Effect of gentamycin in combination with prodigiozan on the immunological reactivity of the body

The effect of gentamicin sulphate and its combination will prodigiozan on antibody formation in experiments and the levels of the immunobiologic reactivity of patients with purulent inflammatory processes was studied with a purpose of developing rational schemes of antibiotic therapy of infectious diseases. A decrease in the titers of the antibodies to Aeromonas and the number of antibody-forming cells in the spleen was noted on repeated administration of gentamicin to albino mice in a dose of 20 mg/kg. This was prevented by the use of prodigiozan in a dose of 500 micrograms/kg once every 4 days. The use of gentamicin in patients with purulent inflammatory diseases in doses of 40 or 80 mg twice a day for 7--10 days had no significant effect on the titers of IgA, IgG, IgM, lysozyme blood serum levels, serum bactericidal activity and absorption activity of the peripheral blood neutrophils. Still, it induced a marked suppression of the neutrophil digestive capacity as compared to the initial levels, especially on administration of gentamicin in a dose of 40 mg twice a day. An increase in the level of IgM and no suppression of the neutrophil digestive capacity were noted after completion of the therapy in the patients treated with gentamicin administered in a dose of 40 mg twice a day and prodigiozan administered in a dose of 50 micrograms once every 4 days. It is recommended to use prodigiozan in combinaed therapy with gentamicin for correction of the changes in the specific and nonspecific protective forces of the host.     

Clinico-laboratory basis for the endolymphatic use of beta-lactam antibiotics in pulmonology

Clinical efficacy and effect of cefuroxime, claforan and pentrexyl used endolymphatically were studied in 85 patients with acute abscess forming and persisting pneumonia. Previous routine antibiotic therapy in these patients was little effective. Administration of the antibiotics into the peripheral lymph nodes provided blocking of the lymphagenic pathway for the infection due to high levels in the lymphatic system. Endolymphatic use of cefuroxime and claforan resulted in a significant improvement of the functions of the T- and B-immunity systems and the indices of natural resistance. The levels of the autoimmune reactions and sensitization to the bacterial antigens decreased. Endolymphatic use of cefuroxime and claforan once every 3 days provided recovery of 9 2.8 per cent of the patients, the treatment periods being decreased 2.5--3 times. Intravenous administration of the drugs according to the routine schemes, endolymphatic use of pentrexyl (5 g once every 3 days) and endolymphatic administration of cefuroxime in a single dose followed by intravenous therapy was less effective. The efficacy of pentrexyl increased, when it was used endolymphatically in combination with lysozyme. Endolymphatic use of claforan in doses of 2--3 g once every 3 days (3--4 infusions during the treatment course) was most effective.     

Effect of tobramycin and gentamicin on the activity of some glycosidases in rat serum and urine

beta-Galactosidase, alpha-D-mannosidase, alpha-L-fucosidase and N-acetyl-beta-D-glucosaminidase activities were assayed in serum and urine from rats treated with three different doses of the nephrotoxic antibiotic tobramycin (100 mg/kg/day for 5 days, 10 mg/kg/day for 10 days and 5 mg/kg/day for 20 days) and gentamicin (100 mg/kg/day for 5 days). A significant increase of beta-galactosidase, N-acetyl-beta-D-glucosaminidase and alpha-L-fucosidase activities occurred in urine following the administration of high doses of antibiotic. The enzyme activity was dependent on the dose level used. The excretion of alpha-D-mannosidase was atypical and elevated activities were observed on some days but no pattern of excretion of this enzyme was established. No change in any of the four glycosidase activities was found in serum of treated rats. The results obtained when high doses of gentamicin were employed are similar to those obtained with a similar dose of tobramycin. These results indicate that the assay of urinary glycosidase activities provides a useful method for monitoring the nephrotoxicity of antibiotics.     

