Search

"In vitro" synthesis of benzylpenicillin and phenoxymethylpenicillin has been carried out by direct N-acylation of 6-aminopenicillanic acid (6-APA) with S-phenylacetyl- and (S-phenoxyacetyl)glutathione. The reactions were catalyzed by the enzyme acyl-CoA: 6-APA acyltransferase (AT) from Penicillium chrysogenum and in both cases the synthesis of antibiotics was enhanced by CoA. Penicillin K, a natural penicillin, was also synthesized "in vitro" by incubating (S-octanoyl)glutathione, 6-APA and AT, but in this case the formation of antibiotic required the presence of CoA. Furthermore, benzylpenicillin was obtained from (S-phenylacetyl)cysteinylglycine and 6-APA, suggesting that some intermediates of the gamma-glutamyl cycle are directly involved in the biosynthesis of penicillins. To explain "in vivo" formation of this beta-lactam antibiotic, a biosynthetic pathway which includes several glutathione-S-derivatives and a non-enzymatic reaction, is proposed.

A regimen of a single intramuscular dose of penicillin G-streptomycin was compared with regimens of three oral doses of amoxicillin and two oral doses of penicillin V to prevent Streptococcus sanguis endocarditis in rabbits with experimentally induced valvular heart lesions. Challenge doses of 10(4), 10(6), and 10(8) CFU of a strain of S. sanguis highly tolerant to penicillin and amoxicillin were used. The combination of penicillin and streptomycin was the only regimen tested that provided full protection even against the highest inoculum concentration. A single oral dose of penicillin V (36 mg/kg) or amoxicillin (50 mg/kg), two oral doses of penicillin V (36 and 18 mg/kg with a 7-h interval between doses), or six oral doses of amoxicillin (50 mg/kg followed by 8.5 mg/kg at 8-h intervals) protected recipients of the lowest inoculum concentration; protection diminished with increasing inocula. In contrast, administration of two high oral doses of amoxicillin (50 mg/kg) with a 10-h interval between doses provided full protection against challenge doses of 10(4) and 10(6) CFU, preventing endocarditis in 10 (66%) of 15 recipients of 10(8) CFU. All regimens evaluated were highly effective in preventing endocarditis when rabbits were challenged with 10(4) CFU. The combination of penicillin and streptomycin was the best regimen tested. Administration of two high oral doses of amoxicillin (50 mg/kg) with a 10-h interval between doses led to significantly fewer infections when compared with the other oral regimens when rabbits were challenged with 10(6) and 10(8) CFU.

It was previously found that Arcanobacterium haemolyticum, which can cause tonsillitis with exanthema, is not eradicated from the pharynx by administration of phenoxymethylpenicillin, despite minimum inhibitory concentration values of 0.015-1.0 micrograms/ml. Therefore, recent clinical isolates were studied for penicillin tolerance by using a disk diffusion screening test and a pour plate assay. Macrobroth dilution minimum inhibitory and bactericidal concentrations and antibiotic kill kinetics were determined for 4 isolates. Tolerance was present in 38 of 40 clinical isolates with the disk diffusion assay. With the pour plate assay all 40 isolates were tolerant, 34 of them highly tolerant. The presence of the tolerant phenotype was confirmed by macrobroth dilution assays. It is concluded that A. haemolyticum is often penicillin-tolerant, suggesting that phenoxymethylpenicillin administration would be ineffective in eradicating A. haemolyticum from the pharynx.

