in 27 of 28 infants examined between two weeks and two months of treatment completion. Neither the existence of concomitant viral infection nor the duration of illness or hospitalization before starting treatment influenced the interval between initiation of treatment and onset of clinical improvement. While these observations do not prove, they are at least compatible with the hypotheses that C trachomatis plays a central etiologic role in this illness and that termination of chlamydial infection is beneficial clinically. Pending the availibility of data from controlled studies, we believe that either of the treatment programs outlined warrant consideration in the clinical management of patients with chlamydial pneumonia of infancy.

Chronic vulvovaginitis in children due to Shigella flexneri.

Although previous reports have implicated Shigella flexneri in resistant or chronic cases of vulvovaginitis in children, no authors have described the clinical findings of this condition. The report presents four cases of persistent vulvovaginitis in prepubertal Indian girls from different reservation communities in Arizona. S. flexneri was isolated in pure culture from the vaginal discharge of each patient. All four cases were characterized by a prolonged vaginitis with a bloody, purulent discharge which responded poorly or not at all to various topical modes of therapy for nonspecific vaginitis. Three cases cleared completely when treated with orally given ampicillin for one week. The striking similarity of these cases suggests that chronic Shigella vulvovaginitis is a recognizable clinical entity and should be considered in the differential diagnosis of persistent vaginitis in children, especially in those from communities where Shigella is endemic.

Nocardiosis in children: report of three cases and review of the literature.

The clinical illnesses observed in three adolescents with Nocardia asteroides infection are described. The organism has been classified as a bacterium and placed in the Actinomycetaceae family. Sulfonamides remain the first choice for chemotherapy but alternative drugs are available and may be essential in successful therapy. Nocardial infections in children indicate the need for evaluation for an underlying immunological deficiency. Nocardia species should be considered as possible causative agents in immunocompromised patients with infection.

Nocardia asteroides pericarditis: report of a case and review of the literature.

In this report, we describe a patient who had purulent Nocardia asteroides pericarditis. In addition, we identified 13 previously suspected and reported cases of Nocardia pericarditis, but only 5 of these studies reported isolation of Nocardia from cultures of pericardial fluid or pericardium. Analysis of the clinical course of these five patients and our patient revealed the importance of long-term sulfonamide antibiotic therapy in combination with surgical pericardial drainage procedures. In our review, only patients who received antibiotics and underwent pericardiectomy survived. Our case substantiates the excellent penetration of sulfisoxazole into the pericardial fluid, even with oral administration of the drug, and provides evidence in support of aggressive management of Nocardia pericarditis.

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.

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.

Comparative efficacies of erythromycin-sulfisoxazole and cefaclor in acute otitis media: a double blind randomized trial.

A prospective double blind trial compared the fixed combination of erythromycin-sulfisoxazole (E/S) with cefaclor in the treatment of acute otitis media. One hundred nineteen children in six centers across Canada were studied. Diagnostic tympanocentesis of 134 ears yielded 135 bacterial isolates: Streptococcus pneumoniae (42%); Haemophilus influenzae (21%); Branhamella catarrhalis (10%); Streptococcus pyogenes (5%); and other bacteria (22%). Seventy-seven percent of strains of B. catarrhalis and 14% of strains of H. influenzae were beta-lactamase producers. E/S exhibited greater in vitro activity against H. influenzae and B. catarrhalis. Twenty-three patients had bacteriologically sterile middle ear fluid. The overall clinical outcome at Days 10 and 31 was identical in both treatment groups. Otoscopic findings improved more rapidly in the E/S group than in the cefaclor group at 10 and 31 days (P less than or equal to 0.04). In cases where pre-treatment middle ear fluid was negative on routine bacterial culture, complete cure at 10 days was observed in 75% of patients treated with E/S but only in 14% of those treated with cefaclor (P = 0.02). Side effects were infrequent and comparable between the test drugs. E/S is at least as effective as cefaclor in the management of acute otitis media and may be superior, particularly for cases not yielding bacteria on routine culture.

Photosensitivity to sulfisoxazole ointment.

A 35-year-old man demonstrated sulfisoxazole diolamine-induced photosensitivity during treatment for staphylococcal blepharitis. This reaction was easily avoided by applying the ointment at bedtime and covering the eyelids during sun-bathing while in therapy. A drug-induced photosensitivity reaction should be considered in cases of staphylococcal blepharitis resistant to or aggravated by eyelid-margin therapy with sulfonamides.