An evaluation of ampicillin pharmacokinetics and toxicity in guinea pigs

Sodium ampicillin was administered subcutaneously to 350-550 g male Dunkin Hartley guinea pigs at doses of 6, 8 and 10 mg/kg tid for 5 days. Over a period of 12 days, the lowest ampicillin dose appeared to be tolerated well. However, significant body weight reduction and mortality occurred with the two higher dosage regimens. Cecal cultures of dead animals confirmed the presence of Clostridium difficile, an organism associated with antibiotic-induced enterotoxemia. Assay of serum collected from ampicillin-treated animals revealed ampicillin concentrations of approximately 10 micrograms/ml at 5 minutes post-dosing which fell precipitously to less than 0.2 micrograms/ml at 60 minutes. Determination of biliary ampicillin levels during the 60 minutes after administration of a single 10 mg/kg SQ dose revealed concentrations ranging from 18 micrograms/ml to 90 micrograms/ml. Estimates of total urinary ampicillin content after a single 10 mg/kg SQ dose were less than 500 micrograms/animal at 7.5 minutes, but increased to greater than 2000 micrograms/animal at 60 minutes after dosing. Results of this study indicated that due to its short serum half-life, sodium ampicillin probably has little systemic therapeutic efficacy in guinea pigs. Because high concentrations of ampicillin accumulated in the urine and bile, the antibiotic probably would have therapeutic efficacy for urinary and intestinal infections. However, its associated toxicity at large doses probably precludes its use. In view of the rapid clearance of ampicillin in guinea pigs in comparison to other species, the pharmacokinetics of other antibiotics, especially those reported to be less toxic for guinea pigs, should be considered.     

Ampicillin treatment trial in gonorrhea recurrences]

The results of using ampicillin in treatment of 54 gonorrhea patients (41 males and 13 females) previously treated with other antibiotics without success are presented. Ampicillin was used in a daily dose of 500 mg administered 5 times a day at equal intervals and an 8-hour interval during the night time. The course dose was 6--10 g. Patients with chronic and fresh gonorrhea with insignificantly pronounced symptoms were subjected to immunotherapy before the treatment with ampicillin. Pure gonococcal strains sensitive to ampicillin were isolated from 16 patients before the ampicillin use. Clinical improvement after the treatment with ampicillin in most of the patients was observed by the end of the 1st day and was evident from elimination of the urethral discharges, absence of urination colics and urea clarification. Etiological recovery was recorded in all the gonorrhea patients due to the treatment with ampicillin. All the patients were crossed off the register. The clinical and laboratory investigations showed high efficiency of ampicillin in treatment of gonorrhea relapses. The antibiotic is rapidly absorbed into the blood. Its therapeutic blood levels are maintained during 24 hours. It is well tolerated by the patients.     

Therapy of urinary tract infections in patients with diabetes mellitus]

Clinical and microbiological efficacy of Cifran OD (Ranbaxy, India), a formulation with prolonged action and extended release of ciprofloxacin was studied in 22 patients with bacteriuria and lingering diabetes mellitus. Ciprofloxacin was used in doses of 500 or 1000 mg orally once a day depending on the severity of the disease singns for 2-3 weeks as etiotropic therapy and only in 2 cases with severe pyelonephritis it was used intravenously drop-wise and orally simultaneously. Twenty eight microbial strains isolated from urea of the patients were tested. The main species of the isolates belonged to the family Enterobacteriaceae. Twenty five isolates (89.3%) were susceptible to ciprofloxacin and 3 isolates (10.7%) were resistant. The clinical efficacy of ciprofloxacin was 90.9%.     

Intralymphatic administration of antibiotics in the complex treatment of suppurative complications in patients with neurosurgical pathology

