trimethoprim--sulfamethoxazole-drug-combination and Disease-Models--Animal

Topics: Acetamides; Aminoglycosides; Animals; Anti-Bacterial Agents; beta-Lactams; Clindamycin; Daptomycin; Disease Models, Animal; Fluoroquinolones; Fosfomycin; Guidelines as Topic; Humans; Linezolid; Microbial Sensitivity Tests; Oxazolidinones; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Teicoplanin; Tetracyclines; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin

Burkholderia pseudomallei is the causative agent of melioidosis and presents with diverse clinical manifestations. Naturally occurring infection occurs following contamination of cuts or skin abrasions, or ingestion of contaminated water, and occasionally through inhalational of infected soil or water particles. The influence of the route of disease acquisition on the efficacy of medical countermeasures has not been explored in humans or in appropriate animal models. The efficacy of co-trimoxazole against melioidosis acquired by different routes of exposure was assessed in postexposure prophylaxis (PEP) and treatment studies in marmoset models of melioidosis. Following challenge with B. pseudomallei by the inhalational, subcutaneous, or ingestion routes of administration, animals were given co-trimoxazole at 12 hourly intervals for 14 days, starting either 6 h postchallenge or at the onset of fever. Animals were then observed for 28 days. All animals that received antibiotic 6 h postchallenge survived the duration of dosing. All animals that received antibiotics at the onset of fever completed the treatment, but 10%, 57%, and 60% of those with ingestion, subcutaneous, and inhalation challenge relapsed, respectively. Bacteriological and histological differences were observed between placebo-control animals and those that relapsed. Immunological profiles indicate difference between animals given placebo and those that relapsed or survived the duration of the study. A broad T-cell activation was observed in animals that survived. Overall, these data suggest the efficacy of co-trimoxazole, as measured in the incidence of relapse, differs depending on the disease-acquisition route. Therefore, there are implications in treating this disease in regions of endemicity.

Topics: Animals; Anti-Bacterial Agents; Burkholderia pseudomallei; Disease Models, Animal; Humans; Melioidosis; Trimethoprim, Sulfamethoxazole Drug Combination; Water

Antibiotics can alter the gut microbiome (GMB), which may be associated with stone disease. We sought to determine the effect that antibiotics have on the GMB, urine ion excretion and stone formation in genetic hypercalciuric stone-forming (GHS) rats. 116th generation GHS rats were fed a fixed amount of a normal calcium (1.2%) and phosphate (0.65%) diet, and divided into three groups (n = 10): control (CTL) diet, or supplemented with ciprofloxacin (Cipro, 5 mg/day) or Bactrim (250 mg/day). Urine and fecal pellets were collected over 6, 12 and 18 weeks. Fecal DNA was amplified across the 16S rRNA V4 region. At 18 weeks, kidney stone formation was visualized by Faxitron and blindly assessed by three investigators. After 18 weeks, urine calcium and oxalate decreased with Bactrim compared to CTL and Cipro. Urine pH increased with Bactrim compared to CTL and Cipro. Urine citrate increased with Cipro compared to CTL and decreased by half with Bactrim. Calcification increased with Bactrim compared to CTL and Cipro. Increased microbial diversity correlated with decreased urinary oxalate in all animals (R = - 0.46, p = 0.006). A potential microbial network emerged as significantly associated with shifts in urinary pH. Bactrim and Cipro differentially altered the GMB of GHS rats. The Bactrim group experienced a decrease in urine calcium, increased CaP supersaturation and increased calcification. The GMB is likely a contributing factor to changes in urine chemistry, supersaturation and stone risk. Further investigation is required to fully understand the association between antibiotics, the GMB and kidney stone formation.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Calcium; Ciprofloxacin; Disease Models, Animal; Feces; Gastrointestinal Microbiome; Humans; Hypercalciuria; Kidney Calculi; Rats; Renal Elimination; RNA, Ribosomal, 16S; Trimethoprim, Sulfamethoxazole Drug Combination

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the Paracoccidioides genus. Most of the patients with chronic form present sequelae, like pulmonary fibrosis, with no effective treatment, leading to impaired lung functions. In the present study, we aimed to investigate the antifibrotic activity of three compounds: pentoxifylline (PTX), azithromycin (AZT), and thalidomide (Thal) in a murine model of pulmonary PCM treated with itraconazole (ITC) or cotrimoxazole (CMX). BALB/c mice were inoculated with P. brasiliensis (Pb) by the intratracheal route and after 8 weeks, they were submitted to one of the following six treatments: PTX/ITC, PTX/CMX, AZT/ITC, AZT/CMX, Thal/ITC, and Thal/CMX. After 8 weeks of treatment, the lungs were collected for determination of fungal burden, production of OH-proline, deposition of reticulin fibers, and pulmonary concentrations of cytokines and growth factors. Pb-infected mice treated with PTX/ITC presented a reduction in the pulmonary concentrations of OH-proline, associated with lower concentrations of interleukin (IL)-6, IL-17, and transforming growth factor (TGF)-β1 and higher concentrations of IL-10 compared to the controls. The Pb-infected mice treated with AZT/CMX exhibited decreased pulmonary concentrations of OH-proline associated with lower levels of TGF-β1, and higher levels of IL-10 compared controls. The mice treated with ITC/Thal and CMX/Thal showed intense weight loss, increased deposition of reticulin fibers, high pulmonary concentrations of CCL3, IFN-γ and VEGF, and decreased concentrations of IL-6, IL-1β, IL-17, and TGF-β1. In conclusion, our findings reinforce the antifibrotic role of PTX only when associated with ITC, and AZT only when associated with CMX, but Thal did not show any action upon addition.

Topics: Animals; Antifungal Agents; Azithromycin; Cytokines; Disease Models, Animal; Drug Therapy, Combination; Immunosuppressive Agents; Intercellular Signaling Peptides and Proteins; Itraconazole; Male; Mice; Mice, Inbred BALB C; Paracoccidioides; Paracoccidioidomycosis; Pentoxifylline; Pulmonary Fibrosis; Random Allocation; Thalidomide; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

Acinetobacter baumannii is a critical nosocomial pathogen. A. baumannii infections have become a grave challenge due to their ability to develop resistance to different antimicrobial agents. The current study aimed to evaluate the potential synergism and bactericidal activity of a combination of colistin and cotrimoxazole against carbapenem-resistant A. baumannii (CRAB) in a Galleria mellonella model.. Four clinical A. baumannii isolates were biochemically and molecularly identified. Their antimicrobial susceptibility levels were established and the molecular characterization of the carbapenemase-encoding genes was performed. The synergism and bactericidal effect of the colistin/cotrimoxazole combination was assessed using the checkerboard assay and time-kill experiments. An in vivo evaluation of the activity of the combination was performed using the Galleria mellonella model.. A fractional inhibitory concentration index (FICI) of ≤0.5 was found for all strains, indicating that the colistin/cotrimoxazole combination exhibited powerful synergistic activity. The combination displayed both synergistic and bactericidal activity at sub-breakpoint concentrations for all strains. Cotrimoxazole monotherapy showed the least protective activity in the G. mellonella model. The survival rate ranged from 66.7-79.2 % at 24 h and was 29.2-60.4 % at 96 h for the tested isolates. Colistin monotherapy performed better than cotrimoxazole monotherapy; the G. mellonella survival rate ranged from 77.1-97.9 %, at 24 h and from 64.5-72. % at 96 h. The colistin/cotrimoxazole combination improved G. mellonella's survival rate at 96 h remarkably in comparison to colistin or cotrimoxazole monotherapy.. Finally, the combination of colistin and cotrimoxazole appears to be a promising therapeutic option for the management of CRAB-associated infections. It is essential to assess the clinical application and the dose-response relationships of combinations such as colistin plus cotrimoxazole.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Carbapenems; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Humans; Lepidoptera; Microbial Sensitivity Tests; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Animals; Bardet-Biedl Syndrome; Basal Bodies; Cells, Cultured; Cilia; Disease Models, Animal; Flagella; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Microtubule-Associated Proteins; Olfactory Receptor Neurons; Phenotype; Protein Transport; Smell; Trimethoprim, Sulfamethoxazole Drug Combination; Tubulin

This study aimed to investigate the synergistic effects of resveratrol and sulfamethoxazole-trimethoprim (ST) on the treatment of mice experimentally infected by Toxoplasma gondii during the chronic phase of the disease considering infection, behavior, and oxidative/antioxidants profile aspects. For the study, 60 mice were initially divided into two groups: uninfected (n = 24) and infected by T. gondii (n = 36). These two groups were later subdivided into other groups and treated with resveratrol (free and inclusion complex containing resveratrol) alone and co-administered with ST: groups A to D were composed by healthy mice and groups E to J were consisted of animals infected by T. gondii (VEG strain). Treatments began 20 days post-infection for 10 consecutive days with oral doses of 0.5 mg kg(-1) of ST (groups B and F), 100 mg kg(-1) of free resveratrol (groups C and G) and inclusion complex of resveratrol (nanoparticles containing resveratrol) (groups D and H), and lastly an co-administration of both drugs (groups I and J). Behavioral tests (memory, anxiety and locomotion) were performed after treatment. Liver and brain fragments were collected to evaluate pathological changes, brain cysts counts, as well as oxidant and antioxidant levels. A reduction on the number of cysts in the brain of animals treated with both drugs combined was observed; there was also reduced number of lesions on both organs. This drug combined effect was also able to reduce oxidative and increase antioxidant levels in infected mice, which might be interpreted as a resveratrol protective effect. In addition, the combination of ST and resveratrol was able to prevent behavioral changes in infected mice. Therefore, the use of co-administration drugs enhances the therapeutic effect acting on a synergic way, reducing the oxidizing effects of the chemical treatment for toxoplasmosis. In addition, resveratrol in inclusion complex when co-administered with ST showed an improved therapeutic effect of ST reducing oxidative damage, liver damage and the number of cysts in the brain of T. gondii infected mice.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Behavior, Animal; Brain; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Liver; Mice; Oxidants; Oxidative Stress; Resveratrol; Stilbenes; Toxoplasmosis, Animal; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

Sulfonamide hypersensitivity has a high incidence in HIV infection and correlates with low CD4+ counts, but the mechanisms are not understood. The aims of this study were to determine whether trimethoprim/sulfamethoxazole (TMP/SMX) led to SMX adduct formation, immunogenicity, or signs of drug hypersensitivity in SIV-infected rhesus macaques, and whether differences in antioxidants, pro-inflammatory mediators, or SMX disposition were predictive of drug immunogenicity.. Four of 9 of SIV-positive (44%), and 3 of 7 SIV negative (43%) macaques had drug-responsive T cells or antibodies to SMX. Two macaques developed facial or truncal rash; these animals had the highest levels of lymph node drug adducts. Antioxidants, pro-inflammatory mediators, and SMX metabolites were not predictive of drug immunogenicity; however, the Mamu DRB1*0401/0406/0411 genotype was significantly over-represented in immune responders.. Unlike other animal models, macaques develop an immune response, and possible rash, in response to therapeutic dosages of TMP/SMX. Studying more animals with CD4+ counts <200cells/μl, along with moderately restricted ascorbate intake to match deficiencies seen in humans, may better model the risk of SMX hypersensitivity in HIV-infection. In addition, the role of Mamu-DRB1 genotype in modeling drug hypersensitivity in retroviral infection deserves further study.