The two monoclonal antibodies (mAb), L6 (anti-carcinoma), and 1F5 [anti-(B-cell-lymphoma)], were chemically linked to the enzyme penicillin-V amidase (PVA), which hydrolyzes phenoxyacetamides, to explore the potential of using mAb-enzyme conjugates for the localization of chemotherapeutic drugs at tumor cells. The phenoxyacetamide derivatives of doxorubicin and melphalan were prepared, yielding the less toxic amides, doxorubicin-N-p-hydroxyphenoxyacetamide (DPO) and melphalan-N-p-hydroxyphenoxyacetamide (MelPO). These were hydrolyzed by PVA to doxorubicin and melphalan respectively. In vitro studies with the L6-positive lung carcinoma cell line, H2981, and the 1F5-positive B-cell lymphoma line, Daudi, showed that DPO was 80-fold less toxic to H2981 cells and 20-fold less toxic to Daudi cells than doxorubicin, and its toxicity was substantially increased when the H2981 cells were pretreated with L6-PVA or the Daudi cells were pretreated with 1F5-PVA. The cytotoxic effect was antigen-specific, since only the binding mAb-enzyme conjugate increased the cytotoxicity of the prodrug. MelPO was more than 1000-fold less toxic than melphalan to H2981 cells and more than 100-fold less toxic than melphalan to Daudi cells. Pretreatment with the mAb-PVA conjugates did not enhance the toxicity of MelPO in either cell line, because PVA hydrolyzes the phenoxyacetamide bond of MelPO too slowly to generate a toxic level of melphalan.

The excretion of phenoxymethylpenicillin in vaginal fluid was determined in five women after intake of a single dose of 1 g phenoxymethylpenicillin and in five women on a 10-day medication scheme with 1 g twice daily. After the single dose, there was a steady increase of penicillin in vaginal secretion during the following 3 hours. During the same period, the concentrations in serum and saliva peaked and started to decline. Fifteen hours after intake, vaginal fluid contained more than 1 mg/L, whereas no activity was found in serum or saliva. During the 10-day course of treatment, vaginal concentrations ranged between 2-3 mg/L. The drug was not eliminated from the vagina until the second day after ceasing medication. The accumulation and slow pharmacokinetics of phenoxymethylpenicillin in the vagina may be explained by the countercurrent vascular system supplying the internal genitalia and upper vagina. The effect of the high concentrations of penicillin on the vaginal microflora is discussed.

The mutagenic and lethal effects of N-methyl-N'-nitro-N-nitrosoguanidine (NTG), ethyl methanesulphonate (EMS), ultraviolet light irradiation and near-ultraviolet light irradiation with 8-methoxypsoralen on the bacterium Acinetobacter calcoaceticus NCIB8250 were examined. The production of auxotrophic mutants was used as a measure of mutagenic efficiency. Under appropriate conditions all four agents were mutagenic. EMS and NTG although more effective than irradiation, did not cause such a high frequency of mutation as has been observed with other bacteria. A combination of vancomycin and penicillin V gave enrichment of non-metabolizing bacteria and optimum conditions were found for the use of these compounds in a selection technique.

This bacteriological study involved 92 young married couples who required medical help because of infertility. Colonization of male urethra or the presence of Streptococcus agalactiae in the ejaculate was detected in 9.78% of men. Vagina or vagina and cervix were colonized in 4.35% of women. Oral application of phenoxymethylpenicillin temporarily eliminated S. agalactiae from the genital tract of all colonized partners. Repeated colonization occurred 3-7 months later, in three cases by different serotypes compared with pretreatment period, in one case by the same serotype.

Influences of antibiotics on the fecal flora in children were studied for oral ampicillin, penicillin V, erythromycin, cefaclor, and gentamicin and for intravenous ampicillin, methicillin, cefpiramide, and ceftazidime. All antibiotics affected the normal flora, although the quality and quantity of the changes were variable. No substantial differences were noted between the oral and intravenous use of ampicillin with regard to its effect on the flora. Three penicillins, ampicillin, penicillin V, and methicillin, caused remarkable changes. The characteristic pattern observed was the considerable suppression of Bifidobacterium, Streptococcus, and Lactobacillus species. Although enterobacteria did not significantly change in number, Klebsiella spp. frequently replaced Escherichia coli. In patients given erythromycin and cefaclor, the reduction in the number of Bifidobacterium spp. was 1 log10 and that of members of the family Enterobacteriaceae was 3 log10. Gentamicin administered orally caused a drastic change, including a remarkable decline of E. coli to less than 2 log10/g of feces. Cefpiramide, a parenteral expanded-spectrum cephalosporin, suppressed normal flora so markedly that almost all species of organisms were eradicated, and the active growth of yeasts was promoted (2.6 log10 increase). Ceftazidime caused similar changes as cefpiramide, but the changes were less extensive. Yeasts increased after treatment with most antibiotic groups. This increase was particularly prominent in patients given oral penicillins and expanded-spectrum cephalosporins.