The efficacy of endolymphatic route of gentamicin and ceporin administration was studied in 89 patients with neurosurgical pathological processes complicated by acute pneumonia (80 patients) and meningoencephalitis (9 patients) usually after ineffective antibiotic therapy according to the routine methods. The antibiotics were used in accordance with the antibiograms of the causative agents isolated from the bronchial tree or CSF. The endolymphatic use of gentamicin or ceporin once a day in doses of 80 mg or 1 g respectively provided rapid sanation and arresting of the inflammatory foci, lowering of the intoxication level, more rapid promotion of the positive time course of the clinico-roentgenological and laboratory indices and decreasing of the recovery periods by 1.5-2 times in 86 per cent of the patients with pneumonia. The endolymphatic administration of gentamicin in a dose of 80 mg twice a day or ceporin in a dose of 1 g twice a day allowed one to maintain the antibiotic therapeutic levels in the cerebrospinal fluid and to obtain satisfactory clinical results in the combined treatment of meningoencephalitis. The endolymphatic administration of the drugs was well tolerated by the patients and no adverse reactions were observed. This route of administration of antibiotics and in particular broad spectrum antibiotics may be recommended for urgent antibacterial therapy of especially severe neurosurgical patients with pyo-inflammatory complications and patients who did not respond to the routine antibiotic therapy.     

Combined antibiotic therapy following heart surgery

In vitro efficacy of combinations of broad and narrow spectrum semi-synthetic penicillins, broad spectrum semi-synthetic penicillins with macrolides or aminoglycosides and tetracyclines with other biosynthetic antibiotics was studied with respect to the causative agents of surgical infections. Correlation between the sensitivity of the isolates and the antibiotics levels in the organism of the surgical patients was shown. The role of the etiological factor in the development of the post-operative complications in the patients after surgical operations on the heart was elucidated. The most rational schemes of the antibiotic use in therapy of the patients with purulent complications after operations on the open heart were developed and the maximum doses of different semi-synthetic penicillins for the treatment of patients with purulent processes after operations under conditions of artificial blood circulation were determined.     

Pharmacokinetics of penicillins in the blood of dogs administered the combination preparation, ampiox, internally]

The pharmacokinetics of penicillins in the blood of dogs treated with ampiox, a combination of ampicillin and oxacillin at a ratio of 1 : 1 was studied. The drug was administered orally in single or repeated doses of 25, 50 and 100 mg/kg. The maximum levels of ampicillin in the blood serum were observed 1 hour after a single administration of the drug. The therapeutic concentrations of the antibiotic were preserved for 6 hours, its value being depended on the dose used. The maximum concentration of oxacillin was detected 1 hour after the drug administration in various doses and it was preserved in the blood at the therapeutic levels for 3 hours. The dynamics of circulation of ampicillin and oxacillin administered separately did not differ from that established for the use of ampiox. The regularities of the pharmacokinetics of ampiox on its repeated use remained practically unchanged.     

Use of an experimental design method for studying the effect of proteolytic enzymes on the pharmacokinetics of antibiotics]

The effect of chemotripsin on the pharmacokinetics of ampicillin as dependent on the drug dose and the administration intervals was studied on rats using the method of the experiment design. With the use of the method it was found that intramuscular injections of chemotripsin to rats in doses of 3, 4.5, 6, 8 and 10 mg/kg, 0.5, 1, 1.5 and 2 hours before intramuscular administration of ampicillin in doses of 10, 20, 35, 75 and 100 mg/kg caused a simple effect inducing an increase in the antibiotic levels in the blood and organs, when the enzyme and antibiotic were present simultaneously in the animal organism for an hour. The increase in the antibiotic levels in the rat organs due to simultaneous presence of chemotripsin and ampicillin the animal organism for 2 hours was less pronounced     

Serum and urine levels of interleukin-6 and interleukin-8 in children with acute pyelonephritis

Urinary tract infection (UTI) is a common clinical disorder in younger infants and children and may result in permanent renal damage. The inflammatory cytokines interleukin (IL)-6 and IL-8 play an important role in response to bacterial infection. This prospective study investigated the association between serum and urine IL-6 and IL-8 levels and acute pyelonephritis confirmed by (99m)Tc-dimercaptosuccinic acid (DMSA) scan. A total of 78 children aged 1-121 months with a diagnosis of first-time febrile UTI were included. The following inflammatory markers were assessed: fever; white blood cells count (WBC); C-reactive protein (CRP); and serum and urine IL-6 and IL-8. The patients were divided into the acute pyelonephritis group (n=42) and the lower UTI group (n=36) according to the results of DMSA scan. Fever, WBC and CRP levels were significantly higher in children with acute pyelonephritis than in those with lower UTI (all p <0.001). Significantly, higher initial serum and urine IL-6 and IL-8 levels were found in children with acute pyelonephritis than in those with lower UTI (all p <0.001). Serum and urine IL-6 in children with acute pyelonephritis were positively correlated with fever, CRP and leucocyturia. These results indicate that both serum and urine IL-6 and IL-8 levels, particularly IL-6, are useful diagnostic tools for early recognition of acute pyelonephritis in febrile children.     