Topics: Animals; Anti-Infective Agents; Antioxidants; Ascorbic Acid; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cytochrome-B(5) Reductase; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Hypersensitivity; Female; Glutathione; HIV Infections; Interferon-gamma; Lipopolysaccharides; Lymph Nodes; Macaca mulatta; Male; Trimethoprim, Sulfamethoxazole Drug Combination

Trimethoprim-sulfamethoxazole (SXT) is a possible alternative for the treatment of community- and hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) due to the susceptibility of most MRSA strains to the drug. However, after long-term treatment with SXT, thymidine-dependent (TD) SXT-resistant small-colony variants (SCVs) emerge. In TD-SCVs, mutations of thymidylate synthase ([TS] thyA) occur. Until now, it has never been systematically investigated that SXT is triggering the induction and/or selection of TD-SCVs. In our study, we performed induction, reversion, and competition experiments in vitro and in vivo using a chronic mouse pneumonia model to determine the impact of SXT on the emergence of TD-SCVs. SCVs were characterized by light and transmission electron microscopy (TEM) and auxotrophism testing. Short-term exposure of S. aureus to SXT induced the TD-SCV phenotype in S. aureus SH1000, while selection of TD-SCVs with thyA mutations occurred after long-term exposure. In reversion experiments with clinical and laboratory TD-SCVs, all revertants carried compensating mutations at the initially identified mutation site. Competition experiments in vitro and in vivo revealed a survival and growth advantage of the ΔthyA mutant under low-thymidine availability and SXT exposure although this advantage was less profound in vivo. Our results show that SXT induces the TD-SCV phenotype after short-term exposure, while long-term exposure selects for thyA mutations, which provide an advantage for TD-SCVs under specified conditions. Thus, our results further an understanding of the dynamic processes occurring during SXT exposure with induction and selection of S. aureus TD-SCVs.

Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; Chronic Disease; Disease Models, Animal; Drug Resistance, Bacterial; Gene Expression; Genetic Fitness; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred C57BL; Mutation; Pneumonia, Bacterial; Selection, Genetic; Staphylococcal Infections; Thymidine; Thymidylate Synthase; Trimethoprim, Sulfamethoxazole Drug Combination

A deletion of a telomerase RNA component (Terc(-/-)) in C57BL/6 (B6) mice resulted in hematopoietic lineage skewing with increased neutrophils and CD11b(+) myeloid cells and decreased red blood cells and CD45R(+) B lymphocytes when animals reach ages older than 12 months. There was no decline in bone marrow (BM) c-Kit(+)Sca-1(+)Lin(-) (KSL) cells in old Terc(-/-) mice, and the lineage skewing phenomenon was not transferred when BM cells from old Terc(-/-) donors were transplanted into young B6 recipients. Necropsy and histological examinations found minimal to no change in the lung, spleen and liver but detected severe epithelia degeneration, ulceration and infection in small and large intestines, leading to enteritis, typhlitis and colitis in old Terc(-/-) mice. In a mouse model of dextran-sulfate-sodium-induced typhlitis and colitis, development of intestinal pathology was associated with increases in neutrophils and CD11b(+) myeloid cells and a decrease in CD45R(+) B cells, similar to those observed in old Terc(-/-) mice. Treatment of 11-13 month old Terc(-/-) mice with antibiotic trimethoprim-sulfa water reduced neutrophils and myeloid cells and increased B lymphocytes in the blood, indicating that mitigation of intestinal infection and inflammation could alleviate hematological abnormalities in old Terc(-/-) animals.

Topics: Aging; Animals; B-Lymphocytes; Bone Marrow; Bone Marrow Transplantation; Cell Lineage; Colitis; Disease Models, Animal; Female; Flow Cytometry; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Mice, Knockout; RNA; Sequence Deletion; Telomerase; Trimethoprim, Sulfamethoxazole Drug Combination

Burkholderia pseudomallei is the causative agent of the disease melioidosis, which is prevalent in tropical countries and is intractable to a number of antibiotics. In this study, the antibiotic co-trimoxazole (trimethoprim/sulfamethoxazole) was assessed for the post-exposure prophylaxis of experimental infection in mice with B. pseudomallei and its close phylogenetic relative Burkholderia mallei, the causative agent of glanders. Co-trimoxazole was effective against an inhalational infection with B. pseudomallei or B. mallei. However, oral co-trimoxazole delivered twice daily did not eradicate infection when administered from 6h post exposure for 14 days or 21 days, since infected and antibiotic-treated mice succumbed to infection following relapse or immunosuppression. These data highlight the utility of co-trimoxazole for prophylaxis both of B. pseudomallei and B. mallei and the need for new approaches for the treatment of persistent bacterial infection.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Burkholderia mallei; Burkholderia pseudomallei; Chemoprevention; Disease Models, Animal; Female; Glanders; Inhalation Exposure; Melioidosis; Mice; Mice, Inbred BALB C; Post-Exposure Prophylaxis; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

Pneumocystis pneumonia (PcP) is a major cause of mortality and morbidity in immunocompromised patients. There are limited alternative therapeutic choices to trimethoprim-sulfamethoxazole (TMP-SMX) which is the standard first line therapy/prophylaxis for PcP. The efficacy of low doses of caspofungin and caspofungin in association with TMP-SMX standard-prophylactic dose was evaluated in an experimental model of Pneumocystis. Susceptibility of Pneumocystis spp. to low doses of caspofungin and caspofungin/TMP-SMX was evaluated in Balb/c immunosuppressed mice, infected intranasally with P. murina. Caspofungin was administered once daily at 0.1 mg/kg, 0.05 mg/kg, and 0.001 mg/kg and TMP-SMX was administered by oral gavage (12.25 mg/62.5 mg/day), for 21 days. Efficacy was calculated based on the reduction in organism burden determined through quantitative fluorescent-based real-time PCR (qPCR). Serum β-1,3-D-glucan was measured as an additional marker of infection. The present data showed that caspofungin demonstrated anti-Pneumomocystis effect. However, the doses administrated were too low to achieve Pneumocystis eradication, which suggests that echinocandin treatment should not be administrated as mono-therapy. After 21 days of treatment, P. murina was not detected in the lungs of mice with either TMP-SMX or caspofungin/TMP-SMX. The results showed that, even at the lowest concentrations tested, the efficacy of caspofungin in association with TMP-SMX was higher than the efficacy of either drug used alone. The administration of caspofungin/TMP-SMX was at least 1.4 times more effective against P. murina infection than TMP-SMX used alone. The most promising result was achieved with the combination of caspofungin 0.05 mg/kg/day with TMP-SMX 12.5 mg-62.5 mg/day, which reduced the parasite burden to undetectable levels immediately at the 14(th) day of treatment, showing a highly marked anti-Pneumomocystis effect. These data suggest that the administration of low doses of caspofungin in combination with low doses of TMP-SMX may provide an improved treatment protocol for Pneumocystis infection clearance.

Topics: Animals; Caspofungin; Disease Models, Animal; Drug Combinations; Echinocandins; Lipopeptides; Male; Mice; Mice, Inbred BALB C; Pneumonia, Pneumocystis; Trimethoprim, Sulfamethoxazole Drug Combination

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) frequently causes skin and soft tissue infections, including impetigo, cellulitis, folliculitis, and infected wounds and ulcers. Uncomplicated CA-MRSA skin infections are typically managed in an outpatient setting with oral and topical antibiotics and/or incision and drainage, whereas complicated skin infections often require hospitalization, intravenous antibiotics, and sometimes surgery. The aim of this study was to develop a mouse model of CA-MRSA wound infection to compare the efficacy of commonly used systemic and topical antibiotics. A bioluminescent USA300 CA-MRSA strain was inoculated into full-thickness scalpel wounds on the backs of mice and digital photography/image analysis and in vivo bioluminescence imaging were used to measure wound healing and the bacterial burden. Subcutaneous vancomycin, daptomycin, and linezolid similarly reduced the lesion sizes and bacterial burden. Oral linezolid, clindamycin, and doxycycline all decreased the lesion sizes and bacterial burden. Oral trimethoprim-sulfamethoxazole decreased the bacterial burden but did not decrease the lesion size. Topical mupirocin and retapamulin ointments both reduced the bacterial burden. However, the petrolatum vehicle ointment for retapamulin, but not the polyethylene glycol vehicle ointment for mupirocin, promoted wound healing and initially increased the bacterial burden. Finally, in type 2 diabetic mice, subcutaneous linezolid and daptomycin had the most rapid therapeutic effect compared with vancomycin. Taken together, this mouse model of CA-MRSA wound infection, which utilizes in vivo bioluminescence imaging to monitor the bacterial burden, represents an alternative method to evaluate the preclinical in vivo efficacy of systemic and topical antimicrobial agents.

