Hypokalaemia,Metabolic Alkalosis,and Hypernatraemia due to “Massive” Sodium Penicillin Therapy

Hypokalaemia and metabolic alkalosis were seen in three patients and additionally hypernatraemia in two patients treated with 100 mega units of sodium penicillin G for subacute bacterial endocarditis. The hypernatraemia was probably due to the administration of insufficient fluid, while urinary potassium loss was an important factor in producing hypokalaemia and metabolic alkalosis after. Penicillin may promote urinary potassium excretion by acting as a non-reabsorbable anion.Potassium depletion during treatment with massive doses of sodium penicillin G may be prevented by concurrently administering potassium-sparing diuretics or by using the potassium salt of penicillin.     

Subacute bacterial endocarditis; a report on 57 patients treated with massive doses of penicillin

Fifty-seven patients with subacute bacterial endocarditis were treated with doses of penicillin varying from 500,000 to 20,000,000 units per day. Diagnosis was confirmed in some cases by growths on blood culture, in others by postmortem examination. In those cases in which the diagnosis was established by blood culture, the in vitro sensitivity of the organism to penicillin was determined and penicillin then was administered by continuous intramuscular infusion in a dosage calculated to produce blood levels of penicillin four to five times that required for in vitro inhibition. Penicillin was given for a period of 21 days, and blood cultures were made periodically during and after treatment. Of the 57 patients, 38 were cured (66.7 per cent), and 19 died (33.3 per cent). Of the 19 who died, three did so within 48 hours of hospitalization and seven died despite adequate treatment. Of these seven, three died of cerebral emboli, two because of resistance to penicillin and streptomycin, one because of congestive heart failure, and one of undetermined cause. The remaining nine who died were considered to have been inadequately treated in that there was (1) failure to obtain sensitivity, (2) inadequate dossage of penicillin, (3) delay in starting treatment, or (4) failure to recognize mixed infections. There were five patients with repeatedly sterile blood cultures during life. In all of these cases, streptococcus viridans was recovered at postmortem examination. In an attempt to determine how long therapy should justly be withheld in patients with repeatedly sterile blood cultures, 140 cases of subacute bacterial endocarditis in which positive blood cultures had been obtained were reviewed. From the review it was determined that if blood cultures taken during the first two days are reported sterile, the chance of subsequent cultures proving positive is minimal. Therefore, for patients in whom the diagnosis seems otherwise obvious, delaying treatment for more than two days is not justified even though the blood culture be sterile. In cases in which blood cultures are repeatedly sterile, a dosage of 6,000,000 to 10,000,000 units of penicillin daily for 21 days is advisable.High bacterial resistance to penicillin and streptomycin was found in four fatal cases. In one of these, the infecting organism was streptococcus viridans, and in three it was staphylococcus albus. There was one patient with penumococcal meningitis complicated by unrecognized streptococcal viridans bacterial endocarditis.     

SUBACUTE BACTERIAL ENDOCARDITIS—A Report on 57 Patients Treated with Massive Doses of Penicillin

Fifty-seven patients with subacute bacterial endocarditis were treated with doses of penicillin varying from 500,000 to 20,000,000 units per day. Diagnosis was confirmed in some cases by growths on blood culture, in others by postmortem examination. In those cases in which the diagnosis was established by blood culture, the in vitro sensitivity of the organism to penicillin was determined and penicillin then was administered by continuous intramuscular infusion in a dosage calculated to produce blood levels of penicillin four to five times that required for in vitro inhibition. Penicillin was given for a period of 21 days, and blood cultures were made periodically during and after treatment.Of the 57 patients, 38 were cured (66.7 per cent), and 19 died (33.3 per cent).Of the 19 who died, three did so within 48 hours of hospitalization and seven died despite adequate treatment. Of these seven, three died of cerebral emboli, two because of resistance to penicillin and streptomycin, one because of congestive heart failure, and one of undetermined cause. The remaining nine who died were considered to have been inadequately treated in that there was (1) failure to obtain sensitivity, (2) inadequate dossage of penicillin, (3) delay in starting treatment, or (4) failure to recognize mixed infections.There were five patients with repeatedly sterile blood cultures during life. In all of these cases, streptococcus viridans was recovered at postmortem examination. In an attempt to determine how long therapy should justly be withheld in patients with repeatedly sterile blood cultures, 140 cases of subacute bacterial endocarditis in which positive blood cultures had been obtained were reviewed. From the review it was determined that if blood cultures taken during the first two days are reported sterile, the chance of subsequent cultures proving positive is minimal. Therefore, for patients in whom the diagnosis seems otherwise obvious, delaying treatment for more than two days is not justified even though the blood culture be sterile. In cases in which blood cultures are repeatedly sterile, a dosage of 6,000,000 to 10,000,000 units of penicillin daily for 21 days is advisable.High bacterial resistance to penicillin and streptomycin was found in four fatal cases. In one of these, the infecting organism was streptococcus viridans, and in three it was staphylococcus albus. There was one patient with penumococcal meningitis complicated by unrecognized streptococcal viridans bacterial endocarditis.     

