Concentrations of trimethoprim and sulfamethoxazole in cerebrospinal fluid and serum in mares with and without a dimethyl sulfoxide pretreatment.

Each of seven mares was given an intravenous (IV) injection of 40% dimethyl sulfoxide (DMSO) at a dosage of 1 g/kg, over 35 min, immediately followed by a single IV injection of a trimethoprim (TMP) and sulfamethoxazole (SMZ) combination (SMZ 83%, TMP 17%) at a combined dosage of 44 mg/kg (7.48 mg/kg TMP; 36.52 mg/kg SMZ). Each horse served as its own control and was alternately treated with an identical dose of TMP-SMZ treatment alone at least seven days following or preceding the DMSO and TMP-SMZ treatment. Serum and cerebrospinal fluid (CSF) concentrations of TMP and SMZ were measured over a six hour period. Dimethyl sulfoxide treatment caused no significant difference in the mean serum concentration of SMZ or in the mean CSF concentrations of TMP or SMZ. The mean serum concentration of TMP was significantly (p less than 0.05) increased at the two, four and six hour sampling time in the mares receiving pretreatment with DMSO. The clearance of TMP was also significantly (p less than 0.05) decreased from 675 mL/h/kg to 327 mL/h/kg by DMSO administration. Concentrations of TMP and SMZ in the CSF in both treatment groups exceeded the minimum inhibitory concentrations for many common bacterial pathogens of equine origin. In addition, CSF concentration of TMP exceeded the serum concentrations required for 50% inhibition of dihydrofolate reductases of protozoan origin. Serum TMP and SMZ concentration were similar to those reported to be effective against Toxoplasma gondii in in vitro studies on the killing or inhibition of the organism.

[Nocardial brain abscess: case report].

A 25-year-old man, who was slightly immunosuppressed, presented headache and right motor weakness due to multiple brain abscesses disseminated from lung abscess. They were diagnosed, by bacteriological examination, as nocardial brain abscesses (nocardia asteroides) 4 weeks after the first operation. In spite of delay in the diagnosis, he was relieved by operations (three times) and chemotherapy including high doses of Sulfamethoxazole-Trimethoprim. He was eventually discharged. We stress the necessity of early diagnosis and the efficacy of Sulfamethoxazole-Trimethoprim for nocardial brain abscess.

Changes in trimethoprim pharmacokinetics after the newborn period.

The pharmacokinetics of trimethoprim administered orally or intravenously were investigated in six infants aged 1.7 months to 1.1 years. In these infants trimethoprim had a mean half life of 4.6 hours; this was comparable with the values found in young and school age children (3.8 and 5.4 hours respectively) and about a quarter of the half life in newborns. The volume of distribution (1.5 l/kg) was smaller than in newborns but larger than in young or school age children (0.9 and 1.1 l/kg respectively). The plasma clearance in these infants (3-3 ml/min/kg) was slightly larger than in newborns or in either group of older children (2.9 and 2.4 ml/min/kg respectively). Thus the most dramatic changes in trimethoprim pharmacokinetics seem to occur during the first two months of life. A reduced daily dose of trimethoprim is necessary during the first two months only. An increased daily dose, by addition of a third dose each day, is recommended from two months.

Pharmacokinetics of sulfadiazine/trimethoprim in neonatal male calves: effect of age and penetration into cerebrospinal fluid.