Targeting of Antibiotics in Bacterial Infections Using Pegylated Long-Circulating Liposomes

Abstract

PEGylated long-circulating liposomes were used as a delivery system of antibiotics providing enhancements in antibiotic pharmacokinetics and penetration to infected sites. Pharmacokinetic and therapeutic efficacy studies were performed in the model of unilateral pneumonia/septicemia caused by Klebsiella pneumoniae in rats with intact host defense or leukopenic rats. Gentamicin was encapsulated in PEGylated liposomes designed to achieve delivery of antibiotic to the infected left lung tissue. Our data show that the efficacy of liposomal gentamicin was superior to free gentamicin particularly in difficult to treat infection due to impaired host defense (leukopenia) or low antibiotic susceptibility of the infectious organism. In leukopenic rats infected with a high gentamicin-susceptible bacterial strain, free gentamicin must be administered at the maximum tolerated dose to be therapeutically effective. The addition of a single dose of liposome-encapsulated gentamicin on the first day of treatment with free gentamicin leads to full therapeutic efficacy while keeping the antibiotic doses low. In even more difficult to treat infection due to both an impaired host defense (leukopenia) and low gentamicin-susceptibility of the bacterial strain, free gentamicin is not effective, and the addition of the liposome-encapsulated form of gentamicin is needed to achieve full therapeutic efficacy. In this respect, the lipid composition of the liposomes is an important determinant in establishing both sufficient antibiotic levels in blood and sufficient release of antibiotic from the liposomes at the infectious focus.

Ciprofloxacin was encapsulated in PEGylated liposomes designed to serve as a microreservoir of antibiotic during circulation in blood. Our data show that the administration of ciprofloxacin in the liposomal form resulted in slow release of ciprofloxacin from the liposomes over time in blood. Delayed ciprofloxacin clearance, as well as increased and prolonged ciprofloxacin concentrations in blood and tissues was observed. The therapeutic efficacy of liposomal ciprofloxacin was superior to that of free ciprofloxacin. PEGylated liposomal ciprofloxacin was well tolerated in relatively high doses (increasing the maximum tolerated dose for free ciprofloxacin), permitting the administration on a once-a-day schedule without loss in therapeutic efficacy.     

Lymphotropic antibiotic therapy of obstetrical suppurative-septic diseases]

The pharmacokinetics and efficacy of gentamicin after its direct and indirect endolymphatic administration were comparatively studied. It was shown that the time course of the blood pharmacokinetics of the antibiotic was almost the same as under the both conditions. Therefore, in many cases the less complicated and more available indirect endolymphatic therapy may replace the direct labor-consuming and traumatic endolymphatic administration of drugs.     

Erythromycin penetration into the cerebrospinal fluid of patients]

Permeability of erythromycin through the barrier of blood-cerebrospinal fluid in neurosurgical patients after its oral administration in a dose of 300-500 mg and intravenous administration in a dose of 200 mg was studied. The erythromycin was determined after the antibiotic single administration at intervals of 40 minutes to 6 hours. A total of 31 observations were performed. Low penetration of erythromycin into the cerebrospinal fluid of the patients was shown. The administration route (oral or intravenous) practically had no effect on the antibiotic penetration level into the subarachnoidal spaces. The highest liquor levels were observed within the period of 3 to 6 hours after the drug administration. The maximum index of penetration from the blood into the cerebrospinal fluid was about 10 per cent. The erythromycin penetration increased in cases with inflammatory changes in the meninges.     

Clinical pharmacokinetics of kanamycin in endolymphatic therapy of peritonitis]

The pharmacokinetics of kanamycin in patients with peritonitis was studied after its intramuscular, endolymphatic and lymphotropic administration. Endolymphatic administration of kanamycin provided an increase in its activity in the inflamed tissues of the peritoneum and omentum and markedly prolonged its halflife as compared to those after the routine intramuscular administration of the drug. Lymphotropic administration of kanamycin failed to provide the same effect. Endolymphatic therapy of the patients during the postoperative period provided a decrease in the lethality, development of complications and the terms of the treatment in the hospital. The therapeutic effect of the endolymphatic administration of kanamycin to the patients with peritonitis proved to be high. The more efficient antibiotic therapy of the cases was likely due to favourable shifts in the pharmacokinetics of kanamycin after its endolymphatic administration.     

