Antimicrobial substances in secretion, interstitial fluid, and tissue of normal and infected canine prostate glands.

Seven antimicrobial substances--three basic, three acidic and one amphoteric--were given in constant infusion experiments to dogs to monitor their distribution in the prostate gland. In some of the dogs an experimental bacterial prostatitis had been induced prior to the experiments. Drug levels were measured in plasma (P1), prostatic interstitial fluid (PIF), prostatic secretion (PS) and prostatic tissue (PT). Drug levels in PIF differed considerably from those in PS. In PS and PIF only basic substances exceeded the corresponding plasma levels. Concentrations of acidic substances in PS and PIF never exceeded the simultaneous plasma levels. In PIF the concentration of these drugs was significantly higher than in PS. Our results show that previous studies of prostatic secretion levels only were too optimistic for alkaline drugs and too pessimistic for acidic drugs.

Penicillanic acid derivatives in the canine prostate.

Distribution of ampicillin, amoxicillin, bacampicillin, mecillinam, pivmecillinam, carbenicillin, indanyl sodium was studied in the canine prostate, prostatic interstitial fluid, and prostatic secretion. All seven antibiotics were found in higher concentrations in the prostatic interstitial fluid than in the prostatic secretion. As expected for weak acids, drug concentrations in these fluids were always lower than the simultaneous serum concentrations. Tissue penetration was enhanced for the penicillin ester, pivmecillinam, as shown by its prostatic secretion/serum and tissue/serum ratios, which were higher than those of the other antibiotics, including the esters, bacampicillin, and carbenicillin indanyl sodium. This results may be due to pivmecillinam's long hydrolysis half-life. The concentrations for these penicillanic acid derivatives in prostatic interstitial fluid were above the minimal inhibitory concentrations for most of the commonly encountered gram-negative bacteria encountered in prostatitis. Therefore, these antibiotics should be effective in the treatment of bacterial prostatitis caused by susceptible organisms. Carbenicillin and carbenicillin indanyl sodium had the highest prostatic interstitial fluid/serum ratios of the compounds tested, and theoretically, therefore, they should be the most effective in the treatment of prostatitis. However, clinical trials should be carried out to confirm this.

Netilmicin treatment of complicated urinary tract infections.

Netilmicin was investigated in the treatment of complicated urinary tract infection in 169 elderly male patients. It was found to be safe and effective at the dose levels of 1.0-2.5 mg/kg, three times a day, or 2 mg/kg twice a day, eliminating approximately 50-60% of the infections. The serum half-life of netilmicin was 2-3 hours in subjects with normal renal function but increased to 10-14 hours in subjects with severe uremia. When the dosage was adjusted according to the patient's weight and serum creatinine, some nephrotoxicity occurred, possibly due to drug accumulation. Therefore, we suggest that the dose be adjusted according to reduction in creatinine clearance and when possible, monitoring serum concentrations during treatment.

Antibiotics excretion in canine vaginal and urethral secretions.

Trimethroprim, erythromycin, ampicillin, and rosamicin, a new macrolide antibiotic, were administered to dogs by constant intravenous infusion. Their concentrations in plasma, urine, vaginal and urethral secretions, saliva, and tears were determined by bioassay. Trimethoprim, rosamicin, and, to a lower degree, erythromycin were concentrated in the secretions of the vagina and the urethra whereas the ampicillin concentrations in these secretions never exceeded the simultaneous plasma concentrations. Inasmuch as rosamicin and trimethoprim have antibacterial spectra well suited for the treatment of bacterial urethritis and vaginitis they should be investigated clinically in this respect.

Experimental models for determination of antimicrobials in prostatic tissue, interstitial fluid and secretion.

Two new animal models were used to evaluate the usefulness of several antimicrobials for the treatment of bacterial prostatitis. An experimental bacterial prostatis was created in dogs and the concentraion of six antimicrobials (erythromycin, rosamicin, trimethoprim, sulphamethoxazole, ampicillin and doxycycline) measured in plasma and prostatic secretion and their concentration ratios compared to previous studies in healthy dogs. Prostatic interstitial fluid concentrations of the three basic drugs (erythromycin, rosamicin, trimethoprim) were determined from samples obtained from implanted tissue chambers. At the same time samples of plasma, prostatic secretion and urine were collected and their concentration ratios compared. Drug levels in prostatic secretion of dogs with infected prostatic glands were different from those without inflammation, but the same mechanism of drug diffusion into the prostatic secretion seems to be active during infection. Prostatic interstitial fluid concentrations of the three basic drugs were always lower than the simultaneous prostatic secretion levels. These findings may have clinical application in the treatment of bacterial prostatitis.

The influence of pH on antimicrobial substances in canine vaginal and urethral secretions.

Trimethoprim and rosamicin (a new basic macrolide antibiotic) were administered to normal and oophorectomised female dogs by constant intravenous infusion before and after oestrogen and androgen administration. Their concentrations in plasma and in urethral and vaginal secretions were determined by bioassay and correlated with the pH values of vaginal and urethral secretions. Both compounds were concentrated in the vaginal and urethral secretions in reverse correlation with the pH of these fluids. Trimethoprim and rosamicin have antimicrobial spectra well suited for the treatment of bacterial urethritis and vaginitis and require further clinical investigation.