There are clinical observations indicating that the frequency of postoperative bleeding after oral surgery in patients with coagulation disorders is reduced by prophylactic antibiotic treatment. To assess this effect, the concentrations of phenoxymethylpenicillin in plasma and saliva were determined during treatment and compared with the MIC values for penicillin of the oral bacteria of four patients with coagulation disorders. The concentration of penicillin in plasma of the patients considerably exceeded the MIC values of all isolated bacteria. In mixed saliva and saliva of the parotid and submandibular glands no penicillin activity could be detected. The bacteria isolated from the oral cavity of the patients did not in vitro exhibit either fibrinolytic or plasminogen activator activity. Thus, the oral bacteria of patients with coagulopathies probably do not cause an increased bleeding tendency by their intra- or extracellular enzymes.

Streptococcus salivarius plays a role in the normal oropharyngeal resistance to colonization with group A streptococci. Suppression of Str. salivarius may increase the risk of colonization. Ten subjects were given phenoxymethylpenicillin, ten were given erythromycin, ten were given clindamycin and ten were given doxycycline for seven days. The numbers of Str. salivarius in the oral cavity were determined before, during and after the administration periods. Phenoxymethylpenicillin and doxycycline only slightly suppressed the numbers of Str. salivarius, while erythromycin and clindamycin markedly decreased the numbers. In four and five subjects respectively, Str. salivarius could no longer be isolated after seven days of the drug administration.

Ninety-eight children who had acute tonsillitis due to Group A beta-hemolytic streptococci were treated for 10 days with orally administered penicillin B, potassium. Surface tonsillar cultures were obtained before therapy, at the end of therapy and 10, 21 and 42 days after termination of therapy. The cultures obtained before and after completion of treatment were processed for aerobic and anaerobic organisms, while the other cultures were processed only for Group A beta-hemolytic streptococci. On the basis of bacteriologic results 62 patients were considered "cured" (Group A) and 36 "failed" (Group B) following therapy. Before therapy 18 isolates of beta-lactamase-producing organisms (BLPO) were detected in 16 (26%) children in Group A; after therapy 30 BLPO were detected in 19 (30%) children. In contrast, before therapy 40 BLPO were recovered from 25 (69%) children in Group B; this number increased to 62 BLPO in 31 (86%) of those children. The study demonstrates an association between failure to eradicate Group A beta-hemolytic streptococci and the presence of aerobic and anaerobic BLPO.

In 73% of 167 patients with recurrent tonsillitis, colonization with betalactamase-producing microorganisms was found. Betastreptococci group A were recovered in 6% of the patients and group C and G streptococci in 23%. Other microorganisms found were Staphylococcus aureus in 42%, Haemophilus species in 52%, bacteroides species in 80% and fusobacteria in 40%. Ninety-eight per cent of Staph. aureus, 60% of bacteroides species and 10% of fusobacteria were betalactamase-producing. Phenoxymethylpenicillin (1 g twice a day for ten days) diminished 50% of group A, C and G streptococci. No other microorganisms were affected by this antibiotic. Clindamycin (0.15 g four times a day for ten days) eradicated Staph. aureus, group A, C and G streptococci, bacteroides and fusobacteria. Haemophilus species were not affected by clindamycin. Tinidazole (1 g once a day for 10 days) diminished bacteroides and fusobacteria. Aerobic microorganisms, Staph. aureus, streptococci and Haemophilus, were not affected by tinidazole.