Antibiotics and the Oral Streptococci of Man

The effects of 3 antibiotics, phenoxymethylpenicillin, cephalexin and clindamycin on the normal oral streptococcal flora in the region of the gingival crevice were investigated because these organisms are able to cause subacute bacterial endocarditis. Secretion of these antibiotics into the oral cavity was also examined. Penicillin and clindamycin exerted marked effects on the normal oral streptococci, whereas cephalexin did not cause any obvious change in the total flora. Following penicillin therapy, streptococci resistant to 1.5 μg/ml penicillin were observed and these organisms could be detected at least 8 weeks after the last dose of the antibiotic. They probably arose by selection from the mixed flora. Following cephalexin therapy, a much lower proportion of streptococci resistant to 15 μg/ml was found. The proportion of resistant strains fluctuated appreciably, however, probably due to their transient nature. Streptococci resistant to 1 μg/ml clindamycin were not observed in 10 out of 11 treated subjects.
Penicillin and clindamycin could be detected in the pooled saliva and gingival fluid after administering single doses of 500 mg and 300 mg, respectively. The peak levels were obtained between half and 1 h. The concentration of penicillin dropped rapidly within 3 h but clindamycin could be detected at significant levels for at least 6 h. No cephalexin could be detected in the pooled saliva or gingival fluid after a 500 mg dose. The implications of these findings in the prevention of subacute bacterial endocarditis are discussed.     

SURGICAL TREATMENT OF PATENT DUCTUS ARTERIOSUS

Since it would appear that diagnosis of patent ductus arteriosus can be made accurately in a high percentage of cases, and as the surgical treatment of this lesion is highly successful with a low mortality and morbidity rate, operation is advisable for all patients with this lesion except those who are 35 years of age or older and who have no progressive cardiac hypertrophy and no incapacitation due to the fistula. The optimum age for operation is three years. The vast majority of the patients have a ductus that can be divided, and division has advantages over ligation.In cases in which patent ductus arteriosus is complicated by subacute bacterial endocarditis, operation should be done following intensive penicillin therapy.     

Infective endocarditis due to Leptotrichia buccalis: a case report.

A patient with Down''s syndrome presented with infective endocarditis due to Leptotrichia buccalis. The source of the infection was not detected, but the predisposing factor was a complex cardiac malformation. The disease followed a subacute course, had a number of immunologic manifestations and was successfully treated with a 28-day course of penicillin G, given intravenously. L. buccalis has never been reported before as a cause of endocarditis.     

D-alanyl-D-alanine carboxypeptidase in the bacterial form and L-form of Proteus mirabilis.

Membranes of the bacterial form and the stable and unstable L-forms of Proteus mirabilis contain LD and DD-carboxypeptidase. The DD-carboxypeptidase is inhibited non-competitively by penicillin G. The enzyme of the bacterial form is highly penicillin-sensitive (Ki - 4 X 10(-9) M penicillin G). Inhibition is only partly reversible by treatment with penicillinase or by dialysis against buffer. In contrast, the DD-carboxypeptidase of the unstable L-form, grown in the presence of penicillin, is 175-fold less penicillin-sensitive (Ki = 7 X 10(7) M penicillin G). Inhibition is completely reversed by penicillinase or dialysis. After inhibition by penicillin and subsequent reactivation the penicillin sensitivity of the bacterial DD-carboxtpeptidase is similar to the sensitivity of the enzyme of the unstable L-form. The hypothesis is proposed that P. mirabilis contains two DD-carboxypeptidases of different penicillin sensitivity and with different mechanisms of penicillin binding. Peptidoglycan synthesis in the cell walls of the unstable L-form is probably carried out with the help of only one DD-carboxypeptidase, viz. the completely reactivatable enzyme with the lower penicillin sensitivity.     

