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Abstract: Although there is a lack of data in trimethoprim-sulfamethoxazole (TMP-SMX) serum monitoring utility for invasive nocardial infections, therapeutic drug monitoring is widely used to optimize dosing and avoid adverse reactions that may cause treatment interruption.We retrospectively reviewed all adults who received TMP-SMX to treat nocardial brain abscess and had SMX serum level testing from 2010 to 2020.Twenty-two patients received treatment with TMP-SMX for Nocardia species brain abscess and 16 (72.7%) had a reported SMX level, with a median patient age of 65.5 years (interquartile range, IQR 59.5-72.5). Compared to those who did not have a documented SMX serum level, patients with SMX levels had a shorter median course of TMP-SMX treatment (322 days [IQR 188-365] vs. 365 [IQR 224-365]; P = .31) and higher therapeutic induction dose (10 [62.5%] vs. 3 [50%]; P = .92). Similarly, they were more frequently on hemodialysis (3 [13.6%] vs. 1 [4.5%]; P = > .99). The median peak level was 158.5 (IQR 120-218) μg/mL, collected at 2 hours (75%) post-administration in the induction phase (81.3%). Patients with documented SMX levels had fewer reported drug toxicity (5 [31.3%] vs. 4 [66.7%]; P = .1) than those without SMX levels. Among the five patients who reported TMP-SMX-related toxicity, 4 (80%) had an SMX peak level >150 μg/mL. There was no difference in the cure, relapse, and death rates among the two groups.While SMX level was not associated with Nocardia species brain abscess cure rates and mortality, most patients with SMX peak >150 μg/mL experienced drug toxicity., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

A rapid, sensitive, and reliable ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method has been developed to simultaneously determine the major bioactive components of Xiaoyan Lidan Formula (XYLDF) in rat plasma, using sulfamethoxazole as the internal standard (IS). The seven major bioactive components are andrographolide, dehydroandrographolide, enmein, 1-methoxicabony-β-carboline, 4,5-dimethoxy-canthin-6-one, 4-methoxy-5-hydroxy-canthin-6-one, and 1-hydroxymethyl-β-carboline. After pretreating by protein precipitation with methanol, separation was performed on a UPLC C18 column using gradient elution with a mobile phase consisting of acetonitrile and 0.1% formic acid at a flowing rate of 0.7 mL/min. Detection was performed on TSQ Quantum mass spectrometry set at the positive/negative ionization and multiple reaction monitoring (MRM) mode. The intra- and inter-day precision were less than 9.8%, whereas the intra- and inter-day accuracy were within ± 13.4%. The method was validated and applied to compare the pharmacokinetic profiles of the analytes in serum of Alpha-naphthylisothiocyanate (ANIT)-induced cholestasis and control rats after oral administration of XYLDF. The results showed remarkable differences in pharmacokinetic properties of the analytes between cholestatic (model) and control groups, thereby providing essential scientific information for better understanding of mechanism of XYLDF and a reference for its clinical applications., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis in HIV-uninfected, exposed (HUE) children variably reduces clinical malaria burden despite antifolate resistance, but data regarding achieved serum levels and adherence are lacking. Serum samples from 70 HUE children aged 3-12 months from Rakai, Uganda, enrolled in an observational study were assayed for random SMX levels using a colorimetric assay. Adherence with TMP-SMX prophylaxis data (yes/no) was also collected. Of 148 visits with concurrent SMX levels available, 56% had self-reported adherence with TMP-SMX therapy. Among these 82 visits, mean (standard deviation) level was 19.78 (19.22) µg/mL, but 33% had SMX levels below half maximal inhibitory concentrations (IC50) for Plasmodium falciparum with some, but not all, of the reported antifolate resistance mutations reported in Uganda. With TMP-SMX prophylaxis, suboptimal adherence is concerning. Sulfamethoxazole levels below IC50s required to overcome malaria parasites with multiple antifolate resistance mutations may be significant. Further study of TMP-SMX in this context is needed.

