H. Mattie

Brain abscess due to streptobacillus moniliformis and actinobacterium meyerii

SummaryThis paper deals with a case of brain abscess due toStreptobacillus moniliformis (the cause of the streptobacillary type of rat-bite fever) andActinobacterium meyerii. Brain abscesses due to these micro-organisms are rare. The possible causative mechanisms in this particular case and the diagnostic and therapeutic management of brain abscesses in general are discussed.ZusammenfassungWir berichten über einen Patienten mit Hirnabszeß, der durchStreptobacillus moniliformis (den Erreger der Streptobazillen-Rattenbißkrankheit) und durchActinobacterium meyerii verursacht wurde. Hirnabszesse durch diese Erreger sind selten. Die vermutliche Pathogenese bei diesem Patienten sowie die diagnostischen und therapeutischen Möglichkeiten bei Hirnabszessen im allgemeinen werden besprochen.

Influence of cytostatic agents on the pulmonary defence of mice infected with Klebsiella pneumoniae and on the efficacy of treatment with ceftriaxone

The effect of cytostatic treatment on the cellular defence and the efficacy of treatment with ceftriaxone in Klebsiella pneumoniae pneumonia was studied. Mice, made monocytopenic and granulocytopenic by cyclophosphamide or monocytopenic by etoposide, were infected intratracheally with K. pneumoniae (approximately 10(4) CFU) and then treated with ceftriaxone. At various intervals, the numbers of bacteria in the broncho-alveolar lavage (BAL) fluid and in lungs homogenised after lavage were determined. Cyclophosphamide reduced the numbers of granulocytes in the BAL fluid significantly but reduced only slightly the number of alveolar macrophages at the time of inoculation, 12 and 15 h later. The number of CFU in cyclophosphamide-treated mice was higher than that in controls, being significant in the homogenised lungs at 15 h after infection. In etoposide-treated mice, the numbers of alveolar phagocytes in BAL did not differ from those in control mice, whereas the number of bacteria was lower (only significantly in BAL fluid at 15 h after infection) than that in the controls. In this short experimental infection cytostatic treatment did not affect the outgrowth of Klebsiella pneumoniae substantially or the efficacy of treatment with ceftriaxone.

Quantitative determination of the effect of granulocytes on the course of experimental infections during antibiotic treatment

SummaryWe are presenting a quantitative determination of the effect of granulocytes, monocytes and lymphocytes on the course of infection during antibiotic treatment. The animal model was a short-term infection of the thigh muscle in normal or irradiated mice. Two kinds of antibiotics were used: tobramycin forPseudomonas aeruginosa infections and ampicillin forEscherichia coli infections. The number of granulocytes was changed by irradiating the mice before they were infected. The dose-effect relations for both combinations of bacteria and antibiotics were determined on various days after irradiation. Analysis of the results shows that the effect of an antibiotic was predominantly potentiated by granulocytes. This means that under the conditions of granulopenia, the dose of an antibiotic must be increased to obtain the same antibacterial effect. The present results indicate that the interrelation between host factors, bacterial proliferation and antibiotic treatment can be quantitated and may offer a useful model for screening antimicrobial drugs before they are clinically applied.ZusammenfassungDer Einfluß der Granulozyten, Monozyten und Lymphozyten auf den Verlauf einer Infektion unter Antibiotikabehandlung wurde quantitativ bestimmt. Als Tiermodell wurde eine Kurzzeitinfektion der Oberschenkelmuskulatur bei normalen oder bestrahlten Mäusen gewählt. Zwei Arten von Antibiotika wurden verwendet: Tobramycin fürPseudomonas aeruginosa- und Ampicillin fürEscherichia coli-Infektionen. Die Granulozytenzahl wurde durch Bestrahlung der Mäuse vor Setzen der Infektion verändert. Die Dosis-Wirkbeziehungen für beide Kombinationen von Bakterien und Antibiotika wurden an verschiedenen Tagen nach Bestrahlung bestimmt. Die Analyse der Ergebnisse zeigte, daß der Antibiotikaeffekt vorwiegend durch die Granulozyten potenziert wurde. Das bedeutet, daß unter den Bedingungen der Granulozytopenie die Dosis eines Antibiotikums erhöht werden muß, um einen entsprechenden antibakteriellen Effekt zu erzielen. Die vorgelegten Ergebnisse zeigen, daß es möglich ist, die Wechselbeziehung zwischen Wirtsfaktoren, Bakterienwachstum und Antibiotikatherapie quantitativ zu erfassen; daraus läßt sich möglicherweise ein brauchbares Modell für das Screening von antimikrobiellen Substanzen vor ihrer Anwendung in der Klinik ableiten.