Amino acids have been coupled to the carboxyl group of penicillin V and cephalothin by methods that keep the beta-lactam ring intact. Derivatives were successfully obtained with both neutral (Leu, Val, Ala, Ile, Trp, Tyr, Gly) and one acidic (Glu) amino acids. The new compounds were inactive in vitro against Staphylococcus aureus or Micrococcus luteus. Incubation in the presence of purified carboxypeptidases (A, B), soluble lysosomal fractions from liver, or cellular homogenates from liver, kidney, fibroblasts, and macrophages did not allow recovery of the antibacterial activity. Injection in mice also failed to cause liberation of microbiologically active compounds. HPLC studies confirmed that the amide linkage between the antibiotic and the amino acid was not hydrolyzed in the presence of soluble lysosomal fractions from liver. However, conversion of cephalothin and cephalothin-leucine to desacetyl derivatives was observed in the presence of soluble lysosomal fractions and extracts from liver and semipurified orange peel acetylesterase(s). It is concluded that amino acid derivatives of beta-lactam antibiotics do not offer potential chemotherapeutic use as prodrugs.

Four oral penicillin V regimens were compared for the ability to prevent Streptococcus sanguis infection of experimentally induced valvular heart lesions in rabbits. Challenge doses of 10(4), 10(6), and 10(8) CFU of a penicillin-susceptible strain of S. sanguis were used in this study. Measured by recovery of test organisms from endocardial lesions, the lowest-concentration inoculum was infective for 53% of the recipients; the higher-concentration inocula were infective for all recipients. A single-oral-dose penicillin V regimen (36 mg/kg of body weight) prevented endocarditis when rabbits were challenged with 10(4) CFU, but protection diminished with increasing inoculum concentrations. In contrast, addition of a second penicillin V dose (18 mg/kg of body weight) administered with a 7-h interval between doses achieved fully effective prophylaxis against even the highest inoculum tested (10(8) CFU). A repeated set of experiments in which half the dose of penicillin V was administered showed significantly reduced protection against S. sanguis endocarditis.

The effect of penicillin on the number of oral Streptococcus mutans, Streptococcus sanguis and lactobacilli in hamsters and in man was investigated. This is of interest as S. mutans and lactobacilli are involved in the carious process while S. sanguis is not. Hamsters infected with both S. mutans and S. sanguis or only S. sanguis received penicillin in their drinking water for 14 d. The treatment reduced the proportion of S. mutans and S. sanguis in dental plaque to undetectable levels. After the penicillin treatment the population of S. mutans and S. sanguis gradually increased. In man, the effect of oral penicillin therapy was examined in 21 adults with more than 2 X 10(5) S. mutans per ml saliva. The penicillin treatment had almost no effect on the numbers of S. sanguis and lactobacilli, but a pronounced decrease in the number of S. mutans was observed. The duration of this effect, however, was short. Consequently, such treatment alone is of limited value for the control of the oral infection of these microorganisms.

The activities of six agents commonly used in treating infections of the skin and soft tissues and the action of selected cephalosporins against 15 isolates of Pasteurella multocida were assessed by a macro-broth dilution method. Broad-spectrum cephalosporins, including ceftriaxone and cefixime, had excellent in vitro activities (MIC less than or equal to 0.098) against the isolates tested.

The effect of oral and parenteral penicillin on the development of cellular and humoral immune responses in chimpanzees infected with group A streptococcal M-types 1, 5 and 12 was investigated. The interrelationship between type-specific antibody response and enhancement of phagocytic competence of polymorphonuclear neutrophils was documented. Penicillin depressed or suppressed type-specific antibody response depending on the mode and dose of administration, probably because of its effect on the streptococci responsible for antibody stimulation. Penicillin was not demonstrated to have a direct effect on phagocytic ability in vitro. Therefore the primary effect of antibiotic therapy is the indirect relationship to suppression or inhibition of type-specific antibody response to M-protein which results in a diminution of phagocytic competence.

The effects of orally administered penicillin and tetracycline on the composition of the normal throat flora and its interference with the growth of group A streptococci were evaluated by throat culture and an agar overlay technique. Tetracycline caused only a slight, transient quantitative decrease in the composition of the flora and interference activity. Penicillin caused significant quantitative and qualitative decreases in both the composition of the flora and interference activity. The diminution in interference activity persisted up to 3 weeks after therapy. The differences observed between the antibiotic regimens correlated with differences in initial susceptibility of the flora to the antibiotic used and emergence of the resistance during therapy. Results indicated that although effects of antibiotics on the composition of the flora are transient, effects on its ability to interfere with group A streptococci may persist long after therapy is discontinued. It is thus possible that penicillin therapy may enhance susceptibility of certain individuals to subsequent infection with group A streptococci.

