Broad-spectrum Penicillins Research Articles

In vitro and in vivo antibacterial effects of combinations of beta-lactam antibiotics.

The effects of combining the new broad-spectrum penicillins piperacillin and mezlocillin with cefoxitin, cefamandole, or cephalothin on the antibacterial activities of these antibodies were determined in vitro against 50 to 109 bacterial strains and in six experimental infections in mice. Against strains of Escherichia coli, Klebsiella, Proteus mirabilis, Salmonella, Acinetobacter, Enterococcus, and Staphylococcus, the combinations exhibited synergistic, indifferent, or additive effects, but no antagonism. Against strains of four groups of organisms (Pseudomonas, Serratia, Enterobacter, and indole-positive Proteus), a high incidence of antagonism was observed, particularly with combinations containing cefoxitin (60 to 100%). The penicillins were antagonized by the cephalosporin antibiotics. In vitro effects were reflected in vivo. Mice infected with cultures associated with synergistic or additive in vitro effects were protected with lower doses of piperacillin when this antibiotic was administered with ineffective doses of cefoxitin than when piperacillin was used alone. Infections with cultures associated with in vitro antagonism required two- to eightfold higher doses of piperacillin and mezlocillin when these antibiotics were used in combination with the cephalosporins. The clinical implications of these effects should be considered.

In-vitro inactivation of aminoglycoside antibiotics by piperacillin and carbenicillin.

Clinical microbiology laboratory experiences wherein aminoglycoside serum assay results appeared inconsistent with the amount of the compound given when administered in combination with a semisynthetic penicillin led us to compare the interaction of three currently available aminoglycoside antibiotics with carbenicillin, as a representative semisynthetic penicillin given in large doses, and with piperacillin, a new broad-spectrum semisynthetic penicillin. Amikacin, gentamicin, and tobramycin were incubated in serum in vitro with various concentrations of carbenicillin and piperacillin. In the presence of very high concentrations of the two penicillins, tobramycin was the most rapidly inactivated aminoglycoside, gentamicin was next, and amikacin was only slightly inactivated. With low concentrations of the two penicillins, the rates of aminoglycoside inactivation were negligible. Carbenicillin, in high concentration, inactivated the aminoglycosides more rapidly than piperacillin. In patients experiencing renal failure, the maintenance of moderate serum levels of carbenicillin and piperacillin may be important in attempting to maintain adequate aminoglycoside serum levels.

Pharmacokinetics of Bay k 4999, a new broad-spectrum penicillin.

The pharmacokinetics of the broad-spectrum penicillin Bay k 4999 were studied in six healthy male volunteers. A 2-g dose was given by the intravenous route. The tissue penetration of the antibiotic was studied by both dermabrasion and blister techniques. A total of 26.4% of the drug was recovered in the urine in 24 h, 79% of this being excreted in the first 2 h. The elimination half-life in serum was 1.3 h. The dermabrasion levels of Bay k 4999 were generally similar to those in serum, but after 1 h the blister fluid levels of antibiotic were greater than those in serum. Different drug levels obtained by blister and dermabrasion techniques may be due to the different composition of the two fluids.

Mezlocillin and azlocillin: an evaluation of two new β-lactam antibiotics

Mezlocillin and azlocillin are broad spectrum penicillins for parenteral administration. In this study it was shown that they were very active against a wide range of pathogenic bacteria. Thirty-five patients were treated with mezlocillin, and 5 patients were treated with azlocillin (in combination with cefoxitin in 3 cases). The serum, bile and CSF levels of the drugs were measured. Both antibiotics would appear to be safe and efficacious in treating serious infections by sensitive pathogens. Infections caused by unknown pathogens could be treated by one of these agents in combination with a broad spectrum beta-lactamase stable cephalosporin or cephamycin.

Clinical pharmacology of mezlocillin.

Mezlocillin is a new broad-spectrum semisynthetic penicillin that has shown encouraging in vitro activity against the infecting organisms most likely to cause mortality and morbidity in cancer patients receiving chemotherapy. The serum clearances and urine recoveries of mezlocillin, ampicillin, and carbenicillin were compared after the intravenous administration of single 3-g doses. The peak mean serum concentrations of mezlocillin and carbenicillin were 269 and 278 mug/ml, respectively, whereas the peak ampicillin level was lower at 167 mug/ml. The terminal half-life of mezlocillin, 66 min, was not significantly different from those of ampicillin and carbencillin (63 and 77 min, respectively). Recoveries of mezlocillin, ampicillin, and carbenicillin from urine over 6-h periods after drug dosage were 45, 61, and 80%, respectively. A further study in 11 cancer patients examined serum maintenance levels of mezlocillin when 3-g doses were given intravenously every 4 h for at least 7 consecutive days. After 3 days of therapy, the mean serum concentrations were maintained above 50 mug/ml. Although therapeutic efficacy was not an objective of this study, all of three documented bacterial infections were cured, and no serious toxicity was encountered.