Topics: Acetamides; Administration, Oral; Administration, Topical; Animals; Anti-Bacterial Agents; Bacterial Load; Bridged Bicyclo Compounds, Heterocyclic; Clindamycin; Community-Acquired Infections; Daptomycin; Diabetes Mellitus, Type 2; Disease Models, Animal; Diterpenes; Doxycycline; Linezolid; Luminescent Measurements; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred C57BL; Mupirocin; Oxazolidinones; Skin; Soft Tissue Infections; Staphylococcal Infections; Staphylococcal Skin Infections; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin; Wound Healing

The US Public Health Emergency Medical Countermeasures Enterprise convened subject matter experts at the 2010 HHS Burkholderia Workshop to develop consensus recommendations for postexposure prophylaxis against and treatment for Burkholderia pseudomallei and B. mallei infections, which cause melioidosis and glanders, respectively. Drugs recommended by consensus of the participants are ceftazidime or meropenem for initial intensive therapy, and trimethoprim/sulfamethoxazole or amoxicillin/clavulanic acid for eradication therapy. For postexposure prophylaxis, recommended drugs are trimethoprim/sulfamethoxazole or co-amoxiclav. To improve the timely diagnosis of melioidosis and glanders, further development and wide distribution of rapid diagnostic assays were also recommended. Standardized animal models and B. pseudomallei strains are needed for further development of therapeutic options. Training for laboratory technicians and physicians would facilitate better diagnosis and treatment options.

Topics: Amoxicillin-Potassium Clavulanate Combination; Animals; Anti-Bacterial Agents; Burkholderia mallei; Burkholderia pseudomallei; Ceftazidime; Disease Models, Animal; Disease Susceptibility; Glanders; Humans; Melioidosis; Meropenem; Post-Exposure Prophylaxis; Risk Factors; Thienamycins; Trimethoprim, Sulfamethoxazole Drug Combination

The T cell-mediated immune response elicited by Pneumocystis plays a key role in pulmonary damage and dysfunction during Pneumocystis carinii pneumonia (PcP). Mice depleted of CD4(+) and CD8(+) T cells prior to infection are markedly protected from PcP-related respiratory deficit and death, despite progressive lung infection. However, the therapeutic effectiveness of Ab-mediated disruption of T cell function in mice already displaying clinical symptoms of disease has not been determined. Therefore, a murine model of PcP-related immune reconstitution inflammatory syndrome was used to assess whether Ab to the pan-T cell molecule CD3 is effective for reducing the severity of PcP when administered after the onset of disease. Mice that received anti-CD3 Ab exhibited a rapid and dramatic halt in the PcP-associated pulmonary function decline within 1 week after treatment, and a striking enhancement of survival rate compared with mice receiving the control Ab. Physiologic improvement in anti-CD3 treated mice was associated with a significant reduction in the number of CD4(+) and CD8(+) T cells recovered in lung lavage fluid. This effectiveness of anti-CD3 was noted whether the mice also received antibiotic therapy with trimethoprim-sulfamethoxazole. These data suggest that monoclonal Ab-mediated disruption of T cell function may represent a specific and effective adjunctive therapy to rapidly reverse the ongoing pathologic immune response occurring during active PcP. Thus, the anti-human CD3 monoclonal Ab OKT3, which is already in clinical use, has the potential to be developed as an adjunctive therapy for PcP.

Topics: Animals; Anti-Infective Agents; Antibodies; Bronchoalveolar Lavage Fluid; CD3 Complex; Disease Models, Animal; Inflammation; Lymphocyte Depletion; Mice; Pneumonia, Pneumocystis; Reverse Transcriptase Polymerase Chain Reaction; Trimethoprim, Sulfamethoxazole Drug Combination

The present study reports on the preparation and testing of a sustained delivery system for the immunomodulatory peptide P10 aimed at reducing the in vivo degradation of the peptide and the amount required to elicit a protective immune response against paracoccidioidomycosis.. BALB/c mice were infected with the yeast Paracoccidioides brasiliensis to mimic the chronic form of paracoccidioidomycosis. The animals were treated daily with sulfamethoxazole/trimethoprim alone or combined with peptide P10, either emulsified in Freund's adjuvant or entrapped in poly(lactic acid-glycolic acid) (PLGA) nanoparticles at different concentrations (1 microg, 5 microg, 10 microg, 20 microg or 40 microg.50 microL(-1)). Therapeutic efficacy was assessed as fungal burden in tissues and the immune response by quantitative determination of cytokines.. Animals given combined chemotherapy and P10 nanotherapy presented a marked reduction of fungal load in the lungs, compared with the non-treated animals. After 30 days of treatment, P10 entrapped within PLGA (1 microg.50 microL(-1)) was more effective than 'free' P10 emulsified in Freund's adjuvant (20 microg.50 microL(-1)), as an adjuvant to chemotherapy. After treatment for 90 days, the higher doses of P10 entrapped within PLGA (5 or 10 microg.50 microL(-1)) were most effective. Treatment with P10 emulsified in Freund's adjuvant (20 microg.50 microL(-1)) or P10 entrapped within PLGA (1 microg.50 microL(-1)) were accompanied by high levels of interferon-gamma in lung.. Combination of sulfamethoxazole/trimethoprim with the P10 peptide entrapped within PLGA demonstrated increased therapeutic efficacy against paracoccidioidomycosis. P10 incorporation into PLGA nanoparticles dramatically reduced the peptide amount necessary to elicit a protective effect.

Topics: Animals; Anti-Infective Agents; Delayed-Action Preparations; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Carriers; Drug Therapy, Combination; Freund's Adjuvant; Glycoproteins; Immunologic Factors; Lactic Acid; Male; Mice; Mice, Inbred BALB C; Nanoparticles; Paracoccidioides; Paracoccidioidomycosis; Peptide Fragments; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Trimethoprim, Sulfamethoxazole Drug Combination

Currently, for actinomycetoma, combined antimicrobial therapy is preferred to the use of a single compound. This is in order to provide a broader-spectrum coverage due to a combinatory or synergistic effect between the drugs, and to decrease the possibility of emergence of natural resistant strains. A new oxazolidinone pro-drug, DA-7218 [(R)-3-(4-(2-(2-methyltetrazol-5-yl)-pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl) methyl-disodium-phosphate] (recently re-named TR-701), has shown very good in vitro and in vivo activities against several gram-positive bacteria including Nocardia spp.. In the present work we evaluated the effect of DA-7218 at two different doses, alone and combined with trimethoprim/ sulfamethoxazole (SXT), in an experimental Nocardia brasiliensis actinomycetoma murine model. We also included a negative and a positive control group (linezolid and saline solution respectively).. At the end of the treatment period, we observed a clinically and statistically significant difference among the drug receiving groups (combined, alone and linezolid) and the control group (P=0.004). The difference was higher (P= 0.004) between the groups receiving DA-7218 (25mg/kg) alone or combined with SXT, and the control group (saline solution).. In this work we proved that DA-7218 alone and combined with SXT is effective in the treatment of experimental actinomycetoma by Nocardia brasiliensis and that it could be potentially useful in the treatment of human actinomycetoma.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Disease Models, Animal; Drug Therapy, Combination; Female; Mice, Inbred BALB C; Nocardia; Nocardia Infections; Organophosphates; Oxazoles; Trimethoprim, Sulfamethoxazole Drug Combination

Controversy exists about the most effective treatment options for community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and about the ability of these strains to develop inducible resistance to clindamycin during therapy. Using both in vitro pharmacodynamic and murine thigh infection models, we evaluated and compared several antimicrobial compounds against CA-MRSA. Strains with inducible macrolide lincosamide-streptogramin type B (iMLS(B)) resistance and strains in which resistance was noninducible were evaluated. Two levels of inocula (10(5) and 10(7)) were evaluated for clindamycin activity in the in vivo model. In both models, the antimicrobial evaluation was performed in triplicate, and bacterial quantification occurred over 72 h, with drug doses that were designed to simulate the free drug area-under-the-concentration-time curve values (fAUCs) obtained from human samples. When the activity of clindamycin against the iMLS(B) strains was evaluated, constitutive resistance was noted at 24 h (MIC of >256), and failure was noted at an inoculum of > or =10(6) in the in vivo models. However, at a low inoculum (10(5)) in the murine thigh-infection model, clindamycin demonstrated modest activity, reducing the CFU/thigh count for clindamycin resistance-inducible strains at 72 h (0.45 to 1.3 logs). Overall, administration of daptomycin followed by vancomycin demonstrated the most significant kill against all strains in both models. Against the clindamycin noninducible strain, clindamycin and doxycycline demonstrated significant kill. Doxycycline, linezolid, and trimethoprim-sulfamethoxazide (not run in the murine model) demonstrated bacteriostatic activity against clindamycin resistance-inducible isolates. This study demonstrates that clindamycin's activity against the iMLS(B) strains tested is partially impacted by inoculum size. At present, there are several alternatives that appear promising for treating clindamycin resistance-inducible strains of CA-MRSA.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Clindamycin; Colony Count, Microbial; Community-Acquired Infections; Culture Media; Daptomycin; Disease Models, Animal; Doxycycline; Drug Resistance, Bacterial; Humans; Linezolid; Methicillin Resistance; Mice; Microbial Sensitivity Tests; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Thigh; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin

Sulphonamide antimicrobials, such as sulphamethoxazole (SMX), provide effective infection prophylaxis in immunocompromised patients, but can lead to drug hypersensitivity (HS) reactions. These reactions also occur in dogs, with a similar time course and clinical presentation as seen in humans.. Drug-serum adducts and anti-drug antibodies have been identified in sulphonamide HS humans. The aim of this study was to determine whether similar markers were present in dogs with sulphonamide HS.. Thirty-four privately owned sulphonamide HS dogs, 10 sulphonamide-'tolerant' dogs, 18 sulphonamide-naïve dogs, and four dogs experimentally dosed with SMX and the oxidative metabolite SMX-nitroso, were tested for drug-serum adducts by immunoblotting, and anti-drug antibodies by ELISA.. Sulphonamide-serum adducts were found in 10/20 HS dogs tested (50%), but in no tolerant dogs. Anti-sulphonamide IgG antibodies were detected in 17/34 HS dogs (50%), but in only one tolerant dog; antibody absorbance values were significantly higher in HS dogs. There was a significant association between the presence of sulphonamide-serum adducts and anti-sulphonamide antibodies (P = 0.009). Anti-drug antibodies were also found in dogs experimentally dosed with SMX-nitroso followed by SMX, but not in a dog dosed with drug vehicle, followed by SMX.. Similar humoral markers are present in dogs and humans with sulphonamide HS, supporting the use of dogs as a naturally occurring model for this syndrome in humans. These data suggest the potential use of drug-serum adducts and anti-drug antibodies as markers for sulphonamide HS. Preliminary data indicate that anti-sulphonamide antibodies may be triggered by the SMX-nitroso metabolite, not by the parent drug, in dogs.