Background: Intermittent preventive treatment in pregnancy with sulfadoxine/pyrimethamine is contra-indicated in HIV-positive pregnant women receiving sulfamethoxazole/trimethoprim prophylaxis. Since mefloquine is being considered as a replacement for sulfadoxine/pyrimethamine in this vulnerable population, an investigation on the pharmacokinetic interactions of mefloquine, sulfamethoxazole and trimethoprim in pregnant, HIV-infected women was performed., Methods: A double-blinded, placebo-controlled study was conducted with 124 HIV-infected, pregnant women on a standard regimen of sulfamethoxazole/trimethoprim prophylaxis. Seventy-two subjects received three doses of mefloquine (15 mg/kg) at monthly intervals. Dried blood spots were collected from both placebo and mefloquine arms four to 672 h post-administration and on day 7 following a second monthly dose of mefloquine. A novel high-performance liquid chromatographic method was developed to simultaneously measure mefloquine, sulfamethoxazole and trimethoprim from each blood spot. Non-compartmental methods using a naïve-pooled data approach were used to determine mefloquine pharmacokinetic parameters., Results: Sulfamethoxazole/trimethoprim prophylaxis did not noticeably influence mefloquine pharmacokinetics relative to reported values. The mefloquine half-life, observed clearance (CL/f), and area-under-the-curve (AUC0→∞) were 12.0 days, 0.035 l/h/kg and 431 µg-h/ml, respectively. Although trimethoprim steady-state levels were not significantly different between arms, sulfamethoxazole levels showed a significant 53% decrease after mefloquine administration relative to the placebo group and returning to pre-dose levels at 28 days., Conclusions: Although a transient decrease in sulfamethoxazole levels was observed, there was no change in hospital admissions due to secondary bacterial infections, implying that mefloquine may have provided antimicrobial protection.

Antibody- and cell-mediated responses to sulfamethoxazole (SMX) were analyzed in AIDS patients with or without a history of hypersensitivity and in negative controls. In 20 of 20 (P < 0.01) human immunodeficiency virus (HIV)-seropositive patients with skin reactions to cotrimoxazole, we found SMX-specific antibodies, while only 9 of 20 and 17 of 20 HIV-seropositive patients without a history of hypersensitivity to cotrimoxazole had SMX-specific immunoglobulin M (IgM) and IgG, respectively. The levels of specific IgM and IgG were higher in patients with skin reactions than in patients without reactions (IgM, 1.0 +/- 0.19 versus 0.47 +/- 0.23 [P < 0.001]; IgG, 0.68 +/- 0.15 versus 0.47 +/- 0.14 [P < 0.001] [mean optical density values +/- standard deviations]). Seronegative controls with no history of exposure to sulfa compounds did not have SMX-specific IgG or IgM antibodies, and controls with a history of intake of SMX with or without reactions had low levels of IgG and IgM. The SMX-specific IgG subclasses were exclusively IgG1 and IgG3. None of the patients had detectable SMX-specific IgE or IgA antibodies nor did they exhibit a cell-mediated response as measured by a lymphocyte proliferation assay. Antibodies to SMX recognized N-acetyl-sulfonamide, N-(2-thiazolyl)-sulfanilamide, sulfadiazine, and sulfisoxazole but did not recognize sulfanilamide or 3-amino-5-methyl isoxazole in an inhibition assay. It is not known whether the SMX-specific antibodies associated with hypersensitivity reactions to SMX in HIV-seropositive patients have a pathogenic role in these reactions. Sulfanilamide or 3-amino-5-methyl isoxazole, on the other hand, could be potential alternative therapies in HIV-seropositive patients with a history of skin reactions to SMX.

The formation and elimination of sulphamethoxazole hydroxylamine in relation to the pharmacokinetics of the parent compound and its N4-acetyl metabolite were investigated in six healthy subjects after a single oral dose of 800 mg sulphamethoxazole. The apparent half-lives of sulphamethoxazole and its metabolites were approximately 10 h, indicative of formation rate-limited metabolism. The mean residence time of the hydroxylamine metabolite was 5.5 +/- 1.5 h. The renal clearance of sulphamethoxazole hydroxylamine was 4.39 +/- 0.91 l h-1. The urinary recovery of sulphamethoxazole accounted for 16.5 +/- 5.5% of the dose, N4-acetyl-sulphamethoxazole for 46.2 +/- 6.6% and the hydroxylamine metabolite for 2.4 +/- 0.8%. The remaining 35% of the dose was unaccounted for. Acetylator phenotype was determined using sulphadimidine. The renal excretion of sulphamethoxazole hydroxylamine was 1.9 +/- 0.9% in slow acetylators (n = 3) and 2.8 +/- 0.3% in fast acetylators (n = 3); for N4-acetyl-sulphamethoxazole the values were 48 +/- 6% and 44 +/- 8%, respectively. Sulphamethoxazole is metabolized, although to a limited extent, to a hydroxylamine metabolite. This metabolite may be important for the pathogenesis of adverse reactions.