Pharmacokinetic indices of penicillin and semicillin (ampicillin) in kidney diseases in children

The kinetics of penicillin and semicillin was studied in 80 children at the age of 5 to 14 suffering from glomerulonephritis and pyelonephrities. The Bertolotti penicillin test revealed an isolated or associated (with lowered glomerular filtration and function of the osmotic concentration) decrease in the secretory function of the proxymal nephron in the patients without the signs of chronic renal insufficiency. The results of the study on the pharmacokinetics of simicillin indicated definite regularities in its excretion with urine as dependent on the period of its use and the state of the renal function. When semicillin was used in therapeutic doses, its concentration in urine exceeded the MIC with respect to all bacteria isolated from the urine specimens of the patients with pyelonephritis. Control of the antibiotic blood levels in children with kidney diseases at the stage of chronic renal insufficiency is necessary for choosing the optimal dose and intervals between the drug injections.     

Prolactinomas and resistance to dopamine agonists.

Among 288 patients with prolactinoma (aged 12-62 years; 242 women), 27 were diagnosed as resistant to bromocriptine as their plasma prolactin (PRL) levels remained elevated despite long-term (3 months or more) treatment at high doses (> or = 15 mg daily). These 18 women and 9 men, aged 29 +/- 9 years (mean +/- SD, range 13-50), followed-up for 8 +/- 4 years, had microadenomas (n = 6) or macroadenomas. They were treated by dopamine agonists alone (n = 6) or associated with surgical or radiation therapy. In 8 cases repetitive surgical treatments were necessary. Among the 24 patients who were treated with the nonergot dopamine agonist CV 205-502 after unsuccessful bromocriptine treatment, half of them (9 women, 3 men) resumed normal PRL levels on doses ranging from 0.15 to 0.45 mg/day. Despite daily doses of CV 205-502 from 0.3 to 0.525 mg, the remaining patients were not normalized by this drug which did not prevent tumor growth in 4 of them. Two patients died from invasive cerebral extensions of their tumor and a third had vertebral metastases with positive anti-PRL immunostaining. It is concluded that bromocriptine-resistant prolactinomas represent the most severe aspect of this disease and that a more powerful dopamine agonist like CV 205-502 is effective in only a fraction of these patients.     

Studies on the role of intestinal bacteria in metabolism of synthetic and natural steroid hormones

Administration of antimicrobial agents to subjects taking oral contraceptives has been reported to lead to contraceptive failure and subsequent pregnancy. In women taking oral contraceptives antimicrobial agents could have an effect on both endogenous hormone levels and on the metabolism of the exogenously administered steroids. To investigate these possibilities, antimicrobial agents were administered for short periods to normal women taking various steroid drugs: Megestrol acetate (MA), medroxyprogesterone acetate (MPA), norethisterone (NET), a combination of NET and ethinylestradiol (EE) or a combination of lynestrenol and EE. During ampicillin administration the 24-h morning plasma concentrations of MA, MPA and NET were increased compared to the control values. In the MA and MPA experiments the afternoon values were determined and also found to be increased. In the subjects taking oral contraceptives plasma EE concentration showed a tendency to decrease during ampicillin administration on the third, fourth or fifth morning of ampicillin administration, but was never lower than the pretreatment values. In other experiments plasma estrone (E1) and estradiol (E2), urinary total E1, E2 and estriol (E3) and fecal unconjugated and conjugated E1, E2 or E3 were determined by RIA before, during and after administration of oxytetracycline (2 X 500 mg/day for 5 days) to 5 young male subjects. Furthermore urinary and fecal estrogens were determined in 1 male subject after administration of erythromycin for 6 days and in 2 normally menstruating women after tetracycline and trimethoprim administration, respectively. During treatment with antimicrobial drugs an increase in the excretion of fecal conjugated and, with the exception of the oxytetracycline experiments, also of unconjugated estrogens paralleled a decrease in urinary estrogen excretion, especially for E2 and E3. In both urine and feces the E1/E2 and E1 + E2/E3 ratios increased due to diminished reductive metabolism of estrogens in the gut. No significant effects on plasma unconjugated estrogen concentrations were observed. The results suggest that the intestinal bacterial flora plays a significant role in estrogen metabolism. However, further studies are necessary, because our results do not explain why administration of antibiotics may cause contraceptive failure.     