Topics: Animals; Anti-Infective Agents; Antibody Specificity; Blood Proteins; Cross Reactions; Disease Models, Animal; Dogs; Drug Hypersensitivity; Enzyme-Linked Immunosorbent Assay; Female; Immunoglobulin G; Male; Protein Binding; Sulfamethoxazole; Sulfonamides; Trimethoprim, Sulfamethoxazole Drug Combination

Isogenic mouse strains have previously been characterized as susceptible or resistant to Paracoccidioides brasiliensis infection; the former presented anergy in delayed-type hypersensitivity reactions (DTH) and progressive disease with high numbers of colony-forming units (CFU), while the later presented preserved DTH responses and control of the infectious process. Here, we studied whether susceptible mice infected with P. brasiliensis and treated with the antifungal drug trimethoprim-sulfamethoxazole (SXT) had their behavior pattern altered to the one observed in infected resistant mice. Therapy with either 30 or 150 mg SXT day(-1 )kg(-1), instituted 24 h after infection, elicited more adequate DTH responses than those of non-treated mice, and also diminished the number of viable fungi in the spleen and lungs, but not in epiploo and liver, indicating a partial control of the infectious process. This phenomenon was confirmed by histopathological analyses, in which the spleen was found to be the organ in which differences between the treated and non-treated groups were most remarkable. In control non-treated mice, the spleen parenchyma showed multiple granulomatous foci presenting giant cells, plasmocytes and many yeasts of P. brasiliensis with well-preserved morphology and abundant budding, whereas SXT-treated mice, independently of the dosage used, had no granulomas within the parenchyma and only few capsular lesions, mainly composed of pseudoxantomatous macrophages. Treatment with 150 mg day(-1 )kg(-1) (the dose considered to evoke best responses in CFU assays when therapy was instituted 24 h after infection), initiated at different times after infection, did not led to sustained DTH reactions, but provided an effective control of the disease when therapy began until the 15(th) day post infection, as showed by CFU assays. We conclude that reversal from the susceptible to the resistant pattern in experimental paracoccidioidomycosis can occur, but only when therapy with an adequate SXT dosage is instituted at a very initial phase of the infection. These protocols may constitute a model for further investigations concerning responses during antifungal therapy.

Topics: Animals; Anti-Infective Agents; Colony Count, Microbial; Disease Models, Animal; Female; Hypersensitivity, Delayed; Liver; Lung; Mice; Paracoccidioides; Paracoccidioidomycosis; Spleen; Trimethoprim, Sulfamethoxazole Drug Combination

A rapid, continuous method for noninvasively monitoring the effectiveness of several antibacterial agents in real time by using a model of wound infection was developed. This study was divided into three steps: (i) construction of a plasmid to transform Escherichia coli into a bioluminescent variant, (ii) study of the bioluminescent E. coli in vitro as a function of temperature and pH, and (iii) determination of the MIC and the minimal bactericidal concentration of sulfamethoxazole-trimethoprim (SMX-TMP). Finally, the efficacy of SMX-TMP was monitored in vivo in a cutaneous wound model (hairless rat) infected with this bioluminescent bacterium by using a bioluminescence imaging system. E. coli was transformed by electroporation with a shuttle vector (pRB474) containing the firefly (Photinus pyralis) luciferase gene, resulting in a bioluminescent phenotype. It was found that pH 5.0 was optimal for incorporation of the susbstrate D-luciferin for the luciferase reaction. In vitro, when the agar dilution method, standard turbidity assays, and the bioluminescence imaging system were used, E. coli(pRB474) proved to be susceptible to SMX-TMP. In vivo, at 4 h, SMX-TMP treatment was already efficient compared to no treatment (P = 0.034). At 48 h, no bioluminescence was detected in the wound, demonstrating the susceptibility of E. coli to SMX-TMP. In conclusion, this study points out the advantage of using bioluminescence imaging to evaluate the effects of antibiotics for the treatment of acute infections in vivo in a nondestructive and noninvasive manner.

Topics: Animals; Anti-Bacterial Agents; Colony Count, Microbial; Disease Models, Animal; DNA Primers; Drug Therapy, Combination; Escherichia coli; Escherichia coli Infections; Hydrogen-Ion Concentration; Luminescent Measurements; Male; Microbial Sensitivity Tests; Plasmids; Rats; Reverse Transcriptase Polymerase Chain Reaction; Temperature; Transformation, Bacterial; Trimethoprim, Sulfamethoxazole Drug Combination; Wound Infection

Melioidosis is caused by the Gram-negative bacillus Burkholderia pseudomallei. Most clinical reports of disease are from south-east Asia and northern Australia. The organism is intrinsically resistant to most commonly available antibiotics. Standard therapy includes ceftazidime either alone or in combination with co-trimoxazole. The clinical advantage in adding co-trimoxazole has never been determined; nor has the activity of newer, fourth-generation cephalosporins, such as cefepime, been studied in the treatment of this condition. BALB/c mice have been shown to represent an animal model of melioidosis. This animal model was used in this study to compare the efficacy of ceftazidime and cefepime alone or with co-trimoxazole, in the therapy of melioidosis. Antibiotic levels in the mice were determined by HPLC, and dosing was modified to keep plasma antibiotic levels at or above the MIC for the organism-antibiotic combination for a significant part of a 12 h period. Bacterial load, as determined by splenic counts, showed that ceftazidime in combination with co-trimoxazole was the most effective therapeutic option. The animal model described in this study can be used as a preliminary evaluation of therapeutic options for melioidosis.

Topics: Acute Disease; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Cefepime; Ceftazidime; Cephalosporins; Disease Models, Animal; Drug Therapy, Combination; Injections, Intraperitoneal; Melioidosis; Mice; Mice, Inbred BALB C; Trimethoprim, Sulfamethoxazole Drug Combination

Hematogenous spread of bacillus Calmette-Guerin (BCG) after intravesical instillation for bladder cancer is rare but it may result in systemic infection and hypersensitivity reaction. We investigated fluoroquinolones and steroids in an animal model to improve the therapeutic options in local and systemic BCG infection. Furthermore, the antitumor effectiveness of intravesical BCG with simultaneous application of fluoroquinolones and/or steroids was tested.. Oral antimicrobial therapy with and without steroids was started immediately after intraperitoneal injection using fluoroquinolones or trimethoprim-sulfamethoxazole. To evaluate the therapeutic options against a hyperergic reaction after repeat systemic BCG infection re-challenge was performed with intraperitoneal BCG 7 days after primary infection and oral therapy was given with fluoroquinolones or trimethoprim-sulfamethoxazole with and without steroids. The influence of continuous oral fluoroquinolone therapy on the antitumor effect of BCG was also tested in the MB 49 orthotopic murine bladder tumor model.. After primary systemic infection fluoroquinolone therapy alone led to significantly prolonged survival in mice (log rank test p = 0.041), whereas trimethoprim-sulfamethoxazole was ineffective. There was no additional effect of steroid administration. Steroids alone led to premature death (log rank test p = 0.022). After secondary BCG infection only steroid treated animals had prolonged survival (log rank test p = 0.032), whereas antimicrobials alone had no effect. The therapeutic efficacy of BCG in the orthotopic bladder tumor model was not affected by continuous oral fluoroquinolones in terms of survival (log rank test p = 0.001) or bladder weight (Wilcoxon test p = 0.001) compared with untreated controls.. In a mouse model fluoroquinolones had a beneficial effect for primary systemic BCG infections, whereas the hyperergic reaction after repeat BCG infection was susceptible only to steroids. Administering fluoroquinolones during an intravesical treatment course does not affect the antitumor efficacy of BCG.

Topics: Animals; Cell Survival; Ciprofloxacin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Injections, Intraperitoneal; Mice; Mice, Inbred C57BL; Mycobacterium bovis; Ofloxacin; Prednisolone; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis; Tumor Cells, Cultured; Urinary Bladder Neoplasms; Virulence

One of the more perplexing aspects of urinary tract infections (UTIs) is their high propensity to recur. It has been proposed that recurrent infections are a result of the reintroduction of bacteria from the gastrointestinal tract (GIT) to the urinary tract (UT); however, since a significant subset of recurrent UTIs are caused by an identical bacterial strain, it has been challenging to formally prove this hypothesis for same-strain recurrences by using epidemiologic approaches. We present data here obtained by using a mouse model of UTIs in which it was shown that 36% (5 of 14) of mice infected with uropathogenic Escherichia coli (UPEC) will have at least one bacteriuric recurrence, with 21% (3 of 14) having more than one recurrence during a 6-week period after an acute UTI. Intraurethrally infected mice develop UPEC reservoirs in both their feces and their bladders. Ten days of trimethoprim-sulfamethoxazole (SXT) therapy reduces urinary recurrences and eradicates fecal colonization, whereas 3 days of SXT treatment has no effect over a twenty-eight-day observation period despite clearing fecal colonization acutely. Interestingly, SXT is unable to eradicate bacteria from the bladder reservoir even after a 10-day treatment regimen, thus demonstrating that the bladder reservoir can persist even in the face of long-term antibiotic therapy.