The effect of erythromycin, doxycycline and phenoxymethylpenicillin on human polymorphonuclear leucocyte (PMNL) chemotaxis was studied in vitro with Boyden's filter technique. Both erythromycin base and 2'-acetyl erythromycin stearate increased the PMNL chemotaxis significantly at concentrations greater than or equal to 50 microM, 2'-acetyl erythromycin stearate also at concentrations of 2.5-5 microM. Phenoxymethyl-penicillin reduced migration at 500 microM but lower concentrations had no significant effect. Doxycycline prevented migration significantly at concentrations greater than or equal to 50 microM.

The antibacterial effect of phenoxymethylpenicillin, cloxacillin, and flucloxacillin on pre-opsonized Staphylococcus aureus ingested by human monocytes and on preopsonized S. aureus in suspension was compared. The antibiotics were 1.7-3 times more effective against intracellular S. aureus than against S. aureus in suspension. No influence of acid stability or lipid solubility of the drugs on the antibacterial effect against intracellular S. aureus was demonstrated.

Beromycin, an antitumor anthracycline antibiotic formed in vitro complexes with native and denaturated DNA and ribosomal RNA. Beromycin had a comparatively low constant of DNA binding and to a less extent increased the melting temperature and viscosity of DNA than the other anthracycline antibiotics. A peculiar property of beromycin was very slow binding with DNA, the complex formation was completed in 60 minutes. Beromycin had a selective inhibitory effect on synthesis of nucleic acids in bacterial and tumor cells. Beromycin inhibited synthesis of RNA in the DNA-dependent RNA-polymerase reaction when both the native and denaturated DNA were used as the template. A lower biological activity of beromycin as compared to the other anthracycline antibiotics, such as rubomycin or carminomycin may be explained by lower affinity of this antibiotic to DNA.

The activity of phenoxymethylpenicillin (PcV), ampicillin, cefaclor, cefuroxime, chloramphenicol, co trimoxazole, doxycycline and erythromycin against clinical isolates of Branhamella catarrhalis, Haemophilus influenzae, pneumococci, group A streptococci and Staphylococcus aureus in 1983 was investigated with the MIC-method (plate-dilution technique). Forty-six percent of B. catarrhalis, 2% of H. influenzae and 78% of S. aureus were beta-lactamase producing and had high MIC-values for penicillin and ampicillin. Thus MIC for 90% of all strains of B. catarrhalis was 32 mg/l and 8 mg/l for penicillin and ampicillin while MIC for 90% of non beta-lactamase producing Branhamella strains was 2 mg/l and 0.25 mg/l respectively. This indicates a high susceptibility of penicillins to the action of Branhamella beta-lactamase. Almost all strains of B. catarrhalis, pneumococci, group A streptococci and S. aureus were inhibited at low concentrations of erythromycin. However, 4 mg/l was required to inhibit 90% of H. influenzae. Co-trimoxazole and doxycycline had good activity against all B. catarrhalis and H. influenzae strains while a few pneumococci, streptococci and staphylococci had intermediate sensitivity or were resistant. Essentially all strains were sensitive to cefuroxime and chloramphenicol.

The term antibiotic is now generally used to include antimicrobial substances produced by chemical means as well as those produced by micro-organisms. They may be either bacteriostatic or bacteriocidal. A bacteriostatic antibiotic inhibits the growth and replication of bacteria thereby giving the body's natural defence mechanisms time to become effective in overcoming an infection. In the majority of cases, and particularly in patients whose natural resistance is lowered by disorders of the immune system, it is preferable to choose a bacteriocidal agent. The first bacteriocidal antibiotic was penicillin G. The structure of the penicillin molecule is discussed as a basis for the understanding of its mode of action and of the mechanisms which lead to bacterial resistance. The modified and semisynthetic derivatives of penicillin are discussed and specific indications for their use are described in detail. Alternatives to the use of penicillin are also discussed and particular attention is paid to the cephalosporins and the tetracyclines.

