Penicillinase-resistant Penicillins Research Articles

Relationship Between β-Lactamase Activity and Resistance of Enterobacter to Cephalothin

The relationship between cephalosporin beta-lactamase activity and resistance to cephalothin was investigated in strains of Enterobacter cloacae and E. aerogenes. beta-Lactamase activity was detected in all strains, but a quantitative correlation between amount of beta-lactamase activity and level of resistance to cephalothin was not observed. Permeability barriers to cephalothin were observed and varied from strain to strain. beta-Lactamase activity was increased by growing organisms in the presence of penicillin G. These enzymes hydrolyzed cephalosporins more rapidly than penicillins. Penicillinase-resistant penicillins, especially those of the isoxazolyl series, effectively inhibited Enterobacter beta-lactamase. A synergistic antibacterial effect was observed when organisms were exposed to cephalothin and oxacillin in combination, and the resistance of even very small inocula to cephalothin was reduced by addition of oxacillin. Oxacillin probably exerts its effect by inhibiting beta-lactamase at an intracellular site. Intracellular beta-lactamase may make an important contribution to the resistance of even small inocula of gram-negative bacilli to cephalosporin and penicillin antibiotics. Although beta-lactamase plays a significant role in the resistance of Enterobacter to cephalothin, other factors, such as permeability barriers, also participate in determining the level of resistance.

Resistance of Escherichia coli and Salmonella typhimurium to carbenicillin.

SUMMARY Carbenicillin, a 9-alpha carboxybenzyl penicillin, is bactericidal only for Escherichia coli strains which are resistant to less than 125 μg./ml. of ampicillin. All E. coli and Salmonella typhimurium strains in which penicillinase is a surface enzyme are resistant to carbenicillin. E. coli and S. typhimurium strains in which production of beta-lactamase is episomally mediated are resistant to both ampicillin and carbenicillin. A non-hydrolyzable penicillin (methicillin or dicloxacillin) does not allow carbenicillin to exert its antibacterial effect against resistant strains of E. coli, Pseudomonas, Klebsiella or Enterobacter. Carbenicillin shows no synergy with penicillinase-resistant penicillins.

Effect of beta-lactamase location in Escherichia coli on penicillin synergy.

Resistance to ampicillin in Escherichia coli is due generally to the presence of a beta-lactamase (penicillinase). Resistant strains have been found to fall into two groups: those with high-level resistance (1,000 mug/ml or greater) and those with low-level resistance (8 to 250 mug/ml). Most of the high-level resistant organisms posses beta-lactamases whose synthesis is episomally mediated. These strains release penicillinase from the cell when they are subjected to osmotic shock. Low-level resistant strains do not release the enzyme with osmotic shock. High-level resistant strains are not susceptible to the synergistic action of a penicillinase-resistant penicillin with ampicillin. Seventy eight per cent of low-level resistant strains are susceptible to the synergistic action of ampicillin and oxacillin. The two types of beta-lactamases are similar in regard to most properties; both enzymes are subject to competitive inhibition by penicillinase-resistant penicillins. The difference in location in the cell might explain why only some strains of E. coli are susceptible to the synergistic action of penicillin combinations.

Effect of β-Lactamase Location in Escherichia coli on Penicillin Synergy

Resistance to ampicillin in Escherichia coli is due generally to the presence of a beta-lactamase (penicillinase). Resistant strains have been found to fall into two groups: those with high-level resistance (1,000 mug/ml or greater) and those with low-level resistance (8 to 250 mug/ml). Most of the high-level resistant organisms posses beta-lactamases whose synthesis is episomally mediated. These strains release penicillinase from the cell when they are subjected to osmotic shock. Low-level resistant strains do not release the enzyme with osmotic shock. High-level resistant strains are not susceptible to the synergistic action of a penicillinase-resistant penicillin with ampicillin. Seventy eight per cent of low-level resistant strains are susceptible to the synergistic action of ampicillin and oxacillin. The two types of beta-lactamases are similar in regard to most properties; both enzymes are subject to competitive inhibition by penicillinase-resistant penicillins. The difference in location in the cell might explain why only some strains of E. coli are susceptible to the synergistic action of penicillin combinations.

GROWING CLINICAL SIGNIFICANCE OF METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS

Serious infections caused by methicillin-resistant Staphylococcus aureushave been on the increase throughout the Western world. A clinical and bacteriological study of 139 infections in Zürich, Switzerland, documented most as nosocomial problems. Patients in hospital for more than one week with a chronic, debilitating disease were a high risk. Most patients who got pneumonia and/or bacteræmia died, despite intensive therapy with penicillinase-resistant penicillins or cephalosporins. The resistance of the Staph. aureus strains was due to a peculiar " tolerance " to β-lactam antibiotics. Most strains had multiple antibiotic resistance and belonged to staphylococcal phage-group III. All 66 strains tested, representing several countries, were inhibited by vancomycin, and only 40% of the strains were inhibited by other commonly used antibiotics.

