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The British Journal of Venereal Diseases Dec 1984Paired specimens of cerebrospinal fluid and serum were taken from 21 patients to estimate penicillin concentrations two to three hours after the last dose of a course of...
Paired specimens of cerebrospinal fluid and serum were taken from 21 patients to estimate penicillin concentrations two to three hours after the last dose of a course of 14-21 daily intramuscular injections of procaine penicillin 0.6 MU. Of 10 patients treated with procaine penicillin alone, eight had no detectable penicillin and two had sub-treponemicidal concentrations (less than 0.018 mg/l) in the cerebrospinal fluid. Of 11 patients treated with procaine penicillin as above and probenecid 2 g a day by mouth, three had no detectable penicillin, two had sub-treponemicidal concentrations, and six had treponemicidal concentrations of penicillin in the cerebrospinal fluid. All 21 patients had treponemicidal concentrations of penicillin in the serum. This dose of procaine penicillin alone or with probenecid is therefore not recommended for treating neurosyphilis.
Topics: Biological Assay; Drug Therapy, Combination; Female; Humans; Injections, Intramuscular; Male; Penicillin G; Penicillin G Procaine; Penicillins; Probenecid; Syphilis
PubMed: 6518348
DOI: 10.1136/sti.60.6.371 -
Proceedings of the National Academy of... Nov 2021Understanding the functional role of protein-excited states has important implications in protein design and drug discovery. However, because these states are difficult...
Understanding the functional role of protein-excited states has important implications in protein design and drug discovery. However, because these states are difficult to find and study, it is still unclear if excited states simply result from thermal fluctuations and generally detract from function or if these states can actually enhance protein function. To investigate this question, we consider excited states in β-lactamases and particularly a subset of states containing a cryptic pocket which forms under the Ω-loop. Given the known importance of the Ω-loop and the presence of this pocket in at least two homologs, we hypothesized that these excited states enhance enzyme activity. Using thiol-labeling assays to probe Ω-loop pocket dynamics and kinetic assays to probe activity, we find that while this pocket is not completely conserved across β-lactamase homologs, those with the Ω-loop pocket have a higher activity against the substrate benzylpenicillin. We also find that this is true for TEM β-lactamase variants with greater open Ω-loop pocket populations. We further investigate the open population using a combination of NMR chemical exchange saturation transfer experiments and molecular dynamics simulations. To test our understanding of the Ω-loop pocket's functional role, we designed mutations to enhance/suppress pocket opening and observed that benzylpenicillin activity is proportional to the probability of pocket opening in our designed variants. The work described here suggests that excited states containing cryptic pockets can be advantageous for function and may be favored by natural selection, increasing the potential utility of such cryptic pockets as drug targets.
Topics: Binding Sites; Escherichia coli; Escherichia coli Proteins; Molecular Dynamics Simulation; Mutation; Penicillin G; Penicillinase; Protein Conformation; Proteins; beta-Lactamases
PubMed: 34799442
DOI: 10.1073/pnas.2106473118 -
International Journal of Antimicrobial... Apr 2022An increasing proportion of penicillin-susceptible Staphylococcus aureus (PSSA) has been reported over the last years. The aim of this retrospective study was to compare...
An increasing proportion of penicillin-susceptible Staphylococcus aureus (PSSA) has been reported over the last years. The aim of this retrospective study was to compare penicillin G with cloxacillin in the treatment of PSSA bloodstream infections. The primary outcome was the mortality rate after 90 days and the secondary outcome was the development of treatment complications of varying severity. Medical records from patients with PSSA bacteraemia during 2018-2020 were reviewed. Patient outcome was ranked on an ordinal scale according to severity: (i) alive at 90 days without any complications; (ii) adverse events not requiring treatment; (iii) change or addition of antibiotics owing to treatment failure or adverse events; (iv) relapse within 90 days; and (v) death within 90 days. The outcome ranking scale was dichotomised at every level and was analysed by logistic regression and a propensity score-weighted analysis. A total of 316 patients received cloxacillin and 68 patients received penicillin G as final treatment. Mortality rates did not differ significantly between the treatment groups (cloxacillin 19% vs. penicillin G 13%; P = 0.24), but patients treated with cloxacillin had an increased odds of having any complication compared with patients treated with penicillin G (odds ratio = 2.43, 95% confidence interval 1.30-4.53; P = 0.005). A propensity score analysis confirmed the results. Mortality rates in PSSA bacteraemia did not differ between treatment groups but cloxacillin treatment increased the overall odds of treatment complications.