Beta-streptococci isolated from patients with acute tonsillitis were tested for penicillin tolerance defined as an MBC/MIC ratio greater than or equal to 16. 11/18 strains recovered from patients with clinical treatment failure were tolerant to penicillin in comparison with 0/15 strains from successfully treated patients. The MBC/MIC ratio was less than 16 for all strains versus cefadroxil but above that ratio for many strains versus clindamycin, doxycycline and erythromycin. We suggest that penicillin tolerance may be one reason to treatment failures in individuals with streptococcal tonsillitis and that other antibiotics could be used to treat these patients since penicillin tolerance is not correlated to a general increase in antibiotic resistance.

This report discusses the differences in enzymes of two populations of P. aeruginosa, one sensitive and the other resistant to carbenicillin, which were strains isolated from four patients with chronic urinary infections. These sensitive and resistant strains biosynthetize only one beta-lactamase which appears to be a cephalosporinase of the class Id of Richmond and Sykes (1973). In the four cases the bacterial resistance to carbenicillin does not involve a new beta-lactamase and is due to other factors.

Several penicillins and penicillin-related compounds were tested for their ability to produce epileptiform activity in rat neocortex. (1) Alterations in the side chain of penicillin G decreased epileptogenic capability in all the compounds tested in this study: Phenoxymethylpenicillin produced a primary focus but no mirror focus, suggesting a dissociation of the mechanisms underlying these two processes. Ampicillin, 6-aminopenicillanic acid, and potassium 6-aminopenicillanic acid, and potassium 6-aminopenicillanic acid produced little or no epileptiform activity. All these compounds have free amino grounds and are amphoteric. (2) Breaking the beta lactam ring of penicillin G (potassium penicillin G penicilloate) eliminated epileptogenic capability. (3) Potassium salts of penicillin or its derivatives (potassium penicillin G, propicillin, potassium 6-aminopenicillanic acid, potassium penicillin G penicilloate) consistently suppressed cortical activity, regardless of the ability of the compound to produce spike discharges. Thus, mechanisms underlying these two properties can be dissociated. (4) Antibiotic activity of penicillins bears no relationship to epileptogenic capability.

Cycloaddition of azidoacetyl chloride to benzyl D-5,5-dimethyl-5-phenyl-2-thiazoline-4-carboxylate (1a) gave 5-phenyl-6alpha-azidopenicillanate (2a). By catalytic reduction of 2a and reaction with phenoxyacetyl chloride, 5-phenyl-6-epiphenoxymethylpenicillin benzyl ester (4a) was obtained. Oxidation of 4a gave the sulfoxide 6, which was isomerized in the presence of DBN. The sulfoxide 7 with the normal configuration could be isolated but deoxygenation of the sulfoxide was not successful. Isomerization of 4a with DBN, either with or without silylation of the side chain, gave a mixture from which 5-phenylphenoxymethylpenicillin benzyl ester (5) was isolated. Compound 5 was debenzylated to 5-phenylphenoxymethylpenicillin potassium salt (8). The antibacterial activity of 8 was low, whereas the 6-epimer 9 was inactive. Contary to published information, the 5-phenylpenam derivative 4c could be prepared by the same method.

Phenoxymethylpenicillin was given orally in doses of 800 mg twice daily for seven days to six patients, and bacampicillin was given in doses of 400 mg three times per day for seven days to another six patients. Saliva, throat and faecal specimens were taken for cultivation of aerobic and anaerobic bacteria. Only small changes in the normal saliva and throat flora were observed, and no changes in the faecal flora were noticed during the observation period. Cefoxitin was administered parenterally in doses of 2 g at 6 h intervals for 12 h to six other patients. Pronounced changes in the colon flora occurred. Of the aerobic bacteria, enterobacteria decreased and cefoxitin-resistant enterococci increased in number; of the anaerobic bacteria, gram-negative rods decreased in number. At the end of the administration period, all cefoxitin-resistant strains decreased, and suppressed enterobacteria and bacteroides increased in number.