Bacteria in a hospital nursery: laboratory and clinical studies.

SummaryTwo hundred and twenty-two infants and fifty-one staff were examined for carriage ofStaphylococcus pyogenesand Gram-negative bacilli, and the presence of these bacteria in the ward environment was also investigated. Staphylococci were phage-typed and tested for sensitivity to antibiotics. Assessment of clinical infection caused by these bacteria was made.Infant carriage ofStaphylococcus pyogeneswas maximal on the sixth day, 73·1 % of umbilical swabs yielding significant growth. Carriage of Gram-negative bacilli was maximal on the fifth day, 31·7% of umbilical swabs being positive. Where special nursing was enforced, i.e. premature baby unit, isolation of Gram-negative bacilli was very infrequent.The low nasal carriage of staphylococci seen in infants and nursing staff is attributed to traces of penicillinase-resistant penicillins in the ward air.Staphylococcus pyogeneswas recovered from 23 % of ward surfaces, and constituted 0·7% of the air-borne flora. In contrast, Gram-negative bacilli were recovered from 4·7 % of surfaces, and composed only 0·15% of the air-borne flora.Phage group I constituted 73·0, 44·9 and 41·2% of strains from infants, staff and ward environment respectively.Antibiograms were grouped into three categories, A, B and C. Category A (sensitive to chloramphenicol, erythromycin and methicillin but penicillin-resistant) composed 79·0% of infants' strains, being found mostly in group I, but was rare among staff strains.Of 54 specimens taken from 40 infants showing evidence of infection,Staphylococcus pyogeneswas isolated from 16, of which 14 were category A. Gram-negative bacilli were isolated 7 times. Only 21 infants required antibiotic therapy (9·3%) and none were infected with Gram-negative bacilli—this contrasts with the frequency of these bacilli in nursery infection today.Ward air is considered to be the maindepotofStaphylococcus pyogenes. Infant ‘dispersers’ are probably the principalsourceof the air-borne staphylococci. Infants and staff abstract from the air those staphylococci which become their colonizing strains. No transfer is thought to occur from the staff to the infants. Transmission of Gram-negative bacilli is similar in that the infants are the principal source and the air the maindepotof these bacteria. Nasal colonization by Gram-negative bacilli is low, this is possibly due to poor colonizing properties. Infant umbilical carriage almost certainly results from endogenous faecal spread.We are grateful to Dr J. C. Gould, Director, Central Microbiological Laboratories, Edinburgh, for his continued interest and advice, and to Mr J. C. Ferguson and Mrs M. M. Winton for skilled technical assistance. This study would not have been completed without the co-operation of Sisters McCartney and Struthers and their nursing staff.

Comparative inhibition of methicillin-resistant strains of Staphylococcus aureus by lysostaphin and other antibiotics.

Sixteen methicillin-resistant strains of Staphylococcus aureus obtained from Europe were found to be sensitive to the lytic activity of lysotaphin. With only minor exceptions, the strains were found to be sensitive to novobiocin, erythromycin, fusidic acid, and lincomycin, and slightly less sensitive to vancomycin and chloramphenicol. All strains were resistant to tetracycline, penicillinase-sensitive penicillins (benzylpenicillin, ampicillin, and propicillin), penicillinase-resistant penicillins (methicillin, nafcillin, ancillin, oxacillin, cloxacillin, and dicloxacillin), and two cephalosporin antibiotics (cephalothin and cephaloridine).

Comparative Inhibition of Methicillin-resistant Strains of Staphylococcus aureus by Lysostaphin and Otner Antibiotics

Sixteen methicillin-resistant strains of Staphylococcus aureus obtained from Europe were found to be sensitive to the lytic activity of lysotaphin. With only minor exceptions, the strains were found to be sensitive to novobiocin, erythromycin, fusidic acid, and lincomycin, and slightly less sensitive to vancomycin and chloramphenicol. All strains were resistant to tetracycline, penicillinase-sensitive penicillins (benzylpenicillin, ampicillin, and propicillin), penicillinase-resistant penicillins (methicillin, nafcillin, ancillin, oxacillin, cloxacillin, and dicloxacillin), and two cephalosporin antibiotics (cephalothin and cephaloridine).