Pharmacokinetic prediction of the efficacy of using sisomicin in wound infections

The pharmacokinetics of sisomicin in the blood, infection foci and urine of patients with wound infections was studied comparatively. Higher blood levels of the antibiotic after intravenous injection as compared to those after intramuscular injection provided its more intensive penetration into the tissues of the wound edges and bottom. After intravenous injection the sisomicin concentration in the tissues was sufficient for inhibition of the strains of Staphylococcus, E. coli and Ps. aeruginosa detected in the patients, while after intramuscular injection the antibiotic levels were sufficient only for inhibition of the first two causative agents. Comparison of the data on the sisomicin pharmacokinetics in the blood and tissues of the wounds provided the characteristics of the level of the drug penetration into the focus of the infection ("therapeutic availability"). Since the levels of sisomicin in the blood and infection foci were highly variable in different individuals. It is recommended that the antibiotic be used under the control of its concentrations in patients. It was shown that the data on the sisomicin renal excretion might be used for the purposes of the pharmacokinetic control.     

The Effects of Peritoneal Dialysis on the Physiological Disposition of Oxacillin,Ampicillin and Tetracycline in Patients with Renal Disease

Seven patients with acute or chronic renal failure who were receiving intermittent peritoneal dialysis and who required parenteral oxacillin, ampicillin or tetracycline were studied to determine the disposition of these antibiotics in severe renal disease and the effects of peritoneal dialysis. While severe renal impairment markedly prolongs persistence in the serum of ampicillin and tetracycline, there is little effect on oxacillin. Whereas required doses of ampicillin and tetracycline are lower in the presence of severe renal disease, oxacillin should be given in doses equivalent to those used for patients with normal renal function. Peritoneal dialysis does not alter these dosage requirements.Four patients receiving ampicillin or tetracycline in the infusing solution during peritoneal dialysis were studied to determine the amount of systemic absorption. Local prophylaxis alone is not achieved with this method of administration, since small amounts of both antibiotics are absorbed systemically from the infusing solution. The serum concentration of tetracycline attained is inadequate for treatment of systemic infections but is probably significant, with repeated use in intermittent dialysis, in causing adverse effects. Tetracycline should be abandoned in the local prophylaxis of peritonitis during peritoneal dialysis.     

Isolation of Mycoplasma from the urine of patients with chronic pyelonephritis]

Bacteriological analysis of urine of 150 patients with chronic pyelonephritis was performed. As a result mycoplasma was isolated from urine of 25 patients. Mycoplasma and Coli bacteria or Proteus were isolated simultaneously from urine of 10 patients. Biochemical properties and sensitivity to antibiotics of 9 isolates were studied. The data provided recommendation of the urine analysis for the presence of mycoplasma.     

Raised serum human chorionic gonadotrophin concentrations in hyperemesis gravidarum.

Serum human chorionic gonadotrophin (HCG) concentrations were determined by radioimmunoassay with an antiserum specific to HCG beta-subunit in 42 patients with hyperemesis gravidarum and 115 women with normal pregnancies. Mean concentrations (+/- SE of mean) were higher in the women with hyperemesis gravidarum at 7-8 weeks (40.8 +/- 5.2 IU/ml v 22.1 +/- 1.4 IU/ml; P less than 0.001), 9-11 weeks (38.1 +/- 2.3 IU/ml v 27.1 +/- 2.1 IU/ml; P less than 0.0025), and 12-14 weeks of gestation (35.9 +/- 4.2 IU/ml v 25.1 +/- 1.7 IU/ml; P less than 0.005), but there was no difference between the two groups at 15-20 weeks of gestation. In the hyperemesis gravidarum group primigravid women had a higher (P less than 0.005) mean HCG concentration (41.8 +/- 4.0 IU/ml) than multigravid women (32.2 +/- 2.3 IU/ml). The results suggest a causal relation between a high serum HCG concentration and hyperemesis gravidarum.     