Topics: Anti-Bacterial Agents; Bacteremia; Cloxacillin; Humans; Penicillin G; Penicillins; Retrospective Studies; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome
PubMed: 35288257
DOI: 10.1016/j.ijantimicag.2022.106567 -
Journal of Clinical Pathology Nov 1979The action and interaction of benzylpenicillin and gentamicin on Streptococcus faecalis was studied using mainly turbidimetric methods. The minimum antibacterial...
The action and interaction of benzylpenicillin and gentamicin on Streptococcus faecalis was studied using mainly turbidimetric methods. The minimum antibacterial concentration (MAC) of each antibiotic lay considerably below the conventionally determined minimum inhibitory concentration, and levels of the two agents exceeding the MAC were necessary in order to obtain a synergic interaction. Evidence was obtained that gentamicin interfered with bacterial lysis induced by penicillin, and this suggests that the aminoglycoside is responsible for the bactericidal activity of the combination, the role of the penicillin being solely to facilitate access of the aminoglycoside to its target site. Our findings do not, however, fully support the generally held view that the increased permeability of enterococci to aminoglycosides is due to penicillin-induced cell wall damage. 'Persisters'--cells surviving prolonged exposure to the optimum lethal concentration of penicillin--were not killed by subsequent exposure to gentamicin if the penicillin was removed but were killed if the penicillin remained present.
Topics: Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Enterococcus faecalis; Gentamicins; Penicillin G; Penicillin Resistance
PubMed: 117025
DOI: 10.1136/jcp.32.11.1174 -
European Journal of Biochemistry Jul 1978The penicillin-binding protein that is thought to be the lethal target of penicillin in Bacillus megaterium (protein 1) has been purified to greater than 95%...
Purification and characterization of the penicillin-binding protein that is the lethal target of penicillin in Bacillus megaterium and Bacillus licheniformis. Protein exchange and complex stability.
The penicillin-binding protein that is thought to be the lethal target of penicillin in Bacillus megaterium (protein 1) has been purified to greater than 95% homogeneity. The membrane-bound penicillin-binding proteins were solubilized with a non-ionic detergent and partially separated from each other by ion-exchange chromatography on DEAE-Sepharose CL-6B. Protein 1 was subsequently purified by covalent affinity chromatography on ampicillin-affinose. Bacillus licheniformis contains an equivalent penicillin-binding protein (protein 1) that can be more readily purified to virtual homogeneity in a one-step procedure. It was separated from the other penicillin-binding proteins by utilizing the observation that in this organism, this particular protein is the only one whose covalent complex with benzylpenicillin subsequently breaks down. Membranes were treated with saturating concentrations of benzylpenicillin followed by the removal of free penicillin and further incubation to allow the complex between benzylpenicillin and protein 1 to break down. The penicillin-binding proteins were then solubilized and applied to a column of ampicillin-affinose to which only protein 1 was bound as the other penicillin-binding proteins still had benzylpenicillin bound to them. Pure protein 1 was eluted from the affinity resin with hydroxylamine. The interaction of benzylpenicillin with purified protein 1 has been studied by separating unbound antibiotic from the benzylpenicillin . protein complex by paper electrophoresis. Benzylpenicillin reacts with the protein rapidly to form a covalent complex and the fully saturated complex has a molar ratio of bound [14C] benzylpenicillin: protein of 0.7:1. The complex breaks down, obeying first-order kinetics, with a half-life of 16 min at 35 degrees C, a value identical to that obtained with the membrane-bound protein. The concentration of benzylpenicillin that results in the formation of 50% of the maximum amount of benzylpenicillin . protein complex is that at which the molar amount of benzylpenicillin present is equal to 50% of the molar amount of penicillin-binding protein, rather than being a measure of any of the kinetic parameters of the binding reaction. This observation may be significant in the interpretation of previous results where the amounts of penicillins needed to kill cells or to inhibit penicillin-sensitive reactions have been expressed as concentrations. The possible importance of the breakdown of beta-lactam . protein complexes in the clinical use of these antibiotics is discussed.