Topics: Animals; Anti-Infective Agents, Urinary; Bacteriuria; Disease Models, Animal; Escherichia coli; Escherichia coli Infections; Feces; Female; Mice; Mice, Inbred C57BL; Recurrence; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Urinary Bladder; Urinary Tract Infections

The synthesis and biological properties of a novel water-soluble echinocandin-like lipopeptide, FR131535, are described. This compound displayed potent in vitro and in vivo antifungal activities. The hemolytic activity of FR901379 was reduced by replacing the acyl side chain. This compound showed good water-solubility, comparable to the natural product FR901379.

Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Bronchogenic Cyst; Candida albicans; Candidiasis; Disease Models, Animal; Echinocandins; Female; Fungal Proteins; Glucosyltransferases; Hemolysis; Membrane Proteins; Mice; Mice, Nude; Peptides; Peptides, Cyclic; Pneumonia, Pneumocystis; Schizosaccharomyces pombe Proteins; Solubility

Congenital toxoplasmosis is still one of the most frequent causes of fetal death. Despite a significant improvement in diagnosis, particularly in utero diagnosis, maternal treatment is only partially effective in preventing transmission to the fetus and treating fetal infection. Maternal treatment is based on drugs developed 50 years ago, which may have limited efficacy (spiramycin) or serious side-effects (pyrimethamine). Data on the use of cotrimoxazole in mouse models of toxoplasmosis and for preventing toxoplasmic encephalitis in patients suffering from AIDS have led Francis Derouin and colleagues to consider the potential of cotrimoxazole for prenatal prevention and treatment of toxoplasmic fetal death.

Topics: Animals; Anti-Infective Agents; Disease Models, Animal; Female; Humans; Mice; Pregnancy; Pregnancy Complications, Parasitic; Toxoplasmosis; Toxoplasmosis, Animal; Toxoplasmosis, Congenital; Trimethoprim, Sulfamethoxazole Drug Combination

To determine whether treatment with an antibiotic (trimethoprim-sulfamethoxazole) reduced the inflammatory response in a murine form of Streptococcus pneumoniae-induced rhinosinusitis.. We randomized 18 C57BL/6 mice to either treatment with intraperitoneal trimethoprim-sulfamethoxazole (Bactrim, 30 mg/kg) or no treatment (control). After 2 days, we inoculated all C57BL/6 mice intranasally with a Bactrim-susceptible strain of Streptococcus pneumoniae, ATCC 49619, suspended in Trypticase soy broth. At day 5 after bacterial inoculation, we sacrificed the mice and prepared histopathologic sections of their sinuses after culturing their nasal cavities by lavage.. Animal care facility at a tertiary, academic institution.. The histopathologic sections of the sinuses were examined in a blind manner for the percent of sinus cavity area occupied by neutrophil clusters, and for the number of neutrophils per square millimeter of sinus mucosa.. The Bactrim group had a significantly smaller sinus area occupied by neutrophil clusters (1.58% +/- 1.13 vs 4.38% +/- 3.41; P < 0.05), significantly fewer neutrophils infiltrating the mucosa (58.81 +/- 29.63/mm2 vs 105.85 +/- 48.49/mm2; P < 0.05), and significantly less growth of Streptococcus pneumoniae colonies in the intranasal cultures (8 few and 1 moderate vs 3 few, 3 moderate, and 1 many; P = 0.05) compared to the control group.. In our murine model of acute rhinosinusitis, Bactrim decreased the number of neutrophil clusters in the sinus cavities, the number of neutrophils infiltrating the sinus mucosa, and the growth of Streptococcus pneumoniae. We propose that our murine model can be used for the study of the pathophysiology and treatment of acute rhinosinusitis.

Topics: Animals; Disease Models, Animal; Inflammation; Leukocyte Count; Mice; Neutrophils; Rhinitis; Sinusitis; Streptococcal Infections; Streptococcus pneumoniae; Trimethoprim, Sulfamethoxazole Drug Combination

Burkholderia pseudomallei is the causative agent of melioidosis, a disease endemic in tropical and subtropical regions of South-East Asia and Northern Australia. Antimicrobial therapy regimens for treatment of acute septicemic melioidosis are of variable efficacy. Ceftazidime is the current antibiotic of choice and is commonly administered with other agents such as cotrimoxazole or doxycycline. The emergence of resistant strains of B. pseudomallei and the persistence of high mortality rates prompted the present study. Using an established mouse model of acute disseminated B. pseudomallei infection, we compared the efficacy of ceftazidime versus cefpirome in combination with cotrimoxazole or chloramphenicol therapy in vivo. Control mice that were infected but did not receive antibiotic therapy died within 96 hours of infection. No deaths occurred in treatment groups receiving either cephalosporin or cotrimoxazole, despite the demonstrated resistance of B. pseudomallei to cotrimoxazole in vitro. The mortality rate in treatment groups receiving either cephalosporin and chloramphenicol was 66%. These results demonstrate a comparable level of efficacy between ceftazidime and cefpirome for treatment of acute B. pseudomallei infection in mice.

Topics: Animals; Burkholderia pseudomallei; Cefpirome; Ceftazidime; Cephalosporins; Chloramphenicol; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Liver; Melioidosis; Mice; Mice, Inbred BALB C; Spleen; Trimethoprim, Sulfamethoxazole Drug Combination

Antibiotic therapy for infection with Shiga-toxin-producing Escherichia coli O157:H7 is controversial because of the possibility of its inducing hemolytic uremic syndrome and acute encephalopathy. In a previous study, mice with protein-calorie malnutrition were found to be highly susceptible to this pathogen. The efficacy of oral antibiotic therapy in malnourished mice infected with O157 organisms was assessed. Mice fed a low-protein calorie diet were infected intragastrically with 2 x 10(6) colony-forming units of a Shiga-toxin-producing strain of Escherichia coli O157:H7. Infected mice were orally given a therapeutic dose of an antibiotic, including norfloxacin, fosfomycin, kanamycin, ampicillin, clarithromycin or trimethoprim-sulfamethoxazole for 3 days: mice on protocol A received the antibiotic on days 1-3, starting on the day after infection, and mice on protocol B received the antibiotic on days 3-5. The duration of fecal pathogen excretion was shorter and the toxin level in the stool and blood lower in the mice that received protocol A than in untreated mice; all of the mice treated on protocol A survived the lethal infection. All antibiotics except trimethoprim-sulfamethoxazole, administered on protocol B, exhibited the same effect as that exhibited by the respective antibiotic administered on protocol A. Only the mice treated with protocol B of trimethoprim-sulfamethoxazole had a higher toxin level in the blood than untreated controls, resulting in 95% mortality. These results suggest that the antibiotics used in this study, except for trimethoprim-sulfamethoxazole, could reduce the risk of hemolytic uremic syndrome and acute encephalopathy following Escherichia coli O157:H7 infection in humans, and that fosfomycin, in particular, may be relevant for testing in humans.

Topics: Ampicillin; Animals; Anti-Bacterial Agents; Bacterial Toxins; Brain Chemistry; Disease Models, Animal; Disease Progression; Escherichia coli Infections; Escherichia coli O157; Feces; Fosfomycin; Kanamycin; Mice; Mice, Inbred C57BL; Norfloxacin; Protein-Energy Malnutrition; Reference Values; Sensitivity and Specificity; Shiga Toxins; Statistics, Nonparametric; Survival Rate; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

The combination of trimethoprim (TMP) and sulphamethoxazole (SMX) is commonly used for the prevention of cerebral toxoplasmosis although there is no firm experimental basis to support this regimen. We used strain RH tachyzoites for challenge in the acute murine model of toxoplasmosis and found that TMP administered as a single agent, failed to eradicate toxoplasma even at the highest dose (70 mg/kg per day). SMX alone at 600 mg/kg per day, protected ten out of ten mice, although inoculation of brain from surviving animals to naive mice resulted in the development of an encephalitis. When combined, TMP (60 mg/kg per day) and SMX (300 mg/kg per day) protected ten out of ten mice and gave a 'cure' in four out of four mice. In the chronic cystogenic murine models, the combination TMP plus SMX administered from day 5 for 15 days or from day 28 for 288 days, gave protection and even apparent toxoplasmal eradication ('cure') at the highest dosing (60/300 mg/kg per day). However, microscopic severe encephalitis was found in mice classified as 'cured' after reinoculation. This result makes the interpretation of 'cure' very difficult. In conclusion TMP and SMX act synergistically, SMX being the more active arm of the combination. The combination was efficient in preventing the lethal development of chronic toxoplasma encephalitis, but did not guarantee complete recovery.

Topics: Animals; Chronic Disease; Disease Models, Animal; Drug Evaluation; Mice; Sulfamethoxazole; Toxoplasmosis, Animal; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Terbinafine is a synthetic antifungal agent which has recently been found to be highly effective against Pneumocystis carinii. This study evaluated the efficacy of terbinafine on rat P. carinii antigenic profile and the immune response by Western blot analysis, in comparison with atovaquone and co-trimoxazole in rats with pneumocystosis. Terbinafine was shown to target two specific major antigens, particularly those of 116 and 35-40 kDa. Antibodies reactive against these moieties were found in all rats treated with atovaquone and co-trimoxazole, but not in those treated with terbinafine. These surface antigen modifications could be related to disease severity and could provide additional information for monitoring the efficacy of this treatment.