Substrate specificity of penicillin acylase from Streptomyces lavendulae

The kinetic parameters of several substrates of penicillin acylase from Streptomyces lavendulae have been determined. The enzyme hydrolyses phenoxymethyl penicillin (penicillin V) and other penicillins with aliphatic acyl-chains such as penicillin F, dihydroF, and K. The best substrate was penicillin K (octanoyl penicillin) with a k(cat)/K(m) of 165.3 mM(-1) s(-1). The enzyme hydrolyses also chromogenic substrates as NIPOAB (2-nitro-5-phenoxyacetamido benzoic acid), NIHAB (2-nitro-5-hexanoylamido benzoic acid) or NIOAB (2-nitro-5-octanoylamido benzoic acid), however failed to hydrolyse phenylacetil penicillin (penicillin G) or NIPAB (2-nitro-5-phenylacetamido benzoic acid) and penicillins with polar substituents in the acyl moiety. These results suggest that the structure of the acyl moiety of the substrate is more determinant than the amino moiety for enzyme specificity. The enzyme was inhibited by several organic acids and the extent of inhibition changed with the hydrophobicity of the acid. The best inhibitor was octanoic acid with a K(i) of 0.8 mM. All the results, taking together, point to an active site highly hydrophobic for this penicillin acylase from Streptomyces lavendulae.     

alpha-Aminoadipate pool concentration and penicillin biosynthesis in strains of Penicillium chrysogenum

Intracellular amino acid pools in four Penicillium chrysogenum strains, which differed in their ability to produce penicillin, were determined under conditions supporting growth without penicillin production and under conditions supporting penicillin production. A significant correlation between the rate of penicillin production and the intracellular concentration of alpha-aminoadipate was observed, which was not shown with any other amino acid in the pool. In replacement cultivation, penicillin production was stimulated by alpha-aminoadipate, but not by valine or cysteine. Exogenously added alpha-aminoadipate (2 or 3 mM) maximally stimulated penicillin synthesis in two strains of different productivity. Under these conditions intracellular concentrations of alpha-aminoadipate were comparable in the two strains in spite of the higher rate of penicillin production in the more productive strain. Results suggest that the lower penicillin titre of strain Q 176 is due to at least two factors: (i) the intracellular concentration of alpha-aminoadipate is insufficient to allow saturation of any enzyme which is rate limiting in the conversion of alpha-aminoadipate to penicillin and (ii) the level of an enzyme, which is rate limiting in the conversion of alpha-aminoadipate to penicillin, is lower in Q 176 (relative to strain D6/1014/A). Results suggest that the intracellular concentration of alpha-aminoadipate in strain D6/1014/A is sufficiently high to allow saturation of the rate-limiting penicillin biosynthetic enzyme in that strain. The basis of further correlation of intracellular alpha-aminoadipate concentration and penicillin titre among strains D6/1014/A, P2, and 389/3, the three highest penicillin producers studied here, remains to be established.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of penicillin on the intensity of formation of penicillin-resistant staphylococcal populations in the suppurative foci of patients]

The dynamics of sensitivity to penicillin of staphylococcal populations in purulent inflammatory foci of patients treated and not treated with antibiotics was estimated according to 4 indices. No reliable differences in the dynamics of sensitivity to penicillin were found in 2 groups of the patients, when estimation was performed with respect to the frequency of the penicillin resistant or penicillin sensitive staphylococci and detection of the penicillin resistant staphylococci by direct inoculation of the focal excretion to the medium with penicillin. A reliable increase in the percentage of the penicillin resistant staphylococci in the microbial population was observed only in the patients treated with penicillin.     