Antibiotic use optimization program in the largest Croatian university hospital--benefits of restrictions on unlimited antibiotic use

The aim of this study was to obtain the relevant information on antibiotic use in a 750-bed Croatian university hospital. The study has been designed as a 2-point prevalence interventional analysis. For each patient on antibiotic therapy, diagnosis, indication for treatment, antibiotic therapy, dosage and route of administration together with the results of microbiological studies (if available) were obtained. After the first prevalence analysis in 2001, a restriction on unlimited antibiotic use was introduced. The second analysis, performed in 2002, after restrictions on antibiotic use, revealed reductions in the rates of restricted release antibiotics and overall antibiotic use with decreases from 38.6% to 36.9% and 23.4% to 23.2% respectively (p = 0.87). The first survey showed that the 5 most often prescribed antibiotics in the therapy of bacterial infections were: gentamicin, other aminoglycosides, carbapenems, amoxycillin +clavulanate and vancomycin with proportions of 14.8%, 10.3%, 8.2%, 7% and 7% respectively. In the year 2002, the most prescribed antimicrobial drugs in the therapy of bacterial infections were: gentamicin, quinolones, vancomycin, carbapenems and cefuroxime with proportions of 18.6%, 11.4%, 9.7%, 9.3% and 8% respectively. A reduction in the proportions of doubtful antibiotic therapy, from 24.6% before the intervention, to 24.2% after the restrictions, accompanied by a 0.4% rise in the rates of indicated antibiotic therapy was also observed (p = 0.93). Our study shows that restrictions on formerly unlimited use of antimicrobials, even when leading to an improvement in their prescribing, do not necessarily cause rapid and significant reduction in the overall use of antibiotics or explicit positive financial effects.     

Antibiotic sensitivity of the causative agents of suppurative surgical infection]

Sensitivity of 1492 strains of the causative agents of the surgical purulent infections, i. e. pathogenic Staphylococcus, Proteus, Ps. aeruginosa and E. coli to benzylpenicillin, streptomycin, levomycetin, tetracycline, erythromycin, oleandomycin, monomycin, kanamycin, novobiocin, ampicillin, oxacillin, ceporin, gentamicin and rifampicin was studied. Gentamicin was most active against all the bacterial species tested. The staphylococci were in addition sensitive in a high percentage of the cases to rifampicin, novobiocin, ceporin, monomycin and kanamycin. The isolates of E. coli were in addition sensitive to ceporin, monomycin and kanamycin. Sensitivity of the strains of Ps. aeruginosa and Proteus was low to all of the antibiotics except gentamycin. Most of the strains of the causative agents of the surgical purulent infections were multiresistant to 4 antibiotics. The number of the staphylococcal strains sensitive to benzylpenicillin, streptomycin and levomycetin increased in 1976 as compared to 1975 on the background of a limited use of these antibiotics in clinics.     

Gentamicin nephrotoxicity. II. Physiological, biochemical and morphological effects of prolonged administration to rats.

The purpose of this investigation was to determine the morphological, physiological and biochemical effects of gentamicin upon the rat kidney following prolonged administration of the antibiotic. Sprague-Dawley and Fischer 344 strain rats were given 3, 10, 20 or 40 mg gentamicin per kg body weight per day for 28 days. Morphologic alterations were evaluated by light and electron microscopy. Functional parameters included glomerular filtration rate, PAH secretion, renal plasma flow, sodium reabsorption, potassium excretion, urine volume and protein, and serum urea nitrogen. Oxidative metabolism of mitochondrial fractions from renal cortical homogenates was evaluated by oxygen uptake and P:O ratios. The results indicate focal proximal tubular injury, decreased tubular maximum secretion of PAH, and altered oxidative metabolism at the higher dose levels of gentamicin. Neither elevations of serum urea nitrogen nor alterations in glomerular filtration rate, renal plasma flow, or sodium or potassium excretion were observed. Thus, it appears that high dose levels (40 mg per kg per day) alter the structure and function of some proximal tubular segments when administered over prolonged periods. The alterations appear reversible. Although nephro-toxicity is identified under these conditions in rats, extrapolation to human patients usually receiving much lower doses must be guarded.     

Effect of indirect endolymphatic antibiotic therapy on clinical and immunological indicators in patients with erysipelas of the lower extremities]

Two groups of patients with erysipelas of the lower extremities underwent indirect endolymphatic therapy with bicillin-3 (58 patients) and routine penicillin therapy (79 patients). Comparative clinicoimmunological examinations in the two groups revealed that lymphotropic administration of the antibiotic had a more favourable effect on the disease process, as evidenced by more rapid reverse time courses of erysipelas clinical signs, less frequent incidence of early relapses and normalization of the majority of immunological parameters by the end of the treatment. For estimation of the anti-recurrence efficacy of the antibiotic therapy in the patients with erysipelas, it was recommended to use a specific scale based on the principles of the Wald successive alternative analysis.     