Topics: Animals; Antifungal Agents; Antigens, Fungal; Atovaquone; Blood; Blotting, Western; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Electrophoresis; Immunosuppression Therapy; Male; Naphthalenes; Naphthoquinones; Pneumocystis; Pneumonia, Pneumocystis; Rats; Rats, Sprague-Dawley; Survival Rate; Terbinafine; Trimethoprim, Sulfamethoxazole Drug Combination

The pharmacokinetics of two sulfonamide/trimethoprim combinations were investigated after intravenous administration to clinically healthy pigs and to the same pigs following a challenge with Actinobacillus pleuropneumoniae toxins. Endobronchial challenge with A. pleuropneumoniae toxins resulted in fever, increased white blood cell counts and decreased water and feed consumption. Healthy, as well as febrile, pigs were given sulfadimethoxine (SDM) or sulfamethoxazole (SMX) intravenously at a dose of 25 mg/kg b.w. in combination with 5 mg trimethoprim (TMP) per kg body weight. The pharmacokinetic parameters of the sulfonamides as well as their main metabolites (acetyl sulfonamides) were not significantly different in healthy and febrile pigs. In healthy and pneumonic pigs, the mean elimination half-lives of SDM were 12.9 h and 13.4 h, respectively, those of SMX 2.5 h and 2.7 h, respectively, and those of TMP 2.8 h and 2.6 h, respectively. Distribution volumes in healthy and febrile pigs of SDM and SMX varied between 0.2 and 0.4 L/kg, and those of TMP between 1.1 and 1.6 L/kg. The mean AUC of TMP was decreased and the volume of distribution and total body clearance of TMP were increased in febrile pigs. Protein binding of the drugs and metabolites studied were not significantly changed after toxin-induced fever. The extent of protein binding of SDM, SMX and TMP was in the range 94-99%, 45-56% and 40-50%, respectively. Based on knowledge of in vitro antimicrobial activity of the drug combinations against A. pleuropneumoniae it was concluded that after intravenous administration of the dose administered (30 mg/kg of the combination preparations) to healthy and pneumonic pigs, plasma concentrations of SMX and TMP were above the concentration required for growth inhibition of 50% of A., pleuropneumoniae strains for approximately 16 h, whereas bacteriostatic plasma concentrations of SDM were still present after TMP had been eliminated from plasma. Because of similar elimination half-lives of SMX and TMP in pigs this combination is preferred to the combination of SDM with TMP.

Topics: Actinobacillus Infections; Actinobacillus pleuropneumoniae; Animals; Anti-Bacterial Agents; Bacterial Toxins; Chromatography, High Pressure Liquid; Disease Models, Animal; Drinking; Drug Combinations; Eating; Half-Life; Injections, Intravenous; Male; Metabolic Clearance Rate; Pneumonia, Bacterial; Protein Binding; Regression Analysis; Sulfadimethoxine; Swine; Swine Diseases; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Several drugs have been shown to have anti-Pneumocystis carinii activity in clinical trials. Because of the large number of patients required, no more than 3 drugs can be compared for efficacy in human studies. However, the experimental animal model for P. carinii pneumonitis is remarkably similar to the human disease and was used to compare 10 drugs for the relative potency against this infection. All drugs were compared at doses known to prevent the pneumonitis in > 80% of animals and at one-tenth of this dose. Drugs effective at the lowest dose were further tested at one-hundredth the original doses, and drugs ineffective were retested at 10 and 100 times the original dose. Trimethoprim-sulfamethoxazole was the most effective drug, with azithromycin-sulfamethoxazole and clarithromycin-sulfamethoxazole next most effective. Intravenous pentamidine and clindamycin-primaquine were the least effective. Atovaquone, sulfadoxine-pyrimethamine, erythromycin-sulfisoxazole, PS-15, and dapsone-trimethoprim had intermediate activity.

Topics: Animals; Anti-Infective Agents; Atovaquone; Azithromycin; Clarithromycin; Clindamycin; Clinical Trials as Topic; Dapsone; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Humans; Naphthoquinones; Pentamidine; Pneumocystis Infections; Proguanil; Pyrimethamine; Rats; Sulfadoxine; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

A series of 2,4-diamino-5-methyl-6-(anilinomethyl)pyrido[2,3-d]pyrimidines 4-9 were synthesized as 5-deaza nonclassical antifolates containing trimethoxy, dichloro-, or trichlorophenyl substitutions and a N-H, N-CH3, or N-CHO at the 10-position. The compounds were evaluated as inhibitors of dihydrofolate reductases (DHFR) from Pneumocystis carinii (P. carinii), Toxoplasma gondii (T. gondii), rat liver (RL), and Lactobacillus casei (L. casei); as inhibitors of T. gondii and P. carinii cell growth in culture; and as antitumor agents. The compounds were prepared by modifications of procedures for classical 5-deaza folates. 2,4-Diamino-5-methyl-6-[(3',4',5'-trimethoxy-N- methylanilino)methyl]pyrido[2,3-d]pyrimidine (5a) exhibited high potency as well as selectivity (compared to RL DHFR) for P. carinii and T. gondii DHFR. Compound 5a is one of the most potent and selective nonclassical folate inhibitors of T. gondii DHFR known. The N-10 formyl analogue 2,4-diamino-5-methyl-6-[(N-formyl-3',4',5'-trimethoxyanilino) methyl]pyrido-[2,3-d]pyrimidine (6a) had decreased potency, but it maintained high selectivity for T. gondii DHFR. The corresponding chloro-substituted analogues maintained potency or had decreased potency; N-10 substitution did not increase potency or selectivity to the extent observed in the 3',4',5'-trimethoxy series. Partial reduction of the B ring to afford the dihydro analogue 2,4-diamino-5-methyl-6-[(N-formyl-3',4',5'-trimethoxyanilino) methyl]-5,8-dihydropyrido[2,3-d]pyrimidine (7), its 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine analogue 8, and 2,4-diamino-5-methyl-6-[(3',4',5'-trimethoxyanilino)methyl]-5,6,7, 8- tetrahydropyrido[2,3-d]pyrimidine (9) resulted in a significant decrease in potency. In T. gondii cell culture inhibitory studies, 2,4-diamino-5-methyl-6-[(3',4',5'- trimethoxyanilino)methyl]pyrido[2,3-d]pyrimidine (4a), 5a, and 6a were less potent compared to their DHFR inhibitory potencies. Against P. carinii cells in culture, 4a and 5a at 10 micrograms/mL were as effective as the clinically used combination of trimethoprim/sulfamethoxazole (50/250 micrograms/mL). With the exception of the B ring reduced analogues 7-9, all of the compounds were significantly cytotoxic to leukemia CCRF-CEM cells in culture. The chloro-substituted analogues, in general, were more potent against a variety of other tumor cells in culture than the trimethoxy analogues. These results were corroborated by the preclinical tumor screening program at the Natio

Topics: Animals; Antineoplastic Agents; Disease Models, Animal; Folic Acid Antagonists; Fungal Proteins; Humans; Liver; Mice; Molecular Conformation; Neoplasms, Experimental; Oxidation-Reduction; Pneumocystis; Pneumocystis Infections; Protozoan Proteins; Pyrimidines; Rats; Structure-Activity Relationship; Toxoplasma

To evaluate the efficacy of drugs for treatment, we tried to make an animal model of Pneumocystis carinii (P. carinii) pneumonia. Specific pathogen free (SPF) rats immunosuppressed with corticosteroid were intratracheally inoculated with P. carinii. Six weeks after the inoculation, the lung sections of infected rat lung showed increased numbers of P. carinii in the alveoli and thickening of alveolar septa with mononuclear cell infiltration. From 7 to 9 weeks after inoculation, the intensity of infection became more severe, and some rats died at this period. Then, to evaluate drug efficacy in this model, we finished the drug therapy by the 6th week and used the number of P. carinii in the lung and the inflammation score as an indicator of drug efficacy. In this P. carinii pneumonia animal model, both sulfamethoxazole-trimethoprim clinically established anti P. carinii drug and interferon-gamma which is one of the lymphokines mainly produced by T lymphocytes indicated therapeutic and synergistic efficacy against P. carinii pneumonia.

Topics: Animals; Disease Models, Animal; Drug Synergism; Interferon-gamma; Male; Pneumonia, Pneumocystis; Rats; Rats, Wistar; Trimethoprim, Sulfamethoxazole Drug Combination

Experimental 8-aminoquinolines from Walter Reed Army Institute for Research are effective for prophylaxis or therapy of Pneumocystis carinii pneumonia in rat models. In the present study, primaquine, WR6026, and WR238605 were tested in prophylaxis and treatment models of P. carinii pneumonia to compare the effectiveness of continuous versus intermittent dosing. For treatment of P. carinii pneumonia, the drugs showed detectable effects when given once every 4 days (primaquine and WR6026 at doses greater than 8 mg/kg; WR238605 at doses greater than 2 mg/kg). For prophylaxis, WR6026 and WR238605 were effective given alone daily (WR6026 at doses greater than 0.25 mg/kg; WR238605 at doses greater than 0.57 mg/kg). WR6026 and WR238605 at 4 mg/kg given once every 4 days for prophylaxis were as effective as daily trimethoprim-sulfamethoxazole. These studies suggest that higher doses of 8-aminoquinolines administered at appropriate intervals may be as effective as continuous dosing for prophylaxis of P. carinii pneumonia.