The activity of cefcanel against anaerobic cocci, Clostridium perfringens, Bacteroides fragilis, Bacteroides spp. and fusobacteria was determined by the agar dilution method and compared with the activity of cefaclor, cephalexin, cefadroxil, phenoxymethylpenicillin and ampicillin. Cefcanel showed good activity against Clostridium perfringens, Bacteroides spp. and fusobacteria (MIC90 = 1-4 mg/l). Against anaerobic cocci its MIC90 value was 16 mg/l, and against Bacteroides fragilis, 32 mg/l. Cefcanel has an antibacterial activity that warrants investigation in clinical trials.

In this study the antimicrobial effects of phenoxymethylpenicillin (PM) and pheneticillin (PE) in vitro and in an experimental animal infection model were compared as well as the pharmacokinetic properties of both drugs in patients. For the inhibitory effect of PM on short-term (3 h) growth of S. aureus in vitro, this drug was 2.13 times more potent than PE. The protein binding of both drugs was similar (78-80%). The potency ratio of PM to PE against S. aureus in an experimental mouse-thigh infection was only 1.25 to 1. This is explained by the difference in the AUC after subcutaneous administration of PM (0.47 mg 1(-1) h) and PE (0.92 mg 1(-1) h). The plasma clearance after intravenous administration of PM was 476.4 ml/min and that of PE was 295.1 ml/min; the plasma clearance of both drugs was strongly correlated with the creatinine clearance. The volume of distribution in the steady state of PM was 35.41 and that of PE 22.51. In 10 patients, the absorption after oral administration of PM as the acid was 48% and that of the potassium salt of PE was 86% of the dose. From the present results it can be concluded that a difference in effectiveness of different formulations of PM and PE would depend entirely on differences in absorption.

Tetracyclines can react with enamel and dentin to form relatively insoluble fluorescent compounds. The purpose of this study was to evaluate the possible antimicrobial effect of these reaction products on various microorganisms associated with human dental plaque and periodontal disease. Slabs of native dentin and enamel as well as demineralized dentin were immersed in aqueous solutions of tetracycline HCl, oxytetracycline HCl and doxycycline HCl for periods of 1 h or 24 h. Unimpregnated enamel and dentin slabs sterilized by gamma irradiation and specimens impregnated with phenoxymethylpenicillin calcium were used as controls. Test and control specimens were placed on agar plates seeded with B. cereus, C. ochraceus, S. sanguis, F. nucleatum, B. melaninogenicus or A. viscosus and were subsequently incubated aerobically or anaerobically at 37 degrees C. With the exception of enamel impregnated for 1 h in a 0.01 mg/ml tetracycline solution, all test specimens caused growth inhibition zones, varying in size according to concentration of the drug, immersion period and bacterial species. The results indicate that tetracyclines react with enamel and dentin to form slightly soluble compounds with a pronounced antibacterial effect. In comparison, the antimicrobial effect of dentin treated with penicillin was small.

The emergence of beta-lactamase producing bacteria in the microflora in the oropharyngeal cavity was studied in ten healthy volunteers treated with 1 g phenoxymethylpenicillin b.i.d. for ten days. Beta-lactamase activity in saliva was also investigated. A significant increase in the number of beta-lactamase producing strains of Bacteroides species and Fusobacterium nucleatum was observed. One beta-lactamase producing Staphylococcus aureus strain was recovered in one of the volunteers before the penicillin administration started and three Staphylococcus aureus strains produced beta-lactamase after ten days of antibiotic treatment. Beta-lactamase-production in Haemophilus influenzae, Haemophilus parainfluenzae or Branhamella catarrhalis was not observed before, during or after the antibiotic treatment. Beta-lactamase activity was noted in the broth cultures from one volunteer colonized with a beta-lactamase producing Escherichia coli strain. Beta-lactamase activity in saliva was observed in all volunteers, the activity increasing significantly in parallel to the increase of beta-lactamase producing bacterial strains. Beta-lactamase activity in saliva was completely inhibited in vitro by clavulanic acid and p-chloromercurbenzoate and about 70-80 per cent of the activity was inhibited by cefoxitin. The increase of beta-lactamase producing bacteria in the oropharynx as a consequence of penicillin treatment raises doubt as to whether penicillin is the drug of choice in the treatment of tonsillitis caused by group A streptococci when previous treatment has failed.