Survey of antibiotic prophylaxis in gastrointestinal surgery in Scotland.

The current use of prophylactic antibiotics in gastrointestinal surgery in Scotland was established by postal questionnaire. Twenty-one per cent of surgeons used prophylactic antibiotics during cholecystectomy, 49% during appendicectomy, and 95% for elective colorectal surgery. Two-thirds of those surgeons who did not provide routine antibiotic cover considered that the incidence of wound sepsis in their surgical practice was too low to merit special measures. Most surgeons using prophylaxis chose an appropriate antibiotic. The parenteral route for administration of antibiotic was used by 93% of surgeons during cholecystectomy, 29% during appendicectomy, and 45% in elective colorectal surgery. Most did not prolong cover beyond 24 hours postoperatively. This survey shows that the concepts governing the use of antibiotic prophylaxis have been absorbed into current surgical practice. Most surgeons used appropriate antibiotic regimens; many prefer the parenteral route of administration; most do not prolong cover beyond 24 hours.     

Chronopharmacokinetic Study of Gentamicin in Dogs

The purpose of this experiment was to determine whether the time of day of single intravenous doses of gentamicin affects the drug's pharmacokinetics in dogs maintained under a 12 h light (08:00 to 20:00 h), 12 h dark (20:00 to 08:00 h) cycle. Using a crossover design, 6 mixed‐breed male dogs received a single dose of 2 mg/kg of gentamicin at 8:00 or 20:00 h. Serial blood samples were collected and pharmacokinetic parameters were calculated following each timed dose. The concentration of the antibiotic was lower following the 08:00 h compared to the 20:00 h administration. When gentamicin was administered at 20:00 h, the initial concentration, mean residence time, and area under the disposition curve were significantly higher (p<0.05) and the apparent volume of distribution of the central compartment, apparent volume of distribution, apparent volume of distribution at steady‐state, and total body clearance (1.73±0.55 at 20:00 h versus 3.31±0.67 L/min/kg at 08:00 h) were significantly lower than for the 08:00 h administration (p<0.05). Our results show that the pharmacokinetics of gentamicin exhibits significant temporal variation when administered to dogs at different times of day.     

Effectiveness of acipole in prevention of enteric dysbacteriosis due to antibacterial therapy]

Acipole (Lactobacillus acidophilus + Kefir greins) was used to manage antibiotic dysbacteriosis as an adverse reaction of antibacterial therapy. 120 patients treated with antibacterial drugs for acute pneumonia and exacerbations of chronic bronchitis were observed. 54 of them were treated under the routine regimen with antibiotics and 66 were additionally treated with the eubiotic acipole: 1 tablet (5 doses) 3 times a day 30 minutes before meal. Routine bacteriological examination of the feces was applied to all the patients. High frequency of bacteriologically revealed dysbacteriosis was stated. The therapy under the antibiotic + acipole regimen lowered the frequency of dysbacteriosis events and their severity. The fact that the use of acipole simultaneously with the routine antibacterial therapy prevented the development of dysbacteriosis clinical signs is of practical importance.     

Features of incorporation of several antibiotics into erythrocyte ghosts--a system of targeted delivery of chemotherapeutic drugs

Features of incorporation of cefazolin, ampicillin, kanamycin and gentamicin into erythrocytic shadows in patients with abdominal diseases and apparently healthy persons during hypoosmotic hemolysis were studied. The highest percentage of kanamycin and gentamicin incorporation into the erythrocytic shadows was observed. The parameter of the antibiotic incorporation from the incubation fluid into the erythrocytic shadows depended on the antibiotic type and dose. Rather significant resistance of the erythrocytic carriers with incorporated gentamicin to possible desorption and excretion of the antibiotic from the shadows into the blood flow was revealed which made their use possible for target release of antibiotics in the liver.     

Treatment of Gram-Negative Bacillary Meningitis With Intrathecal Gentamicin

In order to evaluate the effect of intrathecal gentamicin on gram-negative bacillary meningitis, twenty-eight patients were treated with intralumbar or intraventricular gentamicin in combination with systemic gentamicin and with other antibiotics. Sterile cerebrospinal fluid was achieved in 21/22 (95%) episodes of documented gram-negative bacillary meningitis in patients who received more than one day of therapy. Seventy-seven percent of these patients survived their infection. The mean cerebrospinal fluid gentamicin level measured 24 hours after intrathecal administration was 5.9 ug/ml following intralumbar administration and 11.1 ug/ml following intraventricular administration. Toxic side effects due to intrathecal administration of gentamicin were not noted. These findings suggest that both intralumbar and intraventricular administration of gentamicin are safe and efficacious in the treatment of gram-negative bacillary meningitis.     