The disposition of 12 mg of trimethoprim and 60 mg of sulfamethoxazole per kg of body weight in six healthy male volunteers is described. The daily dose was evenly divided and administered orally every 6 h for 13 consecutive doses. Individual drug components were assayed by high-performance liquid chromatography. Steady-state concentrations in serum for trimethoprim and sulfamethoxazole were within the purported therapeutic ranges for treating Pneumocystis carinii pneumonia. Co-trimoxazole was well tolerated, and no subject withdrew from the study because of toxicity. Comparison of the pharmacokinetic parameters in this study with those of our previous findings indicates that the elimination of trimethoprim-sulfamethoxazole follows a first-order process within the dose ranges assessed. Administration of 15- to 20-mg/kg trimethoprim and 75- to 100-mg/kg sulfamethoxazole in four evenly divided doses for the first 24 h followed by 12 and 60 mg/kg/day, respectively, for the remainder of therapy rapidly attains concentrations in serum within the proposed P. carinii pneumonia therapeutic range. Clinical trials are indicated to evaluate this dosing scheme, which may decrease exposure to potentially excessive concentrations of trimethoprim and sulfamethoxazole.

We conducted an open prospective clinical trial to evaluate the efficacy and toxicity of trimethoprim-sulfamethoxazole given as one double-strength tablet thrice weekly for primary and secondary prophylaxis of Pneumocystis carinii pneumonia (PCP) in human immunodeficiency virus-infected (HIV+) patients. A total of 104 HIV+ patients were evaluated, with 74 being in the primary prophylaxis group and 30 being in the secondary prophylaxis group. All except six patients received concomitant zidovudine; five patients on primary prophylaxis and one patient on secondary prophylaxis refused zidovudine. There were 70 patients evaluated for the efficacy of primary prophylaxis. The mean CD4 count was 124.4 +/- 110.1 cells per microliter. The mean follow-up time was 11.8 +/- 5.8 months (median, 12 months; range, 1 to 32 months). Two noncompliant patients developed PCP after 1 and 3 months of chemoprophylaxis. The failure rate (under the intention to treat principle) was 2 of 70 patients (2.9%; 95% confidence interval, 0.35 to 10%), or 1 per 413 patient-months of observation. There were 27 patients evaluated for the efficacy of secondary prophylaxis. The mean follow-up time was 12.4 +/- 7.2 months (median, 11 months; range, 1 to 29 months). Two patients, one of whom was noncompliant, were treatment failures, developing PCP after 14 and 15 months of chemoprophylaxis; this gave a failure rate of 2 of 27 patients (7.4%; 95% confidence interval, 0.9 to 24.3%), or 1 per 167 patient-months of observation. Adverse reactions sufficient to permanently terminate therapy occurred in 9 of 104 patients (8.7%; 95% confidence interval, 4 to 15.7%) overall. The serum trimethoprim, sulfamethoxazole, and N4-acetyl-sulfamethoxazole concentrations measured by high-pressure liquid chromatography were uniformly low. One double-strength tablet of trimethoprim-sulfamethoxazole taken weekly on Monday, Wednesday, and Friday appeared to be well tolerated and efficacious for the prophylaxis of PCP in HIV+ patients at high risk and deserves further investigation.