Activity of erythromycin and clindamycin in an experimental staphylococcus aureus infection in normal and granulocytopenic mice : a comparative in vivo and in vitro study

The activity of 2 bacteriostatic antibiotics, erythromycin and clindamycin, against Staphylococcus aureus was studied in vitro and in an experimental infection in granulocytopenic as well as normal mice. In vivo, on the basis of dosage, erythromycin was 2.20 times more potent than clindamycin in normal mice and 1.95 times more potent in irradiated granulocytopenic mice. Tissue concentrations were calculated from the plasma concentrations, taking plasma protein and tissue binding into account. On the basis of the area under the curve for the free tissue concentrations, clindamycin was 1.48 times more potent than erythromycin in normal mice and 1.64 times more potent in irradiated mice, which is somewhat less than expected from the comparison in vitro. It is concluded that the relative antistaphylococcal efficacies of erythromycin and clindamycin in vivo can be predicted from the in-vitro values if the relevant pharmacokinetics are taken into account. Irradiation decreased the efficacy of both antibiotics such that an about 8-fold increase in dose led to an antibacterial effect similar to that in non-irradiated animals. This could imply that these drugs will not be sufficiently effective against staphylococcal infections in granulocytopenic patients.

Antibacterial efficacy of cefazolin and cephradine in neutropenic mice

SummaryThe activity of cefazolin (CEZ) and cephradine (CED) was studied in experimentally infected neutropenic mice. Neutropenia was induced by 600 rad whole-body irradiation; an infection was induced by the injection of 5 × 106Escherichia coli into the thigh on Day 5 after irradiation. Antibiotics were administered 1 h later, and antibacterial activity was estimated from bacteria counts made in the homogenized individual thighs 3 h after infection. The effect of a low dose of each of the cephalosporins on the infection was significantly lower in the absence of granulocytes than in animals with intact host defence; at higher dosages the effect of both antibiotics on the infection was the same in neutropenic and unirradiated mice. In the neutropenic mice, CEZ was 2.95 times more active than CED againstE. coli in vivo, this difference in activity being similar to that found earlier in normal mice.ZusammenfassungDie Wirksamkeit von Cefazolin (CEZ) und Cephradin (CED) wurde an granulozytopenischen Mäusen, die experimentell infiziert worden waren, untersucht. Die Granulozytopenie wurde durch 600 rad Ganz-Körper-Bestrahlung erzeugt; eine Infektion wurde durch die Injektion von 5 × 106Escherichia coli in den Oberschenkel am fünften Tag nach der Bestrahlung hervorgerufen. Die Antibiotika wurden eine Stunde später gegeben, die antibakterielle Wirksamkeit an der Bakterienzahl in den drei Stunden nach der Infektion homogenisierten einzelnen Oberschenkeln gemessen. Die Wirkung einer niedrigen Dosis jeder der beiden Cephalosporine auf die Infektion war signifikant niedriger bei Abwesenheit von Granulozyten als bei Tieren mit normaler Granulozytenzahl; bei höheren Dosen war die Wirkung von beiden Antibiotika auf die Infektion gleich bei granulozytopischen und unbestrahlten Mäusen. Bei den granulozytopischen Mäusen war CEZ 2,95 mal wirksamer als CED gegenE. coli in vivo. Dieser Unterschied in der Wirksamkeit war ähnlich dem bei normalen Mäusen gefundenen.

Determination of benzylpenicillin and probenecid in human body fluids by high-performance liquid chromatography

A method for the determination of benzylpenicillin and probenecid concentrations in human body fluids using ion-pair reversed-phase chromatography with UV detection has been developed. For plasma samples two extraction techniques were investigated. Precipitation of the plasma proteins with acetonitrile followed by liquid-liquid extraction offered the best results. The limits of detection were 0.5 microgram/ml for benzylpenicillin and 0.25 microgram/ml for probenecid, which offer sufficient sensitivity for application in pharmacokinetic experiments.