In vitro penicillin aminolysis: Application to a radioimmunoassay of trace amounts of penicillin

A specific and sensitive radioimmunoassay of trace amounts of penicillin G in biological fluids is proposed. It is based on the quantitative transformation of penicillin into penicilloyl by rupture of the β-lactam ring of the penicillin molecule, and then the determination of the penicilloyl groups thus formed. Using ?-aminocaproic acid as an acceptor which covalently binds with the penicilloyl groups formed, at alkaline pH, allows a complete and reproducible aminolysis of penicillin. The inhibition of the binding to antipenicilloyl antibodies and the association constant appear to be identical whether penicilloyl groups derive from penicillin or are present under standard penicilloyl ?-aminocaproate form. Besides this application to the radioimmunoassay of penicillin, the study of the in vitro aminolysis of penicillin should permit better understanding of the complex mechanism of the covalent binding of penicilloyl groups to proteins observed in vivo after penicillin therapy, binding which leads to the allergenic metabolite of penicillin.     

Effects of penicillin on procaine-elicited bursts of potential in central neuron of snail, Achatina fulica

Effects of penicillin on changes in procaine-elicited bursts of potential (BoP) were studied in a central neuron (RP4) of snail, Achatina fulica Ferussac. Procaine elicited BoP in the RP4 neuron while penicillin elicited depolarization of the neuron. Penicillin decreased the BoP elicited by procaine in a concentration-dependent manner. The effect of penicillin on the procaine-elicited BoP was not altered in the preparations treated with ascorbate or L-NAME (N-nitro-L-arginine methyl ester). However, the inhibitory effect of penicillin on the procaine-elicited BoP was enhanced with a decrease in extracellular sodium ion. Sodium ion was one of the important ions contributing to the action potential of the neuron. Two-electrode voltage-clamp studies revealed that penicillin decreased the fast sodium inward current of the neuron. It is concluded that penicillin inhibited the BoP elicited by procaine and sodium ion altered the effect of penicillin on procaine-elicited BoP.     

青霉素酶在青霉素菌渣无害化处理中的应用

建立一种快速、有效的方法降解青霉素菌渣中青霉素残留。采用高效液相色谱（HPLC）方法检测湿菌渣,得到其平均青霉素效价残留为2179 U／g,即相对质量分数为1．3mg／g;将青霉素酶以相对于残留青霉素效价比为3：1的比例量混入菌渣中,37℃,1h后可以将残留青霉素完全降解,实现了菌渣的无害化处理,为青霉素菌渣的资源化利用奠定了基础。     

A cellular automata model for simulating fed-batch penicillin fermentation process

A cellular automata model to simulate penicillin fed-batch fermentation process(CAPFM)was established in this study,based on a morphologically structured dynamic penicillin production model,that is in turn based on the growth mechanism of penicillin producing microorganisms and the characteristics of penicillin fed-batch fermentation.CAPFM uses the three-dimensional cellular automata as a growth space,and a Moore-type neighborhood as the cellular neighborhood.The transition roles of CAPFM are designed based on mechanical and structural kinetic models of penicillin batch-fed fermentation processes.Every cell of CAPFM represents a single or specific number of penicillin producing microorganisms,and has various state.The simulation experimental results show that CAPFM replicates the evolutionary behavior of penicillin batch-fed fermentation processes described by the structured penicillin production kinetic model accordingly.     

In vivo protection of penicillin-susceptible Bacteroides melaninogenicus from penicillin by facultative bacteria which produce beta-lactamase

We investigated the possibility that beta-lactamase producing strains of Klebsiella pneumoniae and Staphylococcus aureus can protect organisms of the Bacteroides melaninogenicus group from penicillin. A mixed infection was induced in mice in the form of a subcutaneous abscess involving a penicillin-susceptible encapsulated B. melaninogenicus, and a beta-lactamase producing strain of either K. pneumoniae or S. aureus. The infected animals were treated for 7 days with single or combined antimicrobial therapy. The single agents used were penicillin, clavulanic acid, metronidazole, and gentamicin. The antimicrobial combinations were penicillin and clavulanic acid, penicillin and gentamicin, and metronidazole and gentamicin. Administration of a single agent was effective in treating abscesses caused by susceptible organisms. The only effective therapy for mixed infections was by combination therapy of penicillin and clavulanic acid or metronidazole and gentamicin. This study supports the hypothesis that beta-lactamase producing facultative bacteria may shield their anaerobic counterparts from penicillin therapy, thereby contributing to the persistence of the infection.     