The pharmacokinetics of trimethoprim-sulfamethoxazole were studied in 12 healthy adult subjects receiving trimethoprim at 20 mg/kg of body weight per day and sulfamethoxazole at 100 mg/kg/day, which is the conventional dose for treating Pneumocystis carinii pneumonia (PCP). Daily doses were evenly divided and orally administered every 6 h for 3 days. Trimethoprim, sulfamethoxazole, and N4-acetylsulfamethoxazole concentrations in serum and urine were measured by high-performance liquid chromatography. Five subjects withdrew from the study because of intolerable gastrointestinal and central nervous system toxicities. In the seven subjects that completed the study, the mean maximum serum drug concentrations after the last dose were 13.6 +/- 2.0, 372 +/- 64, and 50.1 +/- 10.9 micrograms/ml for trimethoprim, sulfamethoxazole, and N4-acetylsulfamethoxazole, respectively. The mean half-lives were 13.6 +/- 3.5, 14.0 +/- 2.3, and 18.6 +/- 4.3 h, respectively. Changes in absolute neutrophil count were significantly correlated with the minimum concentrations of trimethoprim and sulfamethoxazole in serum and trimethoprim area under the concentration-time curve (for all three parameters, r2 = 0.6 and P less than 0.05). Our findings add to the evidence that serum drug concentrations in adults following the conventional dose of trimethoprim-sulfamethoxazole for PCP are excessive and contribute to certain adverse reactions. Further studies are indicated in patients to optimize the dosing regimen of trimethoprim-sulfamethoxazole in the treatment of PCP.

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.

Trimethoprim-sulfamethoxazole (TMP-SMX) or trimethoprim (TMP) alone was given on a random double-blind basis to 26 young women to treat urinary tract infections. Fecal and introital aerobic bacterial floras were identified at 1, 7, 14, and 42 days to analyze changes in these floras or development of resistance to TMP or TM-SMX. Neither TMP alone nor the TMP-SMX combination administered for 2 weeks selected a resistant fecal or introital flora. In the few individuals who had strains resistant to TMP or TMP-SMX before initiation of therapy, these organisms did not persist once therapy began. Both programs effectively cleared the introitus and rectal areas of Enterobacteriaceae. Concentrations of TMP adequate to inhibit the majority of Escherichia coli strains causing urinary tract infections were found in the vaginal secretions.

In the present study, rats were given trimethoprim (TMP, 10 mg/kg), sulfamethoxazole (SMZ, 50 mg/kg), or a combination of the respective doses of TMP and SMZ. Thirty-six rats received each of the drugs studied. Six recipients of a compound (or mixture) were evaluated hourly, from 1 to 6 h after intraperitoneal injection of the agent. At each timed interval, serum, urine, cortex, medulla, and papilla were analyzed for drug content. Peak serum values of 1.1 microgram of TMP and 131.1 microgram of active SMZ (nonacetylated sulfonamide) per ml were observed after injection of the combination TMP-SMZ. Although the cortical, medullary, and papillary TMP concentrations were severalfold higher than the respective serum values (P < 0.01), microbiologically active SMZ did not concentrate in the renal parenchyma and was found in lower concentration there than in the serum (P < 0.01). The levels of SMZ in all parts of the kidney of animals which received the mixture SMZ-TMP were lower than those detected in the animals which were given SMZ alone. The average ratio of active SMZ to TMP within the medulla and the papilla was less than 20 to 1 in the first 2 h. The intrarenal distribution of these drugs may have therapeutic implications.

Digital computer simulations of plasma concentration-time profiles of single intravenous infusions of trimethoprim (160 mg)/sulfamethoxazole (800 mg) based on data from other workers showed that increasing the infusion period from the hitherto generally recommended 1 to 1.5 h to 6 h did not significantly affect the interval (approximately 10 h and 8.5 h, respectively) during which trimethoprim and sulfamethoxazole plasma concentrations were maintained above their minimum effective plasma concentrations (selected as 0.6 microgram/ml and 25 microgram/ml, respectively). For the 6-h infusion, the simulated peak plasma concentration of trimethoprim was only approximately 27% less than for the 1-h infusion, and that for sulfamethoxazole was approximately 30% less. The validity of these predictions was confirmed by plasma concentration measurements of trimethoprim and sulfamethoxazole in six patients undergoing gynecological surgery, who received co-trimoxazole (160 mg of trimethoprim, 800 mg of sulfamethoxazole) postoperatively by constant-rate intravenous infusion over a 4-h period. It is concluded that infusions of the dose of intravenous co-trimoxazole over periods from 1 to at least 6 h are therapeutically equivalent.