Endolymphatic delivery of IL2 in patients with melanoma and lymphoma

During this phase I/II study, enodolymphatic cannulae were placed in the iliac lymphatics under general anaesthesia. IL2 was then infused via this route at escalating doses until the highest tolerated dose was achieved; then, continuous infusion was maintained for 2 to 3 weeks. Seven patients with advanced cancer (3 lymphoma, 4 melanoma), resistant to all other modalities of treatment received such therapy.Most patients tolerated 4 to 5 × 10⁶ u/day of IL2 for 2 to 3 weeks with less toxicity as compared to the equivalent dosage given intravenously. No severe perioperative morbidity was experienced. One melanoma patient had a minor clinical response. Changes in circulating lymphocyte numbers and cytotoxicity demonstrated a systemic effect of endolymphatic IL2 therapy.Conclusions: The endolymphatic administration of IL2 is associated with less toxicity than the intravenous route but still achieves a systemic effect; a lower tumour burden may prove more responsive to this therapy.     

Gentamicin level in the prostate and its pharmacokinetics in patients with benign prostatic hypertrophy]

The study involved 15 male patients with periurethral prostatic adenoma without complete anuresis. The patients were given 80 mg of gentamicin intramuscularly one day before surgery and 80 mg in a one-hour infusion immediately before an operation. Gentamicin blood concentrations were measured. Pharmacokinetic parameters were calculated and dosage schemes for each patient basing on the antibiotic blood levels. Gentamicin levels in removed adenomas were also determined. Adenomas weighed between 18.0 and 45.8 grams while gentamicin concentration ranged from 1.31 to 3.8 micrograms/mL. It was found that gentamicin concentration in adenomas depend upon their weight. Moreover, pharmacokinetic parameters of this antibiotic exert negligible effect on its levels in adenoma.     

Accumulation of gentamicin in biological fluids, organs and tissues during regional lymphotropic therapy with antibiotics

Gentamicin distribution in biological fluids, organs and tissues, lymph nodes was studied on 70 dogs. Three administration routes were compared: lymphotropic, intramuscular and regional subcutaneous. The lymphotropic route for the drug administration was recommended not long ago. It was shown that the lymphotropic route provided the antibiotic accumulation mainly in some of the abdominal organs as compared to intramuscular administration. Regional lymphotropic administration of the antibiotic to the experimental animals resulted in higher gentamicin levels in the regional lymph nodes and regional organs as compared to the levels observed after the antibiotic regional subcutaneous administration in the same doses.     

Evaluation of selected indicators of the renal proximal tubule function in patients treated with gentamicin]

The study aimed at evaluating proximal renal tubule function in patients with nephrolithiasis and chronic pyelonephritis, and in patients with infectious diseases treated with gentamicin. The study involved 2 groups of patients: group A--17 patients with nephrolithiasis and chronic pyelonephritis and group B--30 patients with other infectious diseases (pneumonia, biliary tract infections) but with normal glomerular filtration rate. Patients from both groups were treated with gentamicin in a daily dose of 2-3 mg/kg for 7-10 days. Serum and urine creatinine levels were assayed in all patients prior to, 2-3, 7, 10 days, and after the treatment. Patients assigned to group B were divided into two subgroups: B1 included 15 patients with normal beta 2-microglobulinuria, and B2 15 patients with increased renal loss of beta 2-microglobulin and decreased tubular reabsorption of this protein. Significant increase in beta 2-microglobulinuria was seen on the third day of therapy, the decrease in the tubular reabsorption and glomerular filtration rate were noted in all patients on the seventh day of gentamicin administration. Beta 2-microglobulinuria was significantly higher in patients from groups A and B2 in comparison with group B1 in which no dysfunction of the proximal renal tubule was present before gentamicin therapy. A degree of beta 2-microglobulinuria is an early and sensitive indicator of gentamicin nephrotoxicity. The risk of nephrotixic symptoms is particularly obvious in patients with deteriorated function of renal proximal tubuli before the treatment with gentamicin.