Prostatic tissue and secretion concentrations of rosamicin and erythromycin. Experimental studies in the dog.

In dogs with normal and infected prostate glands, a new antibacterial substance, rosamicin, chemically a lipid soluble basic macrolide similar to erythromycin but with a better activity against Gram-negative bacteria, was tested, and compared to erythromycin in normal dogs. The two antibiotics were administered by constant intravenous infusion for 4 hr and their concentrations in plasma, urine, prostatic tissue, and secretion were determined by bioassay technique. Rosamicin was highly concentrated in the secretion of both the normal and the infected prostate gland, although in the latter the antibiotic levels were significantly lower. Erythromycin was significantly less concentrated than rosamicin in the prostatic secretion from normal prostates and was also less concentrated in normal prostatic tissue. Inasmuch as rosamicin has an improved antibacterial spectrum, which is well suited for the treatment of bacterial prostatitis, it should be investigated in this respect.

Netilmicin pharmacokinetics after single intravenous doses to elderly male patients.

The pharmacokinetics of the new aminoglycoside antibiotic netilmicin were examined after single intravenous injections at two different dose levels to elderly male patients. The durg obeyed two-compartment model kinetics in serum, and elimination was monoexponential from 1 to 2 h after dosing. Netilmicin levels in serum were above minimum inhibitory concentration values for most susceptible organisms for up to 8 h after dosing in normal individuals and for at least 12 h in uremic patients. Urine levels of netilmicin were uniformly above minimum inhibitory concentration values throughout 24 h after dosing. Netilmicin distribution characteristics were largely independent of both dose level and renal function. Netilmicin elimination kinetics were independent of dose level but were markedly influenced by renal function. Relationships are described between netilmicin elimination and renal function indicators, which provide a basis for dosage adjustment in individuals with renal function impairment.

Rosamicin in urethral and vaginal secretions and tissues in dogs and rats.

In animal studies we investigated the distribution of rosamicin in plasma and urethral and vaginal tissues in rats as well as in urethral and vaginal secretions in dogs. We found concentration ratios between urethral secretion and plasma of 1.9 and between vaginal secretion and plasma of 2.4. The rosamicin concentrations in urethral and vaginal tissue significantly exceeded the levels of all other tissues investigated. Because rosamicin could be valuable for the treatment of bacterial urethritis and the colonization of the vaginal introitus with fecal bacteria in women, it should be investigated clinically in this respect.

Rosamicin--a new drug for the treatment of bacterial prostatitis.

Rosamicin, a new macrolide substance, was investigated in dogs and humans with regard to its usefulness for the treatment of bacterial prostatitis and compared with the well-known macrolide erythromycin. In dogs with normal and experimentally infected prostates, concentration ratios for rosamicin in prostatic secretion, interstitial fluid (obtained from implanted tissue chambers), and tissue were significantly higher than for erythromycin. The difference was even more pronounced in human prostatic tissue, obtained by transurethral resection. With its broad spectrum against many common urinary pathogens, rosamicin seems to be a promising drug for the treatment of acute and chronic bacterial prostatitis.

Secretion of various antimicrobial substances in dogs with experimental bacterial prostatitis.

Bacterial prostatitis in dogs was induced by injection of an E. coli 06 suspension into a branch of the prostatic artery. Three to six days later, secretion from the inflamed glands was obtained by pilocarpine stimulation and the concentrations of trimethoprim, sulphamethoxazole, erythromycin, doxycycline and ampicillin were measured during constant infusion of these drugs. In the prostatic secretion, only the concentrations of the lipid soluble substances trimethoprim and erythromycin exceeded the corresponding plasma levels. These two substances may therefore be of value in the treatment of bacterial prostatitis.

Experimental bacterial prostatitis in dogs.

Bacterial prostatitis was successfully induced in 30 dogs by the injection of E. coli into a branch of a prostatic artery. Inflammation was proven histologically in all cases and by the appearance of E. coli in the prostatic secretion in all but two dogs. In these two dogs cultures from prostatic tissue were positive for E. coli. The pH changes in the prostatic secretion were inconclusive, and the zinc levels increased slightly in the acutely inflamed gland. Antibody coating of the bacteria could not be demonstrated by immunofluorescence.

Prostatic tissue and fluid concentrations of trimethoprim and sulfamethoxazole: experimental and clinical studies.

The concentrations of trimethoprim and sulfamethoxazole were determined in prostatic fluid and tissue of the dog after constant intravenous infusion. Concentrations of trimethoprim in both prostatic fluid and tissue exceeded the simultaneous serum concentrations, whereas the sulfamethoxazole prostatic fluid and tissue concentrations were much lower than the simultaneous serum concentrations. Prostatic tissue obtained from patients undergoing transurethral resection of the prostate also contained trimethoprim in higher but sulfamethoxazole in lower concentrations than the simultaneous serum concentrations after oral administration of these drugs preoperatively. In a patient with urinary diversion, trimethoprim was found in prostatic fluid in concentrations as high as forty-four times the simultaneous serum concentrations whereas sulfamethoxazole was found in concentrations representing only a fraction of the simultaneous serum concentrations. These findings lend support to the use of trimethoprim in the treatment of bacterial prostatitis.