Sulfadiazine (SDZ)/trimethoprim (TMP; 30 mg of SDZ/TMP/kg of body weight) was given IV to the same 6 male calves at 1, 7, and 42 days of age and to 2 additional calves at 7 days of age. Serum concentrations of SDZ and TMP were best represented by a 2-compartment open model, but in 42-day-old calves, CSF concentrations of both drugs were best represented by a 1-compartment open model with first-order input. Between 1 and 42 days of age, the elimination half-life (t1/2(beta)) of SDZ decreased from 5.7 to 3.6 hours, and total body clearance (CLtot) increased from 1.43 to 1.88 ml/min/kg; the area under the curve (AUC0----infinity) decreased from 291.5 to 225.4 mg/L.h. The distribution coefficient (Vd(area)/kg of body weight) decreased with age, changing from 0.72 to 0.59 L/kg, between 1 and 42 days of age. Therapeutic concentrations of SDZ in serum (greater than 2 micrograms/ml) were maintained for 24 hours in 1-day-old calves and for about 15 hours in 7- and 42-day-old calves. The elimination rate of TMP increased about 9-fold; t1/2(beta) was 8.4, 2.1, and 0.9 hours, respectively, at 1, 7, and 42 days of age. Other values also reflected an increase in TMP elimination rate with age: CLtot increased from 2.8 to 12 to 28.9 ml/min/kg, k13 increased from 0.336 to 0.654 to 1.664/h and AUC0----infinity decreased from 32.8 to 7.9 to 3.1 mg/L.h, respectively. Therapeutic concentrations (greater than 0.1 microgram/ml) were maintained for 15 hours, 8 hours, and about 6 hours in 1-, 7-, and 42-day-old calves, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and body fluid and endometrial concentrations of trimethoprim-sulfamethoxazole in mares.

Six healthy adult mares were each given a single IV injection of trimethoprim (TMP)-sulfamethoxazole (SMZ) at a dosage of 2.5 mg of TMP/kg of body weight and 12.5 mg of SMZ/kg. Serum concentrations of each drug were measured serially over a 24-hour period. For TMP, the mean overall elimination rate constant (K) was 0.43/hr and the elimination half-life (t1/2) was 1.9 hours. The apparent volume of distribution (at steady state) was 1.62 L/kg and TMP clearance was 886 ml/hr/kg. For SMZ, K was 0.22/hr and t1/2 was 3.53 hours. The apparent volume of distribution at steady state was 0.33 L/kg and SMZ clearance was 78.2 ml/hr/kg. Each mare was then given 5 consecutive oral doses of TMP-SMZ at a rate of 2.5 mg of TMP/kg and 12.5 mg of SMZ/kg at 12-hour intervals. Trimethoprim and SMZ concentrations were measured in serum, synovial fluid, peritoneal fluid, CSF, urine, and endometrium. Although both mean TMP and SMZ serum concentrations were higher after the 5th dose than after the 1st dose, only the mean TMP concentration was significantly (P less than 0.05) different. After the 5th oral dose, concentrations of TMP and SMZ attained in body fluids (except CSF) and endometrial tissue were equal to or exceeded reported minimum inhibitory concentrations for Corynebacterium pseudotuberculosis, Staphylococcus sp, Streptococcus zooepidemicus, and several obligate anaerobes. Absorption of both drugs was variable after oral administration.

Co-trimoxazole versus nafcillin in the therapy of experimental meningitis due to Staphylococcus aureus.

Co-trimoxazole was compared with nafcillin against Staphylococcus aureus in vitro and in the therapy of experimental Staph. aureus meningitis in rabbits. Co-trimoxazole (trimethoprim:sulphamethoxazole in a 1:20 ratio) was synergistic against 22/24 strains of Staph. aureus in vitro. The MBC90 of co-trimoxazole and nafcillin were 0.156-3.12 mg/l and 0.25 mg/l, respectively, concentrations below those achievable in purulent cerebrospinal fluid. The rate of bacterial killing (Staph. aureus) by co-trimoxazole and nafcillin were similar in both broth and pooled CSF in vitro. However, the MBC increased and the rate of bactericidal activity of both agents declined when tested in CSF at a higher inoculum (10(7) cfu/ml). During continuous intravenous infusion therapy of a reproducible, uniformly fatal (if untreated) model of experimental Staph. aureus meningitis, serum concentrations of all agents closely approximated those found in humans receiving standard parenteral regimens. The mean percent penetration into CSF ([CSF]/[serum] X 100) was 2.9, 35.6 and 27.1% for nafcillin, trimethoprim and sulphamethoxazole, respectively. Although both nafcillin and co-trimoxazole therapy reduced CSF Staph. aureus concentrations significantly more rapidly (P less than 0.001) when compared to untreated controls, the bactericidal rate was modest. The CSF was rendered sterile in 0/64 animals treated with either regimen for 8 h. Nafcillin was more rapidly bactericidal in vivo (P less than 0.03) than co-trimoxazole in this model. Caution is advised in the use of co-trimoxazole for infections of the central nervous system caused by Staph. aureus.