Clinical evaluation of cephaloridine

Cephaloridine was used to treat 136 bacterial infections in 122 hospitalized patients. Its antibacterial and clinical effectiveness against serious staphylococcal infections compared favorably with that of cephalothin sodium and of penicillinase-resistant penicillins in similar cases. Cephaloridine was highly effective clinically and in eradicating the causative organisms in infections due to pneumococci, streptococci, Escherichia coli , and Proteus mirabilis ; but its effectiveness against klebsielleae was variable. Superinfection with resistant gram-negative bacilli and serious noninfectious conditions were the major causes of most of the deaths. Injections of cephaloridine were remarkably well tolerated. Cross sensitization with penicillin was not encountered. Cephaloridine may have caused or contributed to acute renal failure and to an unusual coagulopathy, each observed in two patients. Cephaloridine is a highly effective and useful antibacterial agent when selected and used with due regard to its activity and potential nephrotoxicity.

Clinical Evaluation of Cephaloridine

Cephaloridine was used to treat 136 bacterial infections in 122 hospitalized patients. Its antibacterial and clinical effectiveness against serious staphylococcal infections compared favorably with that of cephalothin sodium and of penicillinase-resistant penicillins in similar cases. Cephaloridine was highly effective clinically and in eradicating the causative organisms in infections due to pneumococci, streptococci,<b>Escherichia coli</b>, and<b>Proteus mirabilis</b>; but its effectiveness against klebsielleae was variable. Superinfection with resistant gram-negative bacilli and serious noninfectious conditions were the major causes of most of the deaths. Injections of cephaloridine were remarkably well tolerated. Cross sensitization with penicillin was not encountered. Cephaloridine may have caused or contributed to acute renal failure and to an unusual coagulopathy, each observed in two patients. Cephaloridine is a highly effective and useful antibacterial agent when selected and used with due regard to its activity and potential nephrotoxicity.

Use of penicillinase-resistant penicillins to increase the susceptibility of gram-negative bacteria to antibiotics.

Article1 October 1967Use of Penicillinase-Resistant Penicillins to Increase the Susceptibility of Gram-Negative Bacteria to AntibioticsW. EDMUND FARRAR JR., M.D., F.A.C.P., NOEL M. O'DELL, B.S., JANE M. KRAUSE, A.B.W. EDMUND FARRAR JR., M.D., F.A.C.P.Search for more papers by this author, NOEL M. O'DELL, B.S.Search for more papers by this author, JANE M. KRAUSE, A.B.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-67-4-733 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptMany gram-negative bacteria elaborate beta-lactamases capable of inactivating penicillin and related antibiotics (1-4). The presence of such enzymes appears to be an important factor in the resistance of these bacteria to the penicillins and cephalosporins (5-8). On the other hand, certain semisynthetic penicillins, such as methicillin, are only slowly hydrolyzed by the penicillinases of gram-negative bacteria but may exhibit high affinities for these enzymes. The semisynthetic penicillins thus may form relatively stable enzyme-substrate complexes and are capable of competitively inhibiting the activity of betalactamases (9-13) even though they are relatively ineffective as antibacterial agents against gram-negative bacilli. This type of...

The treatment of infants with oxacillin sodium.

OXACILLIN SODIUM has been demonstrated to effectively inhibit penicillin-sensitive and resistant staphylococci in vitro at concentrations readily obtainable in vivo 1 and together with other similar penicillinase-resistant penicillins, is considered a drug of choice in staphylococcal infection. 2 As young infants are particularly susceptible to staphylococcal infection, information concerning the effectiveness of oxacillin sodium in treating such infections and the pharmacology of oxacillin sodium in such patients is needed. The study reported herein provides information regarding the serum concentrations of oxacillin sodium achieved with varying dosage schedules in young infants, the effectiveness of the drug in the treatment of severe staphylococcal infection in this age group, and the toxicity of the drug in newborns and in older infants. Material and Methods All patients less than 2 years of age admitted to the service wards or nurseries of the Department of Pediatrics, Mercy Hospital during the period July 1, 1963, to

The effect of the penicillinase-resistant penicillins and other chemotherapeutic substances on the penicillinase of the R1Rv strain of Mycobacterium tuberculosis.

The effect of the penicillinase-resistant penicillins and other chemotherapeutic substances on the penicillinase of the R1Rv strain of Mycobacterium tuberculosis.

Cloxacillin in streptococcal pharyngitis. Primary treatment and retreatment.

SODIUM CLOXACILLIN MONOHYDRATE, one of the new semi-synthetic penicillinase-resistant penicillins, was introduced in England in 1962 1-3 and in the United States in 1965. When tested in vitro it has been found active against both penicillinase-producing and nonproducing staphylococci, β-hemolytic streptococci, and pneumococci. It is highly bound by serum proteins and is relatively resistant to gastric acid. This report is an evaluation of the effectiveness of cloxacillin in group A streptococcal pharyngitis studied in two series, the first employing cloxacillin in primary treatment and the second in retreatment of streptococcal relapses following an original course of phenoxymethyl penicillin (penicillin V). Primary Treatment Materials and Methods. —Twenty-seven consecutive patients with acute pharyngitis associated with group A streptococci from the private practice of one of the authors (M.S.) were studied between September 1964 and January 1965. At initial visit the throats of all patients with acute pharyngitis suggestive of streptococcal origin were

THE TREATMENT OF STAPHYLOCOCCAL INFECTION WITH NAFCILLIN WITH A DISCUSSION OF STAPHYLOCOCCAL NEPHRITIS.