Electroencephalogram and evoked potentials in the primate model of viral encephalitis

Squirrel monkeys with induced canine distemper virus (CDV) encephalitis showed characteristic clinical signs such as seizures or myoclonus, with EEGs showing periodic synchronized discharge (PSD). Histopathologically, there was gliosis and neuronal degeneration diffusely distributed in both the gray and white matters in the subacute phase, the lesions resembling those found in childhood acute viral encephalitis and subacute sclerosing panencephalitis (SSPE). The auditory brain-stem response (ABR) changes were remarkable in the subacute phase, and the recovery of latency was correlated with survival. The visual evoked potential (VEP) abnormalities disappeared in the acute phase and appeared again with delayed latency in the subacute stage. One monkey which did not show clinical signs but had the pathological changes showed the VEP abnormality. These data suggest that the evoked potentials are helpful in judging the prognosis and that this model is useful for the analysis of the pathogenesis of viral encephalitis.     

Assessment of the microbody luminal pH in the filamentous fungus Penicillium chrysogenum

The enzymes of the penicillin biosynthetic pathway in Penicillium chrysogenum are located in different subcellular compartments. Consequently, penicillin pathway precursors and the biologically active penicillins have to cross one or more membranes. The final enzymatic step that is mediated by acyltransferase takes place in a microbody. The pH of the microbody lumen in penicillin producing cells has been determined with fluorescent probes and mutants of the green fluorescent protein and found to be slightly alkaline.     

Improvement of Aspergillus nidulans penicillin production by targeting AcvA to peroxisomes

Aspergillus nidulans is able to synthesize penicillin and serves as a model to study the regulation of its biosynthesis. Only three enzymes are required to form the beta lactam ring tripeptide, which is comprised of l-cysteine, l-valine and l-aminoadipic acid. Whereas two enzymes, AcvA and IpnA localize to the cytoplasm, AatA resides in peroxisomes. Here, we tested a novel strategy to improve penicillin production, namely the change of the residence of the enzymes involved in the biosynthesis. We tested if targeting of AcvA or IpnA (or both) to peroxisomes would increase the penicillin yield. Indeed, AcvA peroxisomal targeting led to a 3.2-fold increase. In contrast, targeting IpnA to peroxisomes caused a complete loss of penicillin production. Overexpression of acvA, ipnA or aatA resulted in 1.4, 2.8 and 3.1-fold more penicillin, respectively in comparison to wildtype. Simultaneous overexpression of all three enzymes resulted even in 6-fold more penicillin. Combination of acvA peroxisomal targeting and overexpression of the gene led to 5-fold increase of the penicillin titer. At last, the number of peroxisomes was increased through overexpression of pexK. A strain with the double number of peroxisomes produced 2.3 times more penicillin. These results show that penicillin production can be triggered at several levels of regulation, one of which is the subcellular localization of the enzymes.     

模拟青霉素分批补料发酵过程的细胞自动机模型

根据青霉素产生菌的生长机理和青霉素分批补料发酵过程的动力学特性,在Paull等建立的形态学结构动力学模型的基础上,建立了模拟青霉素分批补料发酵过程的细胞自动机模型。模型采用三维细胞自动机作为菌体生长空间,采用Moore型邻域作为细胞邻域,其演化规则根据青霉素分批补料发酵过程中菌体生长机理和简化动力学结构模型设计。模型中的每一个细胞既可代表单个产黄青霉菌体细胞,又可代表特定数量的这种菌体细胞,它具有不同的状态。对模型进行的仿真实验结果表明：模型不但能一致地复现形态学结构动力学模型所描述的青霉素分批补料发酵过程的演化特性,而且较形态学结构动力学模型更加直观地刻画了青霉素分批补料发酵过程的演化行为。最后,对所建模型在实际生产过程中的应用问题进行了分析,指出了需要进一步研究的问题。