Ampicillin concentration in the blood when administered by jet injection and needle-syringe methods]

The studies were carried out on 50 persons. Ampicillin was administered with the help of a jet injector B1-2 and needle syringe in doses of 250 or 500 and 500 mg respectively. When the drug was administered by infusion, its maximum blood levels were achieved earlier than after needle-syringe administration of the drug and were higher (22.83+/-4.10 and 6.3+/-0.09 gamma/ml respectively). Even when ampicillin was administered with the help of the injector in a dose of 250 mg its blood levels were much higher than those after needle-syringe administration in a dose of 500 mg. After jet infusion the prolongation of the drug retention time in the blood at therapeutical levels was observed as compared to the needle-syringe administration.     

Antibiotic therapy in children with pertussis]

The data accumulated within the last years required revision of the indications to the use of antibiotics in treatment of pertussis. One of the aims of antibiotic therapy in pertussis was to prevent colonization of B. pertussis in the respiratory tracts. With that end in view the choice of antibiotics should be limited by those, to which the pathogen is the most sensitive i.e. erythromycin, ampicillin and augmentin. Comparative efficacy of erythromycin and ampicillin during the first 2 weeks of the disease was studied in 79 infants at the age not older than 1 year with pertussis and it was shown that erythromycin was advantageous by its therapeutic activity and less side effects. Expedience of the antibiotic therapy during the spastic period for providing a preventive effect on development of bronchopulmonary complications was studied in 201 patients with pertussis. No preventive effect of the antibiotics on development of the bronchopulmonary complications defined by the secondary bacterial flora was recorded. In the group of the patients treated with the antibiotics prophylactically (group 1) the complications were 2.6 times more frequent than in the patients treated with pathogenetic agents alone (group 2). Intrahospital pneumonia developed in 8.9 per cent of the patients in group 1 and in 1.5 per cent of the patients in group 2. Therefore, antibiotics should not be used at the late periods of pertussis for prophylaxis of secondary bacterial complications.     

Asymptomatic Urinary Tract Infection in Gynaecological Outpatients

In this study mid-stream specimens of urine were collected from all new patients attending a gynaecological outpatient department and tested for significant bacteriuria. Those having an asymptomatic infection were folloWed up, treated, and investigated adiologically.Of 1,506 women screened for bacteriuria 82 (5·4%) were found to have a persistent infection. The predominant organism was Escherichia coli, present in 83% of infections. Treatment with sulphonamides produced a good cure rate, which was improved by ampicillin given to failures. Some patients, however, had infections that persisted or recurred despite several antibiotics. The radiological investigations showed that a high proportion of women with asymptomatic urinary infection had severe renal disease which was quite symptomless. This was more pronounced in those with persistent or recurrent infections.     

Twice-a-day quadruple therapy for eradication of Helicobacter pylori in the elderly

BACKGROUND: Midday and evening twice-a-day quadruple therapy appears to be the most effective therapy for Helicobacter pylori infection in Northern Sardinia, a site where antibiotics resistance is common. Aim: The objective of our study was to estimate the efficacy, side-effects, and compliance of a quadruple therapy containing esomeprazole in a group of dyspeptic elderly patients. PATIENTS AND METHODS: Consecutive elderly patients positive for H. pylori infection and not previously treated for eradication were enrolled. Therapy consisted of esomeprazole 20 mg, tetracycline 500 mg, metronidazole 500 mg, and bismuth subcitrate tablets 240 mg, all twice-a-day with the midday and evening meals, for 10 days. Efficacy was evaluated using 13C-urea breath testing. Compliance was assessed after completing treatment and at follow up. Side effects were graded based on daily activities. RESULTS: Ninety-five dyspeptic patients (range 65-81 years), 52 men and 43 women, were enrolled. The intention-to-treat cure rate was 91% (81 of 89; 95% CI = 88-99%) and, 95% (81 of 85; 95% CI = 83-96%) per-protocol analysis. Compliance was excellent. Mild-moderate side effects occurred in 27 patients. CONCLUSIONS: Esomeprazole containing quadruple therapy was highly successful for initial eradication of H. pylori in elderly patients.