Topics: Aminoquinolines; Animals; Clindamycin; Disease Models, Animal; Drug Administration Schedule; Female; Pneumonia, Pneumocystis; Primaquine; Rats; Rats, Inbred Strains; Specific Pathogen-Free Organisms; Trimethoprim, Sulfamethoxazole Drug Combination

An immunosuppressed rat model of Pneumocystis carinii pneumonia is described that utilizes simple, noninvasive intratracheal (i.t.) inoculation of cryopreserved parasites and results in development of severe P. carinii pneumonia within 5 weeks. This is an improvement over the most commonly used models of P. carinii pneumonia that rely on immune suppression to activate latent P. carinii infections and that often require 8 to 12 weeks to produce heavy infections of P. carinii. It is also less labor intensive than more recent models requiring surgical instillation of parasites. Our report describes a series of preliminary studies to select an appropriate strain of rat; to determine suitable methods for inducing uniform immunosuppression, P. carinii inoculation, and laboratory maintenance of P. carinii; and to determine effective animal husbandry methods for maintaining animals free from serious secondary infections. Results of our more detailed studies demonstrate that animals receiving two or three i.t. inoculations of approximately 10(6) cryopreserved P. carinii organisms have a predictable course of disease progression which includes moderate P. carinii infections within 3 weeks, severe P. carinii pneumonia in 5 weeks, and a high percentage of mortality due to P. carinii pneumonia in 6 weeks. Parasites were distributed evenly between the right and left lungs, regardless of the number of P. carinii inoculations administered. Non-P. carinii-inoculated immunosuppressed control rats maintained in microisolator cages remained free of P. carinii, thus providing an important control that is missing from many P. carinii pneumonia models. Most non-P. carinii-inoculated control animals and P. carinii-inoculated rats treated with trimethoprim-sulfamethoxazole that were housed in open caging in the same room containing heavily infected animals had no detectable infections after 5 to 6 weeks of immunosuppression; however, some had a small number of P. carinii in their lungs. Because heavy, reproducible infections are achieved 5 weeks after i.t. inoculation, because few animals are lost to secondary infections, and because animals can be maintained as noninfected contemporaneous controls, this animal model is useful for the maintenance of P. carinii strains, for studies of the transmission and natural history of P. carinii, for the production of large numbers of organisms for laboratory studies, and for the evaluation of potential anti-P. carinii drugs.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Immunologic; Immunosuppression Therapy; Lung; Methylprednisolone; Pneumonia, Pneumocystis; Rats; Rats, Inbred Strains; Trimethoprim, Sulfamethoxazole Drug Combination

A transtracheally inoculated mouse model of Pneumocystis carinii has been developed using BALB/c mice. The advantage of this strain of mice include that they are widely available, inexpensive, and were not infected with Pneumocystis before inoculation. Inoculated mice that were not treated had a mean infectivity score of 4.1 compared with inoculated mice treated with the effective anti-Pneumocystis drug combination of trimethoprim plus sulfamethoxazole, which had a mean infectivity score of 0.1, an approximately 4 log difference. The inoculated BALB/c mouse provides a model to serve as a valuable addition to rat models currently used, providing a source of organisms from a different host for cross-species comparisons and for studies of drug efficacy for therapy and prophylaxis. The inoculated mouse is especially cost effective and allows testing of compounds in short supply.

Topics: Aminoquinolines; Animals; Antimalarials; Clindamycin; Dexamethasone; Disease Models, Animal; Drug Therapy, Combination; Immunosuppression Therapy; Mice; Mice, Inbred BALB C; Pneumocystis Infections; Primaquine; Trimethoprim, Sulfamethoxazole Drug Combination

The relative sensitivity of imaging with 67Ga-citrate (67Ga) and non-specific human polyclonal IgG radiolabelled with 111In (111In-IgG) for the detection of Pneumocystis carinii pneumonia (PCP) was determined in rats. Pneumocystis carinii pneumonia was induced by low protein diet and dexamethasone. The course of the disease was monitored by serial imaging with 111In-IgG and 67Ga. Diffuse accumulation of both radiopharmaceuticals was observed in the lungs of infected animals (infection was verified by histological examination of the lungs), however, accumulation of 111In-IgG was consistently higher. In rats with early PCP, 111In-IgG imaging revealed pulmonary accumulation in animals with normal chest radiographs and 67Ga scans. In animals successfully treated for PCP, decreased pulmonary accumulation of 111In-IgG coincided with histological improvements. Several animals developed superinfection with bacteria or fungi. These animals had striking focal accumulation of 111In-IgG, in addition to the pattern of generalized uptake. Gallium concentration in these animals did not show this focal accumulation. These observations suggest that 111In-IgG may be useful for detecting PCP and pulmonary abscesses in the immunocompromised host.

Topics: Animals; Dexamethasone; Diet; Disease Models, Animal; Gallium Radioisotopes; Immunoglobulin G; Indium; Indium Radioisotopes; Lung; Male; Pentetic Acid; Pneumonia, Pneumocystis; Radionuclide Imaging; Rats; Rats, Inbred Strains; Sensitivity and Specificity; Technetium Tc 99m Aggregated Albumin; Trimethoprim, Sulfamethoxazole Drug Combination

There are now three methods to evaluate treatments of pneumocystosis: (1) the animal model, using adult rats under corticosteroids; the intensity of infection is assessed on pulmonary appositions and can then be evaluated after administration of a potential treatment compared with a reference; (2) the in vitro propagation of P. carinii observed from rat lung extracts cultured on cell lines; this method, however, is limited by the difficulties encountered in quantifying the parasitic types; (3) the inhibition by the drugs tested of enzymes involved in folate synthesis is a method that is still under evaluation. The animal model remains the reference method.

Topics: Animals; Cells, Cultured; Clinical Trials as Topic; Disease Models, Animal; Folic Acid; Humans; Pneumocystis; Pneumonia, Pneumocystis; Rats; Rats, Inbred Strains; Trimethoprim, Sulfamethoxazole Drug Combination

Interferon-gamma (IFN-gamma) was used to treat rats with steroid-induced Pneumocystis carinii pneumonia (PCP). Treatment with 427,000 U/day prophylactically prevented infection in this model. Treatment with 200,000 U, three times/week for 2 weeks caused a significant reduction in the number of cysts in the lungs and prolonged survival of the rats. In addition, IFN-gamma and trimethoprim/sulfamethoxazole behaved synergistically in the treatment of PCP in rats. Reduced dosages of each drug, when given together, caused an almost complete eradication of the infection. This may be a useful approach in patients with acquired immune deficiency syndrome in whom anti-Pneumocystis drugs are often toxic.

Topics: Acquired Immunodeficiency Syndrome; Animals; Combined Modality Therapy; Disease Models, Animal; Female; Interferon-gamma; Opportunistic Infections; Pneumonia, Pneumocystis; Rats; Rats, Inbred Strains; Trimethoprim, Sulfamethoxazole Drug Combination

Lethal enterococcal peritonitis in mice was used to compare trimethoprim-sulfamethoxazole (TMP-SMX) therapy with ampicillin therapy. Peritoneal fluid showed a 10(3)-CFU decrease in enterococci with ampicillin compared with TMP-SMX. Mortality of the untreated mice was 100%, compared with 40% for ampicillin and 95% for TMP-SMX, despite adequately measured levels in serum and peritoneal fluid.

Topics: Ampicillin; Animals; Disease Models, Animal; Enterococcus faecalis; Female; Injections, Intramuscular; Mice; Mice, Inbred Strains; Peritonitis; Streptococcal Infections; Trimethoprim, Sulfamethoxazole Drug Combination

We report a hematogenous implant infection with Salmonella dublin in a renal transplant patient with total hip replacement. A 16-month treatment with cotrimoxazole failed, as evidenced by culture and electron microscopy, despite persisting low MIC after therapy. Data from a foreign body animal model and in vitro tests, which take into account the properties of adhering and stationary-phase bacteria, explain the failure of a long-term treatment with cotrimoxazole. The patient was subsequently cured by ciprofloxacin which was successful in these tests. No relapse was noted after a follow-up of 1 year.

Topics: Adult; Amoxicillin; Animals; Arthritis, Infectious; Bacterial Adhesion; Ciprofloxacin; Diffusion Chambers, Culture; Disease Models, Animal; Guinea Pigs; Hip Prosthesis; Humans; Immunosuppression Therapy; Male; Microbial Sensitivity Tests; Microscopy, Electron, Scanning; Salmonella; Salmonella Infections; Trimethoprim, Sulfamethoxazole Drug Combination

The iron chelator deferoxamine and the polyamine biosynthesis inhibitor eflornithine (DL-alpha-difluoromethylornithine) were examined for anti-Pneumocystis carinii activity in the rat model of P. carinii pneumonia. The activity of deferoxamine at 250, 500, and 1,000 mg/kg given intraperitoneally provides evidence that iron chelation is a promising novel approach to P. carinii chemotherapy. Results with eflornithine at 2, 3, and 4% in drinking water confirm and extend previously reported activity in the rat model.

Topics: Animals; Deferoxamine; Disease Models, Animal; Eflornithine; Female; Pneumonia, Pneumocystis; Random Allocation; Rats; Rats, Inbred Strains; Trimethoprim, Sulfamethoxazole Drug Combination

Rats which were immunosuppressed with adrenal corticosteroids then transtracheally inoculated with Pneumocystis carinii were evaluated as models for study of drug efficacy. Trimethoprim/sulfamethoxazole, known to be effective against Pneumocystis, was given in therapeutic and prophylactic regimens and its long-term effectiveness determined by a protocol to study relapse. Untreated animals uniformly developed severe infection with differences in numbers of organisms between untreated and treated animals being greater than two logs. Therapy of prophylaxis studies could be completed in 6 to 7 weeks. Animals given prophylaxis or therapy with trimethoprim/sulfamethoxazole had few organisms detected in lungs. Numbers of organisms did not increase during the 4 weeks when the animals were continued on immunosuppression after discontinuing treatment as long as reinfection was prevented. These models are useful for evaluating anti-Pneumocystis activity of antimicrobials. Relapse study data suggest that reinfection may have an important role in development of recurrent Pneumocystis pneumonia.

Topics: Animals; Dexamethasone; Disease Models, Animal; Female; Immunosuppression Therapy; Leukocyte Count; Lymphocytes; Pneumonia, Pneumocystis; Rats; Rats, Inbred Strains; Recurrence; Trimethoprim, Sulfamethoxazole Drug Combination

The administration of several compounds that can increase plasma phenylalanine levels and/or inhibit phenylalanine hydroxylase in rats was studied in order to determine their usefulness in inducing a phenylketonuria-like state. The results of this investigation revealed that 4.5 microns/10 g p-chlorophenylalanine is more effective than L-phenylalanine, alpha-methylphenylalanine, trimethoprim, Bactrim and Septra, since the former compound produced both adequate hyperphenylalaninemia and marked inhibition of hepatic phenylalanine hydroxylase activity. In addition, a 24-h study provided important insights into the changing diurnal patterns of specified biochemical parameters.