In vitro and in vivo activity of piperacillin, a new broad-spectrum semisynthetic penicillin.

Piperacillin sodium is a novel semisynthetic penicillin with broad spectrum activity against Gram-negative and -positive bacteria including anaerobes. In agar dilution tests with 522 clinical isolates, it inhibited at least 70-90% of each group of organisms at 16 mcg/ml with the exception of the Serratia group which required 64 mcg/ml to inhibit 70% of the isolates. Piperacillin was more potent than carbenicillin, ticarcillin and ampicillin against Klebsiella, Pseudomonas, Enterobacter and Serratia. Against Gram-positive cocci it was generally comparable to carbenicillin and ticarcillin except in the case of enterococci where it was significantly more potent. Piperacillin exhibited a broader spectrum than the cephalosporins which lacked antipseudomonal activity. It was more potent than cephalothin, cefamandole and cefoxitin against indole-positive Proteus, Acinetobacter and enterococci. Piperacillin is bactericidal; minimal bactericidal concentrations were within four-fold of the minimal inhibitory concentrations. Its activity was not significantly altered by pH, media or serum, but was reduced when inoculum size was increased from 105 to 107 CFU/ml. Synergistic effects were observed when piperacillin was combined with gentamicin or amikacin. Piperacillin was effective against both acute lethal infections and chronic kidney infections in mice. Our results indicate that piperacillin has a spectrum of activity that spans those of other semisynthetic penicillins and cephalosporins.

Antibacterial synergism between beta-lactam antibiotics: Results using clavulanic acid (BRL. 14151) with amoxycillin, carbenicillin or cephaloridine

Bacterial resistance to β-lactam antibiotics is becoming increasingly important. This resistance is often mediated by the production of β-lactamase enzymes which destroy the antibiotics. Such resistance might be overcome firstly by developing antibiotics which are resistant to destruction by β-lactamase; secondly, by developing antibiotics of very high potency; thirdly, antibiotics could be developed which release antibacterially active moities on hydrolysis by β-lactamase. The fourth and perhaps one of the most promising approaches is to develop molecules which inactivate β-lactamases. Combinations of broadspectrum penicillins with isoxazole penicillins have been investigated but for various reasons were not successful in therapy. Recently clavulanic acid, a naturally occurring β-lactam molecule, has been investigated by the authors and other workers. Unlike isoxazole penicillins, clavulanic acid inhibits β-lactamase activity at low concentrations. The activity of ampicillin, cephaloridine or carbenicillin in combination with clavulanic acid against 215 bacterial isolates has been investigated. Concentrations as low as 1 mg/l of clavulanic acid regularly rendered ampicillin-resistant strains ofBacteroides fragilis, Haemophilus influenzae andStaphylococcus aureus sensitive to attainable blood concentrations of amoxycillin. 5 mg/l of clavulanic acid brought the majority of strains ofProteus mirabilis, all strains ofProteus vulgaris, most strains ofKlebsiella pneumoniae and a small proportion of ampicillin-resistant strains ofEscherichia coli into the therapeutic range of amoxycillin. Increasing the concentration of clavulanic acid to 10 mg/l rendered the majority of strains ofE. coli sensitive to amoxycillin. The combination did not show enhanced activity againstEnterobacter species,Serratia marcescens, and most strains ofProteus rettgeri andProteus morganii. There was no enhanced activity between carbenicillin and clavulanic acid against either carbenicillin-sensitive or carbenicillin-resistant strains ofPseudomonas aeruginosa. As would be expected the activity of amoxycillin was not enhanced against ampicillin-sensitive strains of various species or against inherently sensitive species. In a single, simple preliminary experimental mouse infection using intra-peritoneal inoculation ofKlebsiella pneumoniae, protection was suggested by a combination of amoxycillin with clavulanic acid given as two doses where as the individual drugs did not protect. It was concluded that the combined use of clavulanic acid with a broad-spectrum β-lactum antibiotic showed therapeutic potential and was deserving of further evaluation.

Beta-lactam antibiotics. II. Structure-activity relationships of 6-[alpha-(alpha'-ureido-acylamino) acylamino] penicillanic acids.

The influence on the structure-activity relationships (S.A.R.) of the stereochemistry and various alkyl, aryl, aralkyl and heterocyclic substituents at the two chiral centres in the dipeptide side-chain of a new series of penicillins was examined. In many cases the effects of these changes had a pronounced influence on the degree of activity against Gram-positive and especially Gram-negative bacteria. Several compounds indicated that the size, shape and spatial disposition of a substituent were the parameters of importance in influencing activity, rather than it lipophilic or electronic character. The most active homologues in the series provided broad-spectrum penicillins which in terms of their in vitro antibacterial properties showed improvements over certain of the marketed penicillins. Thus 6-[D-alpha(alpha'-ureidoacyl-amino)acylamino]penicillanic acids were found which had a carbenicillin-like profile, with improvements against Pseudomonas aeruginosa, Klebsiella aerogenes, sensitive and beta-lactamase-producing Gram-positive cocci.

Laboratory Evaluation of 3-(5-Tetrazolyl)Penam, a New Semisynthetic Beta-Lactam Antibacterial Agent with Extended Broad-Spectrum Activity

In the new agent 3-(5-tetrazolyl)penam, hereafter referred to as CP-35,587, the carboxyl function at C3 in the penicillin nucleus has been replaced with the 5-tetrazolyl moiety. Marked changes in spectrum and resistance to gram-negative beta-lactamases, particularly with regard to Klebsiella pneumoniae isolates, were conferred by this modification. The anti-Klebsiella activity clearly distinguishes the antibacterial spectrum of CP-35,587 from any known broad-spectrum penicillin. Compared to orally active cephalosporins, the spectrum advantage of CP-35,587 encompasses Enterobacter, Serratia marcescens, Citrobacter, Providencia, Haemophilus influenzae, and Streptococcus faecalis, both in vitro and in murine infections produced by many of the above-named microorganisms. Thus, CP-35,587 combines and extends the antibacterial activity of broad-spectrum penicillins and orally active cephalosporins.

Experimental and clinical studies on talampicillin in urologic diseases

Talampicillin, a new broad-spectrum semisynthetic penicillin for oral use was studied both fundamentally and clinically. Results were summarized as follows.1. Urinary concentration and recovery after oral administration of 250mg of Talampicillin were about twice higher than those of 250mg of Ampicillin.2. Thirty cases of urinary tract infections were treated with Talampicillin at a daily dose of 750mg. Satisfactory results were obtained in 21 cases (81% in 16 cases of acute simple cystitis and 57% in 14 cases of chronic complicated urinary tract infections).3. Subjective side effect was not seen.4. It was considered that the daily dose of 750mg of Talampicillin was sufficient for the treatment of acute urinary tract infections, but for the chronic urinary tract infections, further investigations should be carried out hereafter.

Diabetic pregnancy.

<h3>Abstract</h3> <h3>Background</h3> – Antimicrobial resistance (AMR) poses a colossal threat to global health and incurs high economic costs to society. Economic evaluations of antimicrobials and interventions such as diagnostics and vaccines that affect their consumption rarely include the costs of AMR, resulting in sub-optimal policy recommendations. We estimate the economic cost of AMR per antibiotic consumed, stratified by drug class and national income level. <h3>Methods</h3> – The model is comprised of three components: correlation coefficients between human antibiotic consumption and subsequent resistance; the economic costs of AMR for five key pathogens; and consumption data for antibiotic classes driving resistance in these organisms. These were used to calculate the economic cost of AMR per antibiotic consumed for different drug classes, using data from Thailand and the United States (US) to represent low/middle and high-income countries. <h3>Results</h3> – The correlation coefficients between consumption of antibiotics that drive resistance in <i>S. aureus, E. coli, K. pneumoniae, A. baumanii</i>, and <i>P. aeruginosa</i> and resistance rates were 0.37, 0.27, 0.35, 0.45, and 0.52, respectively. The total economic cost of AMR due to resistance in these five pathogens was $0.5 billion and $2.8 billion in Thailand and the US, respectively. The cost of AMR associated with the consumption of one standard unit (SU) of antibiotics ranged from $0.1 for macrolides to $0.7 for quinolones, cephalosporins and broad-spectrum penicillins in the Thai context. In the US context, the cost of AMR per SU of antibiotic consumed ranged from $0.1 for carbapenems to $0.6 for quinolones, cephalosporins and broad spectrum penicillins. <h3>Conclusion</h3> – The economic costs of AMR per antibiotic consumed were considerable, often exceeding their purchase cost. Differences between Thailand and the US were apparent, corresponding with variation in the overall burden of AMR and relative prevalence of different pathogens. Notwithstanding their limitations, use of these estimates in economic evaluations can make better-informed policy recommendations regarding interventions that affect antimicrobial consumption and those aimed specifically at reducing the burden of AMR.

Prüfung von Amoxycillin (BRL 2333) unter Bedingungen der Allgemeinpraxis

98 patients of all age groups were treated with the new broad-spectrum penicillin, amoxycillin (BRL 2333), for infections of the upper and lower respiratory tract, the urinary tract, otitis media and biliary tract infections. The product had to be discontinued in 5 cases because of side-effects; in 83 cases, there was a complete clinical resolution; and in 10 cases, there was a symptomatic improvement. Amoxycillin has showed its value as a routine antibiotic for the treatment ofbacterial infections in general practice.

Klinische Erfahrungen über die Anwendung von Amoxycillin (BRL 2333) in der Kinderheilkunde

Within the framework of a prospective study, 71 children of various age groups were treated with amoxycillin, a new semi-synthetic broad-spectrum penicillin. Of this number, there were 64 cases of pyelonephritis, 6 of respiratory infections (one combined with salmonellosis) and one case treated prophylactically. The average duration of treatment was 14 days, and the dosage 100 mg/kg body weight. The cases of pyelonephritis were treated strictly in accordance with sensitivity studies – in general, the bacterial isolates were very sensitive to amoxycillin. In 5 of the respiratory cases, there was a clinically proven therapeutic success. 63 of the 64 cases of pyelonephritis were fully followed-up. In 45 cases (71.4%), there was complete sterilisation of the urine, in 18 cases (28.6%), complete sterilisation was not possible, but only in one case, there was persistence of a sensitive organism. In 17 cases, either a development of resistance or a change of pathogen was observed. In cases of the appropriate diagnosis, amoxycillin showed itself to be adequate for the treatment of bacterial infections and, in particular, for the initial treatment of pyelonephritis. It also showed itself to be exceptionally well tolerated with minimal gastrointestinal side-effects – due note must be taken, however, of macropapular exanthema.

BROAD‐SPECTRUM PENICILLINS AND OTHER ANTIBIOTICS IN THE TREATMENT OF URINARY TRACT INFECTIONS*

Annals of the New York Academy of SciencesVolume 145, Issue 2 p. 344-353 BROAD-SPECTRUM PENICILLINS AND OTHER ANTIBIOTICS IN THE TREATMENT OF URINARY TRACT INFECTIONS* Marvin Turck, Marvin Turck Department of Medicine, University of Washington School of Medicine and King County Hospital, Seattle, Wash. Assistant Professor of Medicine, Head, Division of Infectious Diseases, King County Hospital. Recipient of a Research Career Development Award of the National Institutes of Health.Search for more papers by this author Marvin Turck, Marvin Turck Department of Medicine, University of Washington School of Medicine and King County Hospital, Seattle, Wash. Assistant Professor of Medicine, Head, Division of Infectious Diseases, King County Hospital. Recipient of a Research Career Development Award of the National Institutes of Health.Search for more papers by this author First published: September 1967 https://doi.org/10.1111/j.1749-6632.1967.tb50231.xCitations: 5 * Supported in part by Training Grant AI146-07 and Research Grant AI-106311-03 from the National Institutes of Health, U.S.P.H.S. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume145, Issue2Comparative Assessment of the Broad-Spectum Penicillins and Other AntibioticsSeptember 1967Pages 344-353 RelatedInformation

Crystalline Modifications of Ampicillin

SINCE the introduction in 1961 of 6[D(−)α-amino-phenyl-acetamido]penicillanic acid1 (I; ampicillin), its synthesis, bacteriology, pharmacology, and clinical use as a broad-spectrum penicillin have been extensively reported. Recently, attention has been turned to the physical properties of the solid. Thus, Grant and Alburn2 have distinguished between, a crystalline anhydrous form and a monohydrate, which differ in solid-state infra-red absorption spectra, density, solubility, and thermal stability. They make no mention, however, of the highly crystalline ampicillin trihydrate which may be obtained by crystallization from water3 or by treating acid addition salts in moist organic solvents with amines of high molecular weight4. We wish to report further details of the various solid forms of ampicillin, both anhydrous and hydrated, and the means whereby they may be inter-converted.

INTRAOCULAR PENETRATION OF AMPICILLIN. II. CLINICAL EXPERIMENT.

<h3>Introduction</h3> Ampicillin is a new broad-spectrum penicillin that should be a useful and safe antimicrobial agent for the treatment of ocular infections. This agent is an acid stable semisynthesized substance and as such is absorbed well after oral administration. It is currently available from Bristol Laboratories for oral use as Polycillin, 250 mg capsules. This study was undertaken to determine the ocular penetration of ampicillin in human subjects after oral administration. Ampicillin levels in aqueous and blood plasma were determined after administration of a single dose of 250 mg, 1,000 mg, or 2,000 mg orally. In addition, the ocular and plasma levels were determined in several patients who received multiple doses of ampicillin. Studies at the relatively low dosage of 250 mg were prompted by the previous observations of its excellent ocular penetration in rabbits¹and the suggestions by Bunn et al²that a dose of 250 mg

広域ペニシリン“Viccillin”による細菌性赤痢患者の治療経験

広域ペニシリン“Viccillin”による細菌性赤痢患者の治療経験