Topics: Bacillus; Bacillus megaterium; Bacterial Proteins; Carrier Proteins; Cell Membrane; Molecular Weight; Penicillin G; Penicillinase
PubMed: 97081
DOI: 10.1111/j.1432-1033.1978.tb12448.x -
BMJ (Clinical Research Ed.) May 1991To assess whether, on the basis of one blood test, penicillin allergy might be excluded sufficiently for general practitioners to give oral penicillin to patients...
OBJECTIVE
To assess whether, on the basis of one blood test, penicillin allergy might be excluded sufficiently for general practitioners to give oral penicillin to patients claiming a history of penicillin allergy.
DESIGN
Prospective study of patients referred by general practitioners.
SETTING
Outpatient allergy clinic in a district general hospital.
PATIENTS
175 referred patients who gave a history of immediate type reaction to penicillin, of whom 144 attended as requested and 132 completed the investigations.
MAIN OUTCOME MEASURES
History and examination, serum radioallergosorbent test to phenoxymethylpenicillin and benzylpenicillin, and oral challenge with penicillin.
RESULTS
Of 132 patients, four were confirmed to have penicillin allergy by the radioallergosorbent test and 128 had an oral penicillin challenge without ill effect.
CONCLUSIONS
Most patients who gave a history of penicillin allergy are not so allergic, and their actual allergic state should be substantiated whenever feasible. For patients reporting minor or vague reactions negative findings with a radioallergosorbent test to phenoxymethylpenicillin and benzylpenicillin provide sufficient evidence to give oral penicillin safely.
Topics: Administration, Oral; Adolescent; Adult; Aged; Child; Child, Preschool; Drug Hypersensitivity; Female; Humans; Immunoglobulin E; Infant; Male; Medical History Taking; Middle Aged; Penicillin G; Penicillin V; Penicillins; Prospective Studies; Radioallergosorbent Test
PubMed: 1903664
DOI: 10.1136/bmj.302.6784.1051 -
The American Journal of Pathology Oct 2022All tested strains of Streptococcus pyogenes (group A streptococcus, GAS) remain susceptible to penicillin. However, GAS strains with amino acid substitutions in...
All tested strains of Streptococcus pyogenes (group A streptococcus, GAS) remain susceptible to penicillin. However, GAS strains with amino acid substitutions in penicillin-binding proteins that confer decreased susceptibility to beta-lactam antibiotics have been identified recently. This discovery raises concerns about emergence of beta-lactam antibiotic resistance in GAS. Whole genome sequencing recently identified GAS strains with a chimeric penicillin-binding protein 2X (PBP2X) containing a recombinant segment from Streptococcus dysgalactiae subspecies equisimilis (SDSE). To directly test the hypothesis that the chimeric SDSE-like PBP2X alters beta-lactam susceptibility in vitro and fitness in vivo, an isogenic mutant strain was generated and virulence assessed in a mouse model of necrotizing myositis. Compared with naturally occurring and isogenic strains with a wild-type GAS-like PBP2X, strains with the chimeric SDSE-like PBP2X had reduced susceptibility in vitro to nine beta-lactam antibiotics. In a mouse model of necrotizing myositis, the strains had identical fitness in the absence of benzylpenicillin treatment. However, mice treated intermittently with a subtherapeutic dose of benzylpenicillin had significantly more colony-forming units recovered from limbs infected with strains with the chimeric SDSE-like PBP2X. These results show that mutations such as the PBP2X chimera may result in significantly decreased beta-lactam susceptibility and increased fitness and virulence. Expanded diagnostic laboratory surveillance, genome sequencing, and molecular pathogenesis study of potentially emergent beta-lactam antibiotic resistance among GAS are needed.
Topics: Animals; Anti-Bacterial Agents; Fasciitis, Necrotizing; Mice; Myositis; Penicillin G; Penicillin-Binding Proteins; Penicillins; Recombinant Fusion Proteins; Streptococcus pneumoniae; Streptococcus pyogenes; beta-Lactams
PubMed: 35843262
DOI: 10.1016/j.ajpath.2022.06.011 -
Obstetrics and Gynecology Aug 2008Intrapartum penicillin G prophylaxis aims to prevent early-onset group B streptococci (GBS) sepsis by interrupting vertical transmission. We examined the relationship...
OBJECTIVE
Intrapartum penicillin G prophylaxis aims to prevent early-onset group B streptococci (GBS) sepsis by interrupting vertical transmission. We examined the relationship between duration of prophylaxis and fetal serum penicillin G levels among fetuses exposed to fewer than 4 hours of prophylaxis compared with longer durations.
METHODS
In this prospective cohort study, 98 laboring GBS-positive women carrying singleton gestations at 37 weeks or greater were administered 5 million units of intravenous penicillin G followed by 2.5 million units every 4 hours until delivery. Umbilical cord blood samples were collected at delivery, and penicillin G levels were measured by high-performance liquid chromatography. Intraassay and interassay coefficients of variation were less than 3%.
RESULTS
Fetuses exposed to fewer than 4 hours of prophylaxis had higher penicillin G levels than those exposed to greater than 4 hours (P=.003). In multivariable linear regression analysis, fetal penicillin G levels were determined by duration of exposure, time since last dose, dosage, and number of doses, but not maternal body mass index. Penicillin G levels increased linearly until 1 hour (R(2)=.40) and then decreased rapidly according to a power-decay model (R(2)=.67). All subgroups analyzed were above the minimal inhibitory concentration (MIC) for GBS (0.1 micrograms/mL)(P<.002). Individual samples were 10-179-fold above the MIC. In patients receiving maintenance dosing, penicillin G did not accumulate in the cord blood and returned to baseline after each 4-hour interval.
CONCLUSION
Short durations of prophylaxis achieved levels significantly above the MIC, suggesting a benefit even in precipitous labors. The designation of infants exposed to fewer than 4 hours of prophylaxis as particularly at risk for GBS sepsis may be pharmacokinetically inaccurate.
Topics: Adult; Antibiotic Prophylaxis; Female; Fetal Blood; Fetus; Humans; Linear Models; Penicillin G; Prospective Studies; Streptococcal Infections; Streptococcus agalactiae
PubMed: 18669721
DOI: 10.1097/AOG.0b013e31817d0246 -
Clinical Pharmacokinetics Feb 2023Pharmacokinetics (PK) are severely altered in pregnant women due to changes in volume of distribution (Vd) and/or drug clearance (CL), affecting target attainment of...
BACKGROUND AND OBJECTIVE
Pharmacokinetics (PK) are severely altered in pregnant women due to changes in volume of distribution (Vd) and/or drug clearance (CL), affecting target attainment of antibiotics in pregnant women. This review is part of a series that reviews literature on the description of PK and target attainment of antibiotics in pregnant women with specific focus on penicillins.
METHODS
A systematic literature search was carried out in PubMed. Articles were labelled as relevant when information on PK of penicillins in pregnant women was available.
RESULTS
Thirty-two relevant articles were included, 8 of which discussed amoxicillin (with and without clavulanic acid), 15 ampicillin, 4 benzylpenicillin, 1 phenoxymethylpenicillin, and 4 piperacillin (with and without tazobactam). No studies were found on pheneticillin and flucloxacillin in pregnant women. Ten out of 32 articles included information on both Vd and CL. During the second and third trimester of pregnancy, a higher CL and larger Vd was reported than in non-pregnant women and in pregnant women during first trimester. Reduced target attainment was described in second and third trimester pregnant women. Only 7 studies reported dosing advice, 4 of which were for amoxicillin.
CONCLUSION
The larger Vd and higher CL in second and third trimester pregnant women might warrant a higher dosage or shortening of the dosing interval of penicillins to increase target attainment. Studies frequently fail to provide dosing advice for pregnant women, even if the necessary PK information was available.
Topics: Pregnancy; Female; Humans; Penicillins; Anti-Bacterial Agents; Amoxicillin; Ampicillin; Piperacillin
PubMed: 36662480
DOI: 10.1007/s40262-023-01211-z -
Antimicrobial Agents and Chemotherapy Sep 1996Broth MICs and time-kill studies were used to test the activity of RP 59500 (quinupristin-dalfopristin), RPR 106972, pyostacine (RP 7293), erythromycin, clarithromycin,... (Comparative Study)
Comparative Study
MIC and time-kill study of antipneumococcal activities of RPR 106972 (a new oral streptogramin), RP 59500 (quinupristin-dalfopristin), pyostacine (RP 7293), penicillin G, cefotaxime, erythromycin, and clarithromycin against 10 penicillin-susceptible and -resistant pneumococci.
Broth MICs and time-kill studies were used to test the activity of RP 59500 (quinupristin-dalfopristin), RPR 106972, pyostacine (RP 7293), erythromycin, clarithromycin, and cefotaxime for four penicillin-susceptible (MICs of 0.008 to 0.03 microgram/ml), two penicillin-intermediate (MIC of 0.25 microgram/ml), and four penicillin-resistant (MIC of 2.0 to 4.0 micrograms/ml) strains of pneumococci: 6 of 10 strains were resistant to macrolides (MICs of > or = 0.5 microgram/ml). MICs of RP 59500 (0.5 to 1.0 microgram/ml), RPR 106972 (0.125 to 0.25 microgram/ml), and pyostacine (0.125 to 0.25 microgram/ml) did not alter with the strain's penicillin or macrolide susceptibility status. Three penicillin-susceptible strains and one penicillin-intermediate strain were susceptible to macrolides (MICs of < or = 0.25 microgram/ml); the macrolide MICs for the remaining strains were > or = 4.0 micrograms/ml. Cefotaxime MICs rose with those of penicillin G, but all strains were inhibited at MICs of < or = 2.0 micrograms/ml. RP 59500 was bactericidal for all strains after 24 h at 2 x MIC and yielded 90% killing of all strains at 6 h at 2 x MIC; at 8 x MIC, RP 59500 showed 90% killing of six strains within 10 min (approximately 0.2 h). In comparison, RPR 106972 was bactericidal for 9 of 10 strains at 2 x MIC after 24 h and yielded 90% killing of all strains at 2 x MIC after 6 h; 90% killing of six strains was found at 8 x MIC at 0.2 h. Results for pyostacine were similar to those of RPR 106972. Erythromycin and clarithromycin were bactericidal for three of four macrolide-susceptible strains after 24 h at 4 x MIC. Clarithromycin yielded 90% killing of three strains at 8 x MIC after 12 h. Cefotaxime was bactericidal for all strains after 24 h at 4 x MIC, yielding 90% killing of all strains after 6 h at 4 x MIC. All three streptogramins yielded rapid killing of penicillin- and erythromycin-susceptible and -resistant pneumococci and were the only compounds which killed significant numbers of strains at 0.2 h.
Topics: Anti-Bacterial Agents; Cefotaxime; Cephalosporins; Clarithromycin; Erythromycin; Microbial Sensitivity Tests; Penicillin G; Penicillin Resistance; Penicillins; Streptococcus pneumoniae; Time Factors; Virginiamycin
PubMed: 8878583
DOI: 10.1128/AAC.40.9.2071