Topics: Animals; Disease Models, Animal; Drug Combinations; Female; Fenclonine; Phenylalanine; Phenylalanine Hydroxylase; Phenylketonurias; Rats; Rats, Inbred Strains; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Pneumocystis carinii pneumonia is often the terminal event for patients with the acquired immunodeficiency syndrome. Eflornithine (DL-alpha-difluoromethylornithine [DFMO]; Ornidyl; Merrell Dow Research Institute, Cincinnati, Ohio) has been used successfully against this protozoan disease in limited clinical trials, although not all patients respond to therapy. In contrast, results of the only reported experiments with DFMO in an animal model were negative. We retested DFMO against P. carinii in an immunosuppressed rat model by inclusion of 3% DFMO in the drinking water, a dose rate about twice that used previously. A combination of trimethoprim and sulfamethoxazole, a proven anti-P. carinii agent, was used as a positive control. After 3 weeks of anti-P. carinii pneumonia therapy, the surviving rats were sacrificed and the degree of parasitosis was judged by examination of lung sections stained with silver methenamine to reveal cysts. In three separate experiments, DFMO showed definite anti-P. carinii pneumonia activity; the parasitosis of DFMO-treated animals was significantly less than that of control animals (P less than 0.001 for all experiments). DFMO was not as active as trimethoprim-sulfamethoxazole, however. Several other experimental therapies were tested, including dapsone and two additional antiprotozoal agents: suramin and diminazene aceturate (Berenil; Farbwerke Hoechst, Frankfurt, Federal Republic of Germany). Diminazene aceturate, a veterinary drug related to the standard anti-P. carinii pneumonia agent pentamidine, was very active (P less than 10(-10]. Suramin and dapsone were weakly active. The combinations suramin-diminazene aceturate and suramin-DFMO were tested, but they were antagonistic rather than synergistic.

Topics: Amphotericin B; Animals; Antiprotozoal Agents; Dapsone; Diminazene; Disease Models, Animal; Drug Combinations; Eflornithine; Female; Immunosuppression Therapy; Pneumonia, Pneumocystis; Random Allocation; Rats; Rats, Inbred Strains; Sulfamethoxazole; Suramin; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Two sources of rats free of latent Pneumocystis carinii are described. First, rats from a virus-free colony failed to develop infection after 8 weeks of immune suppression unless they were housed with previously infected rats. Second, pregnant rats (non-virus free) received trimethoprim-sulfamethoxazole from day 10 of gestation until the pups were weaned. Pups raised in filter-topped cages and immunosuppressed for 8 weeks were free of P. carinii infection.

Topics: Animals; Disease Models, Animal; Drug Combinations; Female; Immunosuppression Therapy; Pneumonia, Pneumocystis; Pregnancy; Rats; Rats, Inbred Strains; Rodent Diseases; Specific Pathogen-Free Organisms; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Immune consequences of gastrointestinal colonization of CD-1 and CBA/J mice with Candida albicans in the presence or absence of continuous antibiotic treatment with penicillin-tetracycline or trimethoprimsulfamethoxazole were investigated. Intubation with C. albicans in the absence of antibiotics resulted in the induction of low but detectable delayed-type hypersensitivity (DTH), demonstrable by footpad testing with a C. albicans wall glycoprotein (GP), and in the stimulation of a moderate level of protective immunity, demonstrable by intravenous (i.v.) challenge. DTH to a membrane extract, BEX, could not be detected in such animals. However, animals colonized in the presence of antibiotics and then inoculated cutaneously prior to being tested for DTH or protective immunity developed significantly enhanced levels of DTH to GP and BEX and were protected to an even greater extent than animals colonized in the absence of antibiotics who were not inoculated cutaneously. The priming effect of colonization, particularly with respect to the antigen GP, was also obvious from an enzyme-linked immunosorbent assay for GP-specific antibody with sera of mice surviving the i.v. challenge, in that GP-specific antibody was present in the highest titers in colonized animals that had been inoculated cutaneously prior to i.v. challenge. While the antibiotics promoted higher levels of colonization, as evidenced by stomach and fecal cultures of intubated mice, antibiotic administration was not necessary for the induction of C. albicans-specific responses. Moreover, contrary to reports in the literature, antibiotic administration had no adverse effect on the immune responses measured. Females were innately more resistant than males to i.v. challenge with C. albicans, but each sex was capable of developing protective immunity of equal intensity in response to colonization or immunization by cutaneous challenge.

Topics: Animals; Antibodies, Fungal; Candida albicans; Candidiasis; Disease Models, Animal; Drug Combinations; Enzyme-Linked Immunosorbent Assay; Female; Hypersensitivity, Delayed; Immunity, Cellular; Immunization; Male; Mice; Mice, Inbred CBA; Penicillins; Stomach; Sulfamethoxazole; Tetracycline; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

The efficacy and tolerance of pentamidine aerosol were evaluated in the prophylaxis and therapy of murine Pneumocystis carinii pneumonia. P. carinii pneumonia was induced in rats by corticosteroid immunosuppression. Pentamidine was administered three times weekly via a Bird micronebulizer. The actual amount of pentamidine inhaled was estimated by monitoring the ventilation of the rats during the aerosol administration. Pentamidine levels in blood, lung, liver and kidney samples were determined by high-pressure liquid chromatography after completion of the treatment. Efficacy was evaluated by examination of lung imprints. In the prophylactic treatment, 4.8- and 8.6-mg/kg doses of aerosolized pentamidine administered three times weekly for 7 weeks were effective in preventing P. carinii pneumonia in 80 and 100% of the rats, respectively. In the therapeutic studies, a 14.6-mg/kg dose of aerosolized pentamidine administered three times weekly for 3 weeks was effective both in curing the pneumonia and in clearing P. carinii cysts in 70% of the rats. In the remaining animals, although the pneumonia was cured, the cysts persisted. A dose-dependent effect of the drug was demonstrated in both prophylactic and therapeutic treatments. High lung/kidney and lung/liver ratios of pentamidine levels were demonstrated and were associated with good clinical, biological, and histologic tolerance.

Topics: Aerosols; Amidines; Animals; Anti-Infective Agents; Chromatography, High Pressure Liquid; Disease Models, Animal; Drug Combinations; Immunosuppression Therapy; Injections, Subcutaneous; Male; Nebulizers and Vaporizers; Pentamidine; Pneumonia, Pneumocystis; Random Allocation; Rats; Rats, Inbred Strains; Sulfamethoxazole; Tissue Distribution; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

A model of ascending urinary tract infection due to an isolate of Escherichia coli was developed in normal and streptozotocin-induced mice to compare the efficacy of norfloxacin and trimethoprim-sulphamethoxazole. Norfloxacin and trimethoprim-sulphamethoxazole both were effective in reducing the number of colony forming units of E. coli from the kidneys of normal experimentally-infected mice, although norfloxacin yielded a greater quantitative reduction of colony forming units. Norfloxacin was substantially more effective than trimethoprim-sulphamethoxazole in reducing the number of colony forming units from kidney homogenates when the test animals were diabetic. This study supports the initiation of clinical trials to evaluate norfloxacin in diabetic patients.

Topics: Animals; Anti-Infective Agents; Diabetes Mellitus, Experimental; Disease Models, Animal; Drug Combinations; Escherichia coli Infections; Female; Mice; Mice, Inbred Strains; Norfloxacin; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Urinary Tract Infections

Mice infected with a cotrimoxazole-susceptible strain of Listeria monocytogenes (MIC 0.25 mg/l) were highly protected by a short-lived therapy with this drug. The excellent activity of ampicillin, however, was not achieved. Only the combination of trimethoprim and sulfamethoxazole gave sufficient protection. In dextran sulfate-treated mice, highly susceptible to listeria infection, cotrimoxazole showed also good activity. In the nude, athymic mouse, however, when the deficient immune system did not afford assistance to the elimination of bacteria, only transient reduction of bacterial counts occurred.

Topics: Ampicillin; Animals; Anti-Infective Agents, Urinary; Disease Models, Animal; Drug Combinations; Female; Listeria monocytogenes; Listeriosis; Mice; Mice, Nude; Microbial Sensitivity Tests; Spleen; Sulfamethoxazole; Time Factors; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

The purpose of this study was to identify new drugs for the prevention and treatment of Pneumocystis carinii pneumonitis (PCP) induced in rats by continuous daily dosage with dexamethasone. Initially, test drugs were administered prophylactically as a screen for efficacy. Drugs were selected because of their known activity against certain protozoa and their tolerance in human usage. Doses were based on previous studies in rats or estimated from usage in humans and lower animals. Allopurinol (50 mg/kg per day), ketoconazole (25 mg/kg per day), difluoromethylornithine (2.5 g/kg per day), diloxanide (125 mg/kg per day, nifurtimox (100 mg/kg per day), suramin (20 mg/kg per day), melarsoprol (20 mg/kg per day), gentian violet (0.5 mg/kg per week, 5 and 50 mg/kg per day), primaquine (5.6 mg/kg per day) and chloroquine (37.5 mg/kg per day) were ineffective, whereas diaminodiphenylsulfone (daspone) (25 mg/kg per day) was totally effective in preventing the infection. Diaminodiphenylsulfone was then evaluated at dose levels of 5, 25, and 125 mg/kg per day and compared with trimethoprim-sulfamethoxazole (TMP-SMZ), given at 50 per 250 mg/kg per day orally. The two highest dose levels of diaminodiphenylsulfone and TMP-SMZ prevented the infection in all of the animals, and the lowest dose of diaminodiphenylsulfone prevented it in 40% of the rats. All of the untreated controls developed PCP. To determine therapeutic efficacy, animals with extensive PCP were treated for 2.5 weeks with diaminodiphenylsulfone or TMP-SMZ. Based on residual extensive pneumonitis at the completion of treatment, the pneumonitis was reduced to 50% by TMP-SMZ and to 25% by diaminodiphenylsulfone, whereas 100% of untreated controls had extensive PCP. When treatment was begun earlier in the course of the pneumonitis, diaminodiphenylsulfone was totally effective in eradicating the infection. These results suggest that diaminodiphenylsulfone is an effective drug for the treatment and prevention of murine PCP and that it is at least as effective as TMP-SMZ.

Topics: Animals; Dapsone; Disease Models, Animal; Drug Combinations; Male; Pneumonia, Pneumocystis; Rats; Rats, Inbred Strains; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination