Treatment of Infections with Colistimethate Sodium (Coly-Mycin)

Colistimethate sodium (Coly-Mycin) was used in the treatment of 17 patients: 13 had urinary tract infections (two of these had positive blood cultures), three had respiratory tract infections, and one patient had both urinary and respiratory tract infections. In nine of the 17 a foreign body—either a carcinoma, a catheter, or a stone—complicated the infection.The dosage used was 1.1-2.3 mg./lb./day with a maximum in one case of 2.4 g. given over an eight-day period. The organisms so treated included Pseudomonas, six; Aerobacter, six and E. coli, two. Both Pseudomonas and Aerobacter were encountered in three cases.On bacteriological grounds, six patients were cured, eight relapsed, and in three the infecting agent was replaced by another organism. The best responses were obtained in those patients with Pseudomonas infection. Side effects included nausea, vomiting, vertigo, paresthesias, and pain at the site of injection.Colistimethate sodium has a place in the treatment of Gram-negative infections excluding Proteus organisms.     

Efficacy of meropenem in the treatment of severe complicated urinary tract infections]

The clinical and bacteriological efficacies of meropenem in the treatment of 12 patients with urinary tract infection were studied. In 8 patients the drug was administered intravenously in a dose of 1 g every 8 hours and in 4 patients with the creatinine clearance below 50 ml/min it was administered in a dose of 1 g every 12 hours (the treatment course of 7 to 10 days). Meropenem was used in the monotherapy. Severe complicated urinary tract infections were mainly observed in the patients with long-term urolithiasis, subjected to repeated surgical interventions and isolating as a rule polyresistant strains of Pseudomonas aeruginosa and E.agglomerans as the pyelonephritis pathogens at a titre of 5 x 10(5)-5 x 10(8) microbial cells per 1 ml of the urine susceptible to meropenem in 80 to 96 per cent of the cases. The clinical efficacy of the drug was stated in all the patients while the bacteriological efficacy amounted to 88.9 per cent.     

Termination of second trimester pregnancy with laminaria and intramuscular 16 phenoxy-ω-17,18,19,20 tetranor PGE2 methylsuldonylamide (sulprostone) — A randomised study

16 phenoxy-ω-17,18,19,20 tetranor PGE₂ methylsulfonylamide (Sulprostone) was used for termination of second trimester pregnancy in four groups of 30 patients. The drug was administered in intramuscular doses of either 0.5 mg four hourly or 1.0 mg 8 hourly. In two groups of 30 patients a medium size sterile laminaria was inserted into the cervical canal eight hours before the start of prostaglandin treatment. In the group treated with 1.0 mg sulprostone eight hourly, 96.7% of those with laminaria and 86.7% without laminaria aborted in respective mean times of 11.2 hrs and 17.5 hrs. All 30 patients (100%) in the laminaria group treated with 0.5 mg sulprostone four hourly aborted within 30 hours in a mean time of 10.4 hours compared with 26 patients (86.7%) in a mean time of 16.7 hours in the group without laminaria.One patient receiving 0.5 mg sulprostone four hourly (no laminaria) sustained a cervical tear requiring repair. The incidence of nausea, vomiting, diarrhoea, cold and shivering was low and similar in the four groups.     

Neomycin in urinary tract infections; a clinical evaluation

Neomycin was effective in treating 31 cases of severe Gram-negative bacillary urinary tract infections sensitive to neomycin and resistant to other agents. The recommended dosage schedule of 0.5 gm. every 12 hours for five days was demonstrated to be relatively safe. However, close watch should be maintained for signs of nephrotoxicity and ototoxicity.     

The Rationale for Using Rifabutin in the Treatment of MDR and XDR Tuberculosis Outbreaks

Genetically related Mycobacterium tuberculosis strains with alterations at codon 516 in the rpoB gene were observed amongst a substantial number of patients with drug resistant tuberculosis in the Eastern Cape Province (ECP) of South Africa. Mutations at codon 516 are usually associated with lower level rifampicin (RIF) resistance, while susceptibility to rifabutin (RFB) remains intact. This study was conducted to assess the rationale for using RFB as a substitution for RIF in the treatment of MDR and XDR tuberculosis outbreaks. Minimum inhibitory concentrations (MICs) of 34 drug resistant clinical isolates of M tuberculosis were determined by MGIT 960 and correlated with rpoB mutations. RFB MICs ranged from 0.125 to 0.25 µg/ml in the 34 test isolates thereby confirming phenotypic susceptibility as per critical concentration (CC) of 0.5 µg/ml. The corresponding RIF MICs ranged between 5 and 15 µg/ml, which is well above the CC of 1.0 µg/ml. Molecular-based drug susceptibility testing provides important pharmacogenetic insight by demonstrating a direct correlation between defined rpoB mutation and the level of RFB susceptibility. We suggest that isolates with marginally reduced susceptibility as compared to the epidemiological cut-off for wild-type strains (0.064 µg/ml), but lower than the current CC (≤0.5 µg/ml), are categorised as intermediate. Two breakpoints (0.064 µg/ml and 0.5 µg/ml) are recommended to distinguish between susceptible, intermediate and RFB resistant strains. This concept may assist clinicians and policy makers to make objective therapeutic decisions, especially in situations where therapeutic options are limited. The use of RFB in the ECP may improve therapeutic success and consequently minimise the risk of ongoing transmission of drug resistant M. tuberculosis strains.     

A rapid assay of urinary estrogens of the Japanese monkey for routine use

A simplification of Brown’s fluorometry for monkey urinary estrogens has been attained. The method requires only a one-step extraction of estrogens instead of the complicated three-step extractions in the original Brown’s method. The procedure made it possible to shorten the time from the six to seven hours required in the original method to three hours. The present method is satisfactory in precision, sensitivity, accuracy, and specificity. Although the values of urinary estrogens obtained by the simplified method are lower than those obtained by the original method, the use of the present method is validated, since the correlation coefficient between the two assay procedures is excellent (γ=0.90) and also the application of the present method to the measurement of daily changes in urinary estrogens throughout the menstrual cycle has been successful. The simplified assay is expected to be useful in the routine assessment of urinary estrogens in Japanese monkeys. This work was supported by a grant from the Ford Foundation (No. 670-0558).     

Kanamycin levels in treating patients with acute and subacute gonorrhea

Kanamycin levels in blood serum were studied during treatment of patients with acute and subacute not complicated gonorrhea. It was concluded that in treatment of gonorrhea kanamycin should be administered intramuscularly in a dose of 1 g every 12 hours or in a dose of 0.5 g every 6 hours, the course dose being 3 g.     

Ampicillin-Resistant Hemophilus influenzae: Emergence in California's Central Valley

Ampicillin-resistant Hemophilus influenzae had not been identified in Fresno, California, before June 1976. In the 12 months that followed, eight resistant type B strains and three resistant nontypable isolates were cultured from patients treated at two hospitals that provide nearly all of the acute pediatric inpatient care for the area. Two of the resistant strains were obtained from patients with invasive infections and represented 4.2 percent of Hemophilus influenzae isolated from blood, cerebrospinal fluid or joint aspirates during the 12 months. The remaining six resistant type B strains were obtained from 117 patients, and were the predominant organism in cultures of other sites, primarily respiratory secretions.In two of three patients infected with nontypable organisms, resistance appeared to emerge during therapy with ampicillin. Measurement of β lactamase was a practical and accurate method for differentiating between ampicillin-sensitive and resistant strains. All ten of the β lactamase-positive isolates tested had minimal inhibitory concentrations (MIC) for ampicillin of 15 μg per ml, or less. In contrast 30 β lactamase-negative strains had MIC''s of 1.5 μg per ml, or less, of ampicillin. Our results indicate that ampicillin resistance has become a significant problem in the Central Valley of California and probably the entire state.     

Resistance of Haemophilus influenzae to Trimethoprim

Out of 210 isolates of Haemophilus influenzae obtained from the sputum of 63 patients with chronic respiratory infections 109 (52%) were resistant to trimethoprim-sulphamethoxazole by the disc test. The minimal inhibitory concentrations of trimethoprim for 17 out of 18 strains recorded as resistant were 10 μg/ml or higher. Resistant strains were isolated from time to time from 32 (82%) out of 39 patients known to have been treated with trimethoprim-sulphamethoxazole, compared with only 1 (12·5%) out of 8 patients known not to have been treated with this drug combination. Resistant strains were isolated most frequently from patients who had received long-term treatment. Since sulphamethoxazole penetrates from the blood into the bronchial secretions less readily than does trimethoprim it seems likely that the ratio of the two drugs in the bronchial tree is far from ideal. This may be an important factor in the use of these drugs for chest infections.     

TERRAMYCIN IN URINARY TRACT INFECTIONS

Terramycin® is an effective agent in the control of urinary tract infections with organisms of the enteric group.The drug is tolerated by mouth and no serious side-reactions occur. In cases in which there is no organic or obstructive disease, the response to Terramycin as a urinary antiseptic is prompt and effective. In several cases in which there was severe organic and obstructive disease and the organism was highly resistant, the course of the disease was not altered by giving Terramycin.     

Chromosomal and plasmid encoded drug resistances of a <Emphasis Type="Italic">Klebsiella pneumoniae</Emphasis> UTI 2 strain isolated from urine of a post-operative patient

The multi drug resistance Klebsiella pneumoniae in urinary tract infection is a common clinical problem in developing country like India. Use of random antibiotics, resulting multi drug resistance development, creates difficulties for treatment. In our present study, we investigated a strain of Klebsiella pneumoniae UTI 2 with multiple drug resistance, which was isolated from urine of a post operative woman patient (50 years) suffering from urinary tract infection with high fever. This strain is resistant to 36 antibiotics and sensitive to cefotaxime (Ce) and imipenem (I). After curing of plasmids, we observed that, 55% of drug resistant loci of K. pneumoniae UTI 2 are chromosomal and 40% are plasmid encoded. The organism is sensitive to 5% of drugs tested, i.e. Ce and I. This study contributes to understand the drug resistance of Klebsiella pneumoniae, which will enable better clinical management of catheter-associated urinary tract infections, a major health problem.     

Erythrocyte Binding Activity Displayed by a Selective Group of Plasmodium vivax Tryptophan Rich Antigens Is Inhibited by Patients’ Antibodies

Plasmodium vivax is a very common but non-cultivable malaria parasite affecting large human population in tropical world. To develop therapeutic reagents for this malaria, the parasite molecules involved in host-parasite interaction need to be investigated as they form effective vaccine or drug targets. We have investigated here the erythrocyte binding activity of a group of 15 different Plasmodium vivax tryptophan rich antigens (PvTRAgs). Only six of them, named PvTRAg, PvTRAg38, PvTRAg33.5, PvTRAg35.2 PvTRAg69.4 and PvATRAg74, showed binding to host erythrocytes. That the PvTRAgs binding to host erythrocytes was specific was evident from the competitive inhibition and saturation kinetics results. The erythrocyte receptors for these six PvTRAgs were resistant to trypsin and neuraminidase. These receptors were also chymotrypsin resistant except the receptors for PvTRAg38 and PvATRAg74 which were partially sensitive to this enzyme. The cross-competition studies showed that the chymotrypsin resistant RBC receptor for each of these two proteins was different. Altogether, there seems to be three RBC receptors for these six PvTRAgs and each PvTRAg has two RBC receptors. Both RBC receptors for PvTRAg, PvTRAg69.4, PvTRAg33.5, and PvTRAg35.2 were common to all these four proteins. These four PvTRAgs also shared one of their RBC receptors with PvTRAg38 as well as with PvATRAg74. The erythrocyte binding activity of these six PvTRAgs was inhibited by the respective rabbit polyclonal antibodies as well as by the natural antibodies produced by the P. vivax exposed individuals. It is concluded that only selective few PvTRAgs show erythrocyte binding activity involving different receptor molecules which can be blocked by the natural antibodies. Further studies on these receptor and ligands may lead to the development of therapeutic reagents for P. vivax malaria.     

Antibiotic sensitivities of Neisseria gonorrhoeae in the Toronto area

The antibiotic sensitivity pattern of 3872 isolates of N. gonorrhoeae tested in Toronto from 1969 to 1973 is reviewed. An increase in resistance to both penicillin and tetracycline was noted up to 1971, but no further increase has occurred since then. Ninety-seven percent of 135 patients with “sensitive” strains (inhibited by 0.3 U/ml of penicillin and/or 0.5 μg/ml of tetracycline) were cured by either 8 g of tetracycline or 5,000,000 U of penicillin, whereas only 59% of 58 patients with “resistant” strains (requiring 1.0 U/ml of penicillin and/or 2.0 μg/ml of tetracycline for inhibition) were cured by the same dosage. Spectinomycin appears to be an acceptable alternative therapy. Maximum doses of the chosen drug are recommended in the hope of retarding further spread of more resistant organisms.     

The Biopharmaceutical Properties of Solid Dosage Forms: I. An Evaluation of 23 Brands of Phenylbutazone Tablets

The potency, disintegration and dissolution characteristics of 23 brands of phenylbutazone tablets were determined. Five (21.7%) of the 23 brands failed to comply with the minimum requirements of the compendia or the regulations appended to the Food and Drugs Act. The in vitro characteristics of four brands were substantially different from those that disintegrated and released the drug satisfactorily. The in vivo characteristics of three of the four brands were compared with those observed for a pharmaceutically acceptable product. The latter product released the drug to the blood quickly, but the former products released the drug only after the tablets had been in the body for six to eight hours and, in the case of one product, released quantities much below those that would be acceptable to the physician. These results show that different products containing the same drug are not necessarily equivalent. This is contrary to the generic equivalency hypothesis which assumes that all products comply with specifications and, therefore, must be clinically effective.     

Naturally occurring antibiotic resistance inBacillus sphaericus andBacillus licheniformis

Bacillus sphaericus is an aerobic, spore-forming, gram-variable bacillus. Certain strains of this organism are extremely pathogenic for mosquito larvae. Strains from four different serotypes ofB. sphaericus were found to be naturally resistant to streptomycin and to chloramphenicol. Both entomocidal and nonentomocidal strains of this organism exhibited similar patterns of resistance to these antimicrobial agents. In contrast, other members of the genusBacillus, includingB. subtilis, B. thuringiensis, B. laterosporus, andB. amyloliquefaciens, proved to be quite sensitive to these antibiotics. Four strains ofB. licheniformis were found to be resistant to chloramphenicol but sensitive to streptomycin.     

Changes in Gut Flora after Cephalexin Treatment

Eighteen patients with urinary tract infection were treated with cephalexin orally. Absorption was variable, between 29 and 89% of the total daily dose being excreted in the urine in 24 hours. A significant number of patients became faecal carriers of Pseudomonas aeruginosa compared with a control group who received no antibiotics. Four of the cephalexin-treated patients acquired a strain of Ps. aeruginosa known to be present in food from the hospital diet kitchen and one developed a urinary tract infection with this strain.     

Luteinizing hormone concentrations in anestrous ewes administered various estrogens

Twenty four anestrous ewes were evenly assigned to one of six groups and administered either sesame oil, estradiol-17β, estradiol-17α, estrone, estradiol benzoate or estradiol valerate. All estrogen treated ewes received 50 μg of the respective estrogen. Blood plasma was collected for 28 hours post-treatment and quantified for luteinizing hormone (LH) by radioimmunoassay. An estrogen induced LH surge was detected in at least three of the four ewes administered either estradiol-17β, estrone, estradiol benzoate or estradiol valerate whereas only one of the four estradiol-17α treated ewes and none of the ewes administered sesame oil had an LH surge. The interval from treatment to peak LH was similar for estradiol-17β (17.3±2.7 hours), estrone (18.5±1.0 hours) and estradiol benzoate (19.0±0.6 hours) treated ewes but delayed 7 to 9 hours for ewes administered estradiol valerate (26.0±1.2 hours).     

Serum cortisol concentrations during low dose dexamethasone suppression test to screen for Cushing's syndrome.

Forty four subjects (23 obese controls, 11 patients with possible Cushing''s syndrome, and 10 patients with definite Cushing''s syndrome) underwent low dose (0 X 5 mg every six hours for two days) dexamethasone suppression tests during which serum cortisol concentration at 0800 and excretion of urinary free cortisol over 24 hours were measured. Serum cortisol concentration fell to below 60 nmol/1 (2 X 2 micrograms/100 ml) in 31 subjects and remained above 250 nmol/1 (9 X 1 micrograms/100 ml) in the 13 others. Excretion of urinary free cortisol showed a similar response, falling to below 110 nmol (40 micrograms)/24 h in 31 and remaining above 180 nmol (65 micrograms)/24 h in the 13 others. There was complete concordance between the two variables in terms of the pattern of response. Serum cortisol concentration fell to below 60 nmol/1 (2 X 2 micrograms/100 ml) in at least 97% (31 of a possible 32) of subjects without Cushing''s syndrome. On the other hand, a serum cortisol concentration of above 250 nmol/1 (9 X 1 micrograms/100 ml) after low dose dexamethasone gave a false positive diagnosis of Cushing''s syndrome in at most only one of 13 patients (7 X 7%). Measurement of serum cortisol concentration during the low dose dexamethasone test is simpler than, and as accurate and reliable as, measurements of urinary steroids.     

Effective chelation of iron in beta thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one.

The main iron chelator used for transfusional iron overload is desferrioxamine, which is expensive, has toxic side effects, and has to be given subcutaneously. An orally active iron chelator is therefore required. The effects of oral 1,2-dimethyl-3-hydroxypyrid-4-one on urinary iron excretion were studied in eight patients who had received multiple transfusions: four had myelodysplasia and four beta thalassaemia major. Different daily doses of the drug up to 100 mg/kg/day, alone or in combination with ascorbic acid, were used. In three patients with thalassaemia the effect of the drug was compared with that of subcutaneous desferrioxamine at the same daily dose. In all eight patients a single dose of oral 1,2-dimethyl-3-hydroxypyrid-4-one resulted in substantial urinary iron excretion, mainly in the first 12 hours. Urinary iron excretion increased with the dose and with the degree of iron loading of the patient. Giving two or three divided doses over 24 hours resulted in higher urinary iron excretion than a single dose of the same amount over the same time. In most patients coadministration of oral ascorbic acid further increased urinary iron excretion. 1,2-Dimethyl-3-hydroxypyrid-4-one caused similar iron excretion to that achieved with subcutaneous desferrioxamine at a comparable dose. In some cases the iron excretion was sufficiently high (maximum 99 mg/day) to suggest that a negative iron balance could be easily achieved with these protocols in patients receiving regular transfusions. No evidence of toxicity was observed on thorough clinical examination or haematological and biochemical testing in any of the patients. None of the patients had any symptoms that could be ascribed to the drug. These results suggest that the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one is as effective as subcutaneous desferrioxamine in increasing urinary iron excretion in patients loaded with iron. Its cheap synthesis, oral activity, and lack of obvious toxicity at effective doses suggest that it should be developed quickly and thoroughly tested for the management of transfusional iron overload.     

Chemoprophylaxis with oral amoxycillin against bacterial endocarditis: when should second doses be administered after dentistry?

The adequacy of serum bactericidal activity after oral amoxycillin given as prophylaxis against infective endocarditis was studied using a double blind randomised protocol in healthy volunteers having dentistry. One hour before their procedure 38 patients received 3 g amoxycillin syrup and 12 received matching placebo. Venous blood samples were drawn before and one and nine hours after dosing and serum amoxycillin concentrations determined using a standard bioassay. Samples containing amoxycillin had inhibitory titres measured against two reference isolates of viridans streptococci known to have caused infective endocarditis. The susceptibility to amoxycillin of one strain was high and the other low, respective minimal bactericidal and inhibitory concentrations being 0.08 and 0.04 mumol/l (0.03 and 0.015 microgram/ml) and 2.74 and 1.37 mumol/l (1 and 0.5 microgram/ml). Amoxycillin was detected in only post-treatment samples of patients given the active drug. There were no significant correlations between one or nine hour drug concentrations and age or physical characteristics, nor was there any relation to preceding food consumption. Correlations between drug concentrations at one and nine hours were weak (r = 0.34; p less than 0.05), but between corresponding drug concentrations and serum inhibitory titres there were consistent correlations (r = 0.46-0.48; p less than 0.005). Against the low susceptibility reference isolate bactericidal amoxycillin concentrations were encountered in only 20 of the 38 nine hour samples (95% confidence limits 34% and 66%). When repeat doses of amoxycillin are indicated after dentistry they should be given about four hours later, not eight hours later as commonly practised.