Trimethoprim interference in methotrexate assay by an enzyme inhibition assay kit.

Spurious methotrexate (MTX) concentrations in sera and cerebrospinal fluids from leukemia patients who were given trimethoprim (TMP) were estimated using an MTX assay kit which is based on its inhibition of dihydrofolate reductase. The interference of TMP with MTX was confirmed in the assay system. A concentration of 0.17 microgram/ml of TMP gave a value for an apparent MTX of 10 microM.

Pharmacokinetics of trimethoprim and sulfamethoxazole in serum and cerebrospinal fluid of adult patients with normal meninges.

The pharmacokinetics of trimethoprim (TMP) and sulfamethoxazole (SMX) in cerebrospinal fluid (CSF) and serum after a single intravenous infusion of 5 mg of TMP and 25 mg of SMX per kg of body weight over approximately 120 min were studied i nine patients who had uninflamed meninges and were undergoing elective myelography. Peak concentrations of TMP and SMX in CSF were 1 microgram/ml and 13.8 micrograms/ml, respectively. The peak TMP concentration in CSF occurred significantly earlier than the peak SMX concentration (60 versus 480 min postinfusion). At 15 h, there was no detectable TMP in the CSF, and there was 4.7 micrograms of SMX per ml of CSF. In the postdistribution phase (in CSF), simultaneous CSF-to-serum concentration ratios ranged from 0.23 to 0.53 for TMP and from 0.20 to 0.36 for SMX. CSF penetration (measured by comparison of the area under the curve of the composite CSF and serum concentration-time curves) was 18% for TMP and 12% for SMX. A loading dose of TMP-SMX (bases on TMP) of 10 to 12 mg/kg and a maintenance dose of 6 mg/kg every 8 h or 8 mg/kg every 12 h (with a 2-h infusion) should yield steady-state peak concentrations of at least 5 micrograms of TMP per ml of serum and 160 micrograms of SMX per ml of serum. Further studies of TMP-SMX administered in these doses in the treatment of serious bacterial infection, including meningitis, are warranted.

Diffusion of metioprim, tetroxoprim and sulphadiazine in the cerebrospinal fluid of dogs with healthy meninges and dogs with experimental meningitis.

The diffusion of metioprim (MTP), tetroxoprim (TXP) and sulphadiazine (SDZ) in cerebrospinal fluid (CSF), following single intravenous doses and continuous infusions, was studied in dogs. The drugs penetrated well into the CSF of animals with and without experimental Staphylococcus aureus meningitis. In dogs with healthy meninges, the CSF bioavailability - expressed as the ratio of CSF/plasma area under the curve 0-5-hour values - following continuous infusion was determined to be 86.7% for MTP, 58.2% for TXP and 38.8% for SDZ. In infected animals, CSF availability following continuous infusion increases slightly to ratios of 96% (MTP), 70% (TXP) and 50% (SDZ). For all drugs, the concentrations reached in CSF were above the minimum inhibition concentrations for the majority of Enterobacteriaceae, indicating their potential value in treatment of gram-negative bacillary meningitis.

Ventricular cerebrospinal fluid concentrations of trimethoprim-sulphamethoxazole.