A pharmacokinetic study of sulfamethoxazole (SMZ) and trimethoprim (TMP) was carried out on Warren hens after intravenous (iv) dosage of 4:1, and oral administration of dosages of 5:1, and 2.5:1. The SMZ and TMP half-lives were 8.2 and 2.4 hr, respectively. The ratio between SMZ and TMP serum levels (S/T ratio), after iv administration of the 4:1 dosage, was approximately 20 and remained constant for only 1 hr, while after 5:1 and 2.5:1 oral dosages, the S/T ratio was 40 and 20, respectively, and remained invariable for 12 hr. The oral bioavailability of SMZ and TMP was .46 and .36, respectively. The apparently slower elimination of TMP from serum following oral administration should provide an extended duration of the synergistic antibacterial effect when this route of administration is employed. Finally, the 2.5:1 combination, after oral administration, resulted in an appropriate synergistic ratio (S/T ratio = 20:1) of the drugs in the serum.

Several antimicrobial agents were evaluated for activity against experimental Legionella micdadei pneumonia in guinea pigs. Erythromycin, rifampin, doxycycline, and sulfamethoxazole-trimethoprim produced significant reductions in mortality. Penicillin, cefazolin, cefoxitin, chloramphenicol, and gentamicin were not efficacious even though, at the doses administered, the peak concentrations of these agents in serum substantially exceeded their MICs for the test strain. It is suggested that the poor performance of the latter group of agents resulted from poor penetration into cells in which L. micdadei was multiplying.

We conducted a retrospective review of 21 adult patients with osteomyelitis and septic arthritis who were treated with high doses of oral antimicrobial agents, usually after an initial course of intravenous therapy. The mean duration of parenteral and oral therapy was 3.6 days and 43.0 days, respectively. Absorption of oral antibiotics was assessed by determining the trough serum bactericidal titers for the infecting organism; whenever feasible, the dosages were adjusted to achieve trough titers greater than or equal to 1:8. The follow-up period ranged from six to 66 months (mean, 42.4 months). Eighteen of 21 patients had no clinical signs of recurrence after initial therapy. One patient with an infected joint prosthesis developed recurrent infection, and two patients had recurrences accompanied by sequestra. The mean duration of hospitalization was 13.4 days, and the mean duration of outpatient treatment was 31.9 days.

Pharmacokinetic studies of intravenously administered trimethoprim-sulfamethoxazole (TMP-SMX) were conducted in 11 patients with cancer while they received therapy with this drug combination for infection. Each patient received 160 mg of TMP and 800 mg of SMX every 8 h. The highest plasma concentrations of both agents were attained at the end of a 1-h infusion period, and the levels were maintained above 38 mug of free SMX and 2 mug of TMP per ml for 2 to 4 h on day 1. On day 4, these concentrations were exceeded at all time intervals of blood sampling. High concentrations of TMP and free SMX were recovered in the urine during the 8-h period. The plasma half-lives of TMP and free SMX, as determined during the first 8-h period, were 7.6 and 8.6 h, respectively. Compared with SMX, TMP had an approximately 2.5 times higher volume of distribution. This drug combination was well tolerated by the patients and unaccompanied by drug-related toxicity.

A rapid spectrofluorometric method for determining the levels of both trimethoprim and sulfamethoxazole from the same specimen of serum is described. The method involves stepwise extraction of the specimen first with chloroform at an alkaline pH (pH 9.0) for trimethoprim followed by n-butyl chloride at an acidic pH (pH 2.0) for sulfamethoxazole. To quantitate trimethoprim, the chloroform layer was subjected to fluorometry by exciting the specimen at 295 nm and measuring the relative intensity at 330 nm. To determine sulfamethoxazole levels, the n-butyl chloride layer was subjected to fluorometry by exciting the specimen at 285 nm and measuring the relative intensity at 330 nm. Relative intensities were linear (r greater than 0.99) over the concentration ranges of 0.5 to 40 microgram/ml for trimethoprim and 1 to 400 microgram/ml for sulfamethoxazole. Values obtained by this spectrofluorometric procedure were in excellent agreement with those obtained by a conventional fluorometric assay for trimethoprim and a colorimetric assay for sulfamethoxazole. Elevated levels of endogenous metabolic products and numerous other drugs, including a number of antimicrobial agents, did not interfere with the method. Although salicylates interfere with the determination of sulfamethoxazole, an appropriate correction can be made. This method can also be used to determine the drug levels in cerebrospinal fluid.