Renal Clearance of Temocillin in Volunteers

SummaryAfter administration of a loading dose, temocillin was infused intravenously into 5 volunteers for 3 hours (250 and 750 mg/h). A urine flow of more than 500 ml/h was maintained. The mean plasma concentrations were 131.4 and 220.7 mg/L during the lower dose and higher dose infusions, respectively, and protein binding decreased from 83% to 74% with this increase in plasma concentration. The renal clearance of the total drug increased from 29.0 ml/min (low dose) to 50.5 ml/min (high dose) [p < 0.001], but after correction for protein binding the renal clearance of the unbound drug only increased from 169.1 to 197.0 ml/min (not statistically significant). The extrarenal clearance of temocillin was negligible.Blocking of tubular excretion by probenecid caused a maximum decrease of the renal clearance of temocillin from 34.1 to 22.4 ml/min. This maximum effect of 12.3 ml/min subsided by 1.7 ml/min/h. The renal clearance of the free drug decreased to 134.6 ml/min, slightly less than the creatinine clearance (158.1 ml/min).It may be concluded that even at high plasma concentrations of temocillin there is no saturation of the tubular transport mechanism, and that tubular excretion plays a relatively minor role in the renal excretion of the drug.

Influence of aminopenicillins on bacterial growth kinetics in vitro in comparison with the antibacterial effect in vivo.

SummaryTo quantify the relative antibacterial efficacy of β-lactam antibiotics in vitro, a mathematical description of bacterial growth was developed. Curves of growth in the presence of the antibiotic are expressed as quadratic functions of time, with initial growth rate (ko) and rate of change of growth (a) as concentration dependant variables. For these variables the concentration-effect slopes were not parallel; therefore the potency ratio varied between 1 (at about 2 mg/l) and 2 (at higher concentrations). The relative efficacy in vivo was expressed as a potency ratio with regard to the number of bacteria in an infected thigh muscle in mice. The potency ratio was 1.5, which is between the limits of the in vitro results.ZusammenfassungUm die relative antibakterielle Wirksamkeit von beta-lactam Antibiotika in vitro zu quantifizieren, wurde eine mathematische Methode zur Beschreibung des bakteriellen Wachstums entwickelt. Die Wachstumskurven in Anwesenheit eines Antibiotikums wurden ausgedrückt als quadratische Funktion der Zeit mit einer initialen Wachstumsrate (ko) und einer Wachstumsänderungsrate (a) ais Konzentrations-abhängige Variable. Für die Variablen waren die Konzentrations-Wirkkurven nicht parallel, deshalb variierte der Wirksamkeitsfaktor zwischen 1 (bei ungefähr 2 mg/l) und 2 (bei höheren Konzentrationen). Die relative Wirksamkeit in vivo wurde als Wirksamkeitsfaktor in bezug auf die Anzahl der Bakterien in einem infizierten Oberschenkelmuskel der Maus ausgedrückt. Der Wirksamkeitsfaktor betrug 1,5. Er liegt zwischen den Grenzen der In-vitro-Ergebnisse.

Evaluation of cloxacillin concentrations in plasma and muscle tissue during cardiopulmonary bypass

Concentrations of cloxacillin in plasma and deep thoracic muscle tissue were measured in 10 patients who underwent elective coronary bypass surgery or valve replacement. One g of cloxacillin was administered after the induction of anaesthesia and 1 g cloxacillin was added to the oxygenator pump priming fluid before the start of the procedure. Blood and tissue samples were obtained before, during and after cardiopulmonary bypass. The relation between unbound plasma concentrations and total tissue contents of the drug was calculated. It was shown that measurement of the free plasma concentration may provide fairly reliable information on the free concentrations of cloxacillin in the tissues, and that determination of tissue contents may therefore not be necessary. Due to the administration of the second dose of cloxacillin at the start of cardiopulmonary bypass free tissue contents were just adequate in most patients. However, to obtain adequate tissue concentrations after bypass it is recommended that a third dose of the antibiotic be administered before the end of the operation.

Role of granulocytes in the prevention and therapy of experimental Streptococcus sanguis endocarditis in rabbits.

The contributions of granulocytes to the prevention and therapy of Streptococcus sanguis endocarditis with procaine benzylpenicillin (PBP) was investigated in rabbits. Depletion of granulocytes by treatment with mechlorethamine appeared to have no significant effect on either the prophylactic or therapeutic activities of PBP. Administration of 3,000 IU of PBP before inoculation with S. sanguis retarded the course of the endocarditis for only 24 h whether granulocytes were normal or depressed in numbers. Prophylaxis with either 15,000 or 30,000 IU of PBP was equally effective in non-granulocytopenic and granulocytopenic rabbits. Treatment of established infections with PBP at doses of 3,000 to 300,000 IU of PBP at 12-h intervals for 48 h was equally effective in rabbits with normal and depressed numbers of granulocytes. The effect of 3,000 IU of PBP was equivalent, however, to that of granulocytes alone, as shown by the fact that the numbers of CFU per gram of vegetation in the granulocytopenic rabbits treated with this dose of PBP and in the non-PBP-treated control rabbits were not significantly different.