Excerpt Nafcillin (UNIPEN®) is one of the new penicillinase-resistant semisynthetic penicillins. It can be administered orally or parenterally. In vitro studies have shown it to have high activity ...

Clinical Studies With Cloxacillin

A new semisynthetic penicillinase-resistant penicillin, cloxacillin, was used in treatment of 100 hospitalized patients with severe infections. Twenty-three of 25 patients with staphylococcal infections, 30 of 37 with pneumococcal infections, all 13 patients with streptococcal infection, and 17 of 25 with infection due to a variety of organisms responded favorably. At the present time, the drug is available only in oral-dosage form, limiting its use in severely ill patients. A toxic effect on the gastrointestinal tract was not observed; rashes developed in two patients. Serious superinfections occurred in at least three patients with pneumococcal pneumonia. Cloxacillin compares favorably with other semisynthetic penicillinaseresistant penicillins now available in the oral-dosage form.

Clinical Evaluation of Nafcillin in Patients with Severe Staphylococcal Disease

NAFCILLIN, 6-(2-ethoxy-1-naphthamido) penicillin,1 is one of the semisynthetic, penicillinase-resistant penicillins that has been introduced since the isolation of 6-aminopenicillanic acid.2 Each of the newer penicillins in this series — namely, oxacillin, diphenicillin and nafcillin — has several readily apparent advantages over methicillin,3 the first one to become available for clinical use. Most important of these advantages are acid stability, permitting absorption of the drug when it is administered orally, and greater in vitro activity against both penicillinase-producing and nonpenicillinase-producing staphylococci. In addition, some data suggest that nafcillin may have greater therapeutic activity than methicillin or oxacillin in experimental infections in . . .

PENICILLINASE-RESISTANT PENICILLINS IN THE TREATMENT OF SURGICAL STAPHYLOCOCCAL INFECTIONS.

although it has the advantage of being given orally, seems less effective, and ampicillin similarly. Comparative statistical evidence of the value of the various penicillins and of the antibiotics is not available, and would be difficult to obtain, but I have no personal doubt that at present in the acute infection methicillin and chloramphenical are the two most effective drugs. A major anxiety is the development of bacterial resistance in the child with repeated or persistent infection. This develops sooner or later in all these children and makes the continued prophylactic use of antibiotics unwise. An antibiotic free from this drawback would be of the greatest value: in about 12 children with cystic fibrosis treated for up to one year with daily fucidin I have as yet had no case of drug resistance. But this may in any case not develop with any drug given prophyllactically for a year or more. For the pseudomonas there appears to be no 'answer at present, whether the antibiotic is given by mouth, injection or by aerosol.

HOSPITAL-ACQUIRED INFECTIONS AND ANTIBIOTIC USAGE IN THE BOSTON CITY HOSPITAL--JANUARY, 1964.

INFECTION occurring during hospitalization is a major clinical and epidemiologic problem. Previous studies1 2 3 4 have focused primarily on hospital-acquired staphylococcal infections. Because of an impression that the frequency of such infections may have decreased and those caused by gram-negative bacilli correspondingly increased since the introduction of the penicillinase-resistant penicillins, a simple spot survey of clinically apparent infection acquired after admission to the Boston City Hospital was undertaken.MethodAll patients on the wards of the Boston City Hospital were seen by one or another of us during the week of January 21–27, 1964. Patients were considered to have hospital-acquired infection if . . .

SODIUM OXACILLIN TREATMENT OF PRIMARY STAPHYLOCOCCAL PYODERMAS. A DOUBLE-BLIND CONTROLLED STUDY.

Antibiotics are frequently employed in the therapy of staphylococcal pyodermas, yet evidence that the lesions are benefited has never been confirmed by controlled studies. Comparison of oral sodium oxacillin and placebo therapy for staphylococcal pyoderma was made in 41 patients, by means of a random doubleblind technique. Routine therapy, including moist heat, incision, and drainage, was employed in every case. In an evaluation period of seven days, all patients receiving sodium oxacillin were significantly improved; about two thirds of the patients showed a satisfactory response while on placebo therapy. Fewer new lesions developed during the regimen of sodium oxacillin. The high incidence (33%) of penicillin-resistant staphylococcal infections encountered in this out-patient study points up the value of penicillinase-resistant penicillin when antibiotics are used.