One hundred twenty-three patients with nonpulmonary infections due to Mycobacterium fortuitum or Mycobacterium chelonei were treated by wound debridement and with chemotherapy on the basis of in vitro susceptibilities of the organism. Of 76 patients with infections caused by M. fortuitum, 13 required no therapy or were adequately treated with surgery alone. Patients with active localized disease received single drug therapy (usually with a sulfonamide) for a mean period of 10.6 weeks for cellulitis and seven months for osteomyelitis. Patients with extensive disease received amikacin or amikacin plus cefoxitin (mean, four weeks) followed by a sulfonamide (mean, six months). The 47 patients with infections caused by M. chelonei received no therapy or were treated with surgery alone (6); with amikacin (10), erythromycin (6), doxycycline (3), or cefoxitin (1); or with amikacin plus cefoxitin followed by cefoxitin alone for a total of 10-12 weeks (20); or other multiple-drug regimens (1). Surgery was performed on 74 (60%) patients. Schlichter tests or serum drug levels were determined for 81 (66%) patients. Response to therapy was excellent; 68 (90%) infections with M. fortuitum and 34 (72%) with M. chelonei were successfully treated. Cultures became negative within six weeks of chemotherapy, except for sternal osteomyelitis, for which cultures were not negative until up to 14 weeks. Follow-up for a mean period of 12 months following therapy was possible in 80% of cases. Relapses were rare except in patients with disseminated disease, and drug resistance developed in only one patient. These studies demonstrate the value of routine susceptibility testing of these mycobacterial species and the benefit of chemotherapy on the basis of in vitro susceptibilities.

Concentrations of trimethoprim (TMP) and sulfamethoxazole (SMZ) in blood were determined in seven healthy volunteers after ingestion of 720 mg of TMP and 3,600 mg of SMZ (nine tablets of TMP-SMZ, 1:5 ratio) as a single oral dose. The mean levels of drug in blood achieved during the first 8 h after drug administration ranged from 6.12 to 8.32 mug/ml for TMP and 98 to 120 mug/ml for SMZ. These concentrations easily exceeded the previously reported minimal inhibitory concentrations for clinical isolates of Neisseria gonorrhoeae. The combination of TMP-SMZ given as a single, large oral dose may be a useful therapeutic regimen for patients with uncomplicated gonorrhea and susceptible microorganisms.

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.

Trimethoprim-sulfamethoxazole (240 mg of trimethoprim plus 1,200 mg of sulfamethoxazole) was administered intravenously in a volume of 200 ml to 7 volunteers every 12 hr for 4 days. The mean peak levels of TMP and SMZ in plasma were 3.22 and 100 micrograms/ml, respectively, on day 1 and 5.91 and 178 micrograms/ml, respectively, on day 4, when a steady state was achieved. Tests of in vitro susceptibility indicated that these concentrations are bactericidal for a large proportion of enteric gram-negative bacilli.

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.

The concentration of antibacterial agents in the interstitial tissue fluid has been studied in an experimental model using implanted perforated Silastic capsules (tissue cages). Tissue fluid concentrations were always lower than the initial peak concentration in the serum, but for those drugs that were more slowly excreted the tissue fluid was similar to the serum concentration after six hours. In contrast the concentration in the tissue fluid for those drugs that are excreted rapidly was unpredictable, being either negligible or maintained at concentrations significantly better than in the serum. There was no evidence of accumulation in tissue fluid with regular dosage. These results indicate that the tissues may never be exposed to an adequate concentration of some antibacterial agents. This may be of clinical importance in tissue infections. Antibiotics which are rapidly excreted should be given in large enough doses and often enough for adequate blood levels to be maintained, so allowing equilibrium with tissue fluid to be achieved.