Ventricular cerebrospinal fluid (CSF) trimethoprim-sulphamethoxazole (TMP-SMZ) concentrations were measured in 15 patients. At varying times, not exceeding eight hours prior to surgery, each patient received a dose of 5 mg/kg TMP with 25 mg/kg SMZ as a 1 h intravenous infusion. The mean ventricular CSF TMP concentration was 1.1 mg/l with a range of 0.5-3.2 mg/l. The SMZ concentration was 17.9 mg/l with a range of 5-40 mg/l. There was no apparent relationship between achievable CSF concentrations and the time elapsed after drug administration. The CSF concentrations were achieved despite the lack of meningeal inflammation. In 11 of 14 patients, the levels exceeded the minimum inhibitory concentrations for Staphylococcus aureus and Staph. epidermidis.

Trimethoprim-sulfamethoxazole therapy for Nocardia infections.

The optimal therapy for infections due to Nocardia species has not been established. To assess the efficacy of trimethoprim-sulfamethoxazole (TMP-SMX), we reviewed the records of 19 patients with Nocardia infections seen at Duke University Medical Center, Durham, NC, who were treated with this drug, either alone or in combination with other antibiotics or a surgical procedure. Underlying diseases or therapy causing immunosuppression were present in all but five cases. Sites of involvement were lung (ten of 19), wound (two of 19), and brain (two of 19); five of 19 patients had disseminated disease. The mean duration of therapy was 7.2 months. Overall cure or improvement was achieved in 89% (17/19) of cases; 80% of patients with disseminated disease and 60% of those with CNS involvement recovered. This experience, and accumulated clinical evidence in the literature, indicates that TMP-SMX should be considered the therapeutic drug of choice in infections due to Nocardia species.

High-dose co-trimoxazole and its penetration through uninflamed meninges.

Normal doses of co-trimoxazole (two ampoules or two tablets twice a day) gave low cerebrospinal fluid concentrations of trimethoprim and sulphamethoxazole in neurosurgical patients. For two years, four ampoules of co-trimoxazole twice a day, followed by four tablets twice a day, which were administered to neurosurgical patients and to patients admitted to hospital with skull fractures, produced no toxicity and this regimen has not been associated with postoperative meningitis. After the high-dose regimen in patients with uninflamed meninges, trimethoprim concentrations in the cerebrospinal fluid ranged from 2.6 mumol/L to 12.4 mumol/L (0.75 mg/L to 3.6 mg/L), and in the serum from 9.6 mumol/L to 42.7 mumol/L (2.8 mg/L to 12.4 mg/L). However, the bacteriostatic and bactericidal activities of the spinal fluids and sera were very variable, some with high concentrations appearing to have negligible antibacterial activity in vitro. We have treated a few patients with serious infections with dosages of 12 ampoules or 12 tablets twice a day with successful results. Studies of serum folate, 5-methyltetrahydrofolate and granulocyte dihydrofolate reductase levels showed no toxic effects from the high-dose regimen.

Comparison of cotrimoxazole, ampicillin, and chloramphenicol in treatment of experimental Haemophilus influenzae type B meningitis.

To evaluate cotrimoxazole in the treatment of bacterial meningitis, we compared its action with that of ampicillin and chloramphenicol in experimental Haemophilus influenzae type b meningitis. Both trimethoprim and sulfamethoxazole penetrated well into the cerebrospinal fluid of infected rabbits, reaching 40 and 26%, respectively, of their simultaneous serum levels. Levels measured 30 and 60 min after intravenous injection exceeded the minimum inhibitory concentration of this combination for H. influenzae by 10- to 100-fold. The mean ratio of trimethoprim to sulfamethoxazole in cerebrospinal fluid was 1:22. Cotrimoxazole was as effective as ampicillin in therapy of beta-lactamase-negative H. influenzae meningitis and as effective as chloramphenicol for a beta-lactamase positive strain. These findings corroborate favorable preliminary clinical experience reported by others and indicate that cotrimoxazole deserves further study in the therapy of bacterial meningitis.