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Biomedical subjects

R C Moellering

Publications and source records attributed to R C Moellering.

At least 127 records · Page 7Linked to original sources
PubMed1985

In vitro activity and mechanism of action of A21978C1, a novel cyclic lipopeptide antibiotic.

The in vitro activity of A21978C1, a novel cyclic polypeptide antibiotic, was compared with those of vancomycin, teichomycin, and several beta-lactam antibiotics against gram-positive bacteria. The new drug was at least as active as vancomycin against all species of streptococci and staphylococci tested, including methicillin-resistant Staphylococcus aureus and penicillin-resistant pneumococci. Activity of the drug was found to be strongly correlated with the calcium concentration in test media. Against enterococci, A21978C1 was bactericidal at concentrations near the MIC (MIC for 100% of the strains, 2 micrograms/ml), but combining that drug with gentamicin resulted in bactericidal synergism by time-kill methods. Studies were undertaken to examine the mechanism of action of the drug. A21978C1 did not interact with penicillin-binding proteins of bacterial cell membranes. No direct effect of the drug on the synthesis of DNA, RNA, or protein by a susceptible strain of Streptococcus faecalis could be demonstrated. However, A21978C1 inhibited peptidoglycan synthesis in early-log-phase cultures of both Streptococcus faecalis and Staphylococcus aureus.

Anti-Bacterial Agents↗
PubMed1985

Comparative in vitro activities of cefpiramide and apalcillin individually and in combination.

The in vitro activities of cefpiramide and apalcillin were compared with those of other third-generation cephalosporins and extended-spectrum penicillins against over 1,000 clinical bacterial isolates. The activity of cefpiramide against Pseudomonas aeruginosa was comparable to those of piperacillin and cefoperazone, inhibiting 90% of strains at concentrations less than or equal to 16.0 micrograms/ml. This drug was also active against a broad range of gram-negative organisms but was generally less active than many of the other cephalosporins tested against members of the family Enterobacteriaceae. The activity of cefpiramide against gram-positive organisms was comparable to that of cefoperazone. Apalcillin, along with ceftazidime, was the most active agent tested against P. aeruginosa and Acinetobacter calcoaceticus subsp. anitratus, inhibiting 90% of these strains at concentrations less than or equal to 8 micrograms/ml. Against other gram-negative and gram-positive organisms, its activity was similar to that of piperacillin. The activities of both cefpiramide and apalcillin were significantly reduced by the presence of several plasmid-mediated beta-lactamases in a series of otherwise isogenic strains of P. aeruginosa in comparison with their activities against a parent strain which lacks these enzymes. Many strains of Enterobacter cloacae were synergistically inhibited by the combination of gentamicin with either cefpiramide (5 of 10 strains) or apalcillin (6 of 10 strains). Most strains of P. aeruginosa were synergistically inhibited by the combination of gentamicin with either cefpiramide (8 of 10 strains) or apalcillin (10 of 10 strains). However, cefoxitin antagonized the activity of both cefpiramide and apalcillin against most of these same strains.

Ampicillin↗
PubMed1985

Antagonistic effect of penicillin-amikacin combinations against enterococci.

Amikacin has been shown to antagonize the bactericidal effect of penicillin against strains of Streptococcus faecalis which produce aminoglycoside 3'-phosphotransferase. The mechanism by which this phenomenon occurs was studied with an enzyme-producing strain (8436) and an enzyme-negative strain (8436c) derived by curing the former with novobiocin. Combinations of amikacin with beta-lactam antibiotics were antagonistic against strain 8436 but synergistic against strain 8436c. Against strain 8436 penicillin-amikacin combinations resulted in levels of killing comparable to those seen with high concentrations of penicillin (500 micrograms/ml), which were less bactericidal than lower concentrations of penicillin. No antagonism was observed between amikacin and non-beta-lactam cell wall-active drugs or between penicillin and kanamycin or neomycin, both of which are substrates for the enzyme. At concentrations near the MIC, amikacin was bactericidal against strain 8436c but bacteriostatic against strain 8436 (MIC, 250 micrograms/ml; MBC, 2,000 micrograms/ml). Neither penicillin nor phosphorylated amikacin affected the inhibition of ribosomal protein synthesis by amikacin in a cell-free system. Although antagonism of killing by amikacin in enzyme-positive strains was specific for combinations which included beta-lactam antibiotics, amikacin did not influence the binding of [3H]penicillin to penicillin-binding proteins in isolated bacterial cell membranes or in intact cells and did not detectably affect the autolytic system of cells exposed to penicillin. Antagonism of beta-lactam activity by a bacteriostatic effect of amikacin against the enzyme-producing strain is the most likely explanation for this phenomenon.

Amikacin↗
PubMed1985

In vitro activities of the quinolone antimicrobial agents A-56619 and A-56620.

The in vitro activities of two new quinolone antimicrobial agents, A-56619 and A-56620, were compared with those of norfloxacin, ciprofloxacin, and other antimicrobial agents. The activity of A-56620 was comparable to that of ciprofloxacin against Escherichia coli, Enterobacter cloacae, and Aeromonas hydrophila (MICs for 90% of the strains were less than or equal to 0.06 micrograms/ml); Acinetobacter anitratus and Staphylococcus aureus (MIC for 90% of the strains was 0.5 micrograms/ml); and most streptococci. Against other gram-negative strains, A-56620 demonstrated activity comparable to that of norfloxacin, but the new drug was two to eight times more active than norfloxacin against gram-positive isolates. A-56620 was more active than A-56619 against most gram-negative organisms tested. Of the members of the family Enterobacteriaceae examined, 88% were inhibited by A-56619 and 99% by A-56620 at concentrations of less than or equal to 1.0 microgram/ml. By time-kill methods, the new quinolones were bactericidal against gram-negative bacilli during the first 6 h of incubation, but against S. aureus and enterococci the drugs were primarily bacteriostatic during this period. The frequency of spontaneous resistance to 10 micrograms of these drugs per ml was less than 10(-8) for all species tested except E. cloacae, but by serial passage through incremental concentrations of the antimicrobial agents, colonies many-fold more resistant than the initial isolate could be selected. However, resistance to concentrations of the drug greater than 100 micrograms/ml remained stable after passage on antibiotic-free media in only 1 of 35 strains tested.

Anti-Bacterial Agents↗
PubMed1984

Pharmacokinetics of vancomycin.

Vancomycin is poorly absorbed when administered by mouth and, for systemic infections, must be given intravenously. The pharmacokinetics of vancomycin have been well defined in a number of recent studies in man. Since the drug is excreted primarily via the kidneys, dosage modification is imperative in patients with impaired renal function. With the possible exception of aqueous humour and cerebrospinal fluid, vancomycin penetrates well into most body fluids. It appears that excessively high serum concentrations of vancomycin may be associated with ototoxicity. It has not been possible to relate the development of nephrotoxicity to determined previously serum concentrations of vancomycin.

Adult↗
PubMed1984

In vitro activity of ciprofloxacin, a new carboxyquinoline antimicrobial agent.

The in vitro activity of ciprofloxacin (Bay o 9867), a new carboxyquinoline antimicrobial agent, was compared with those of norfloxacin, nalidixic acid, and several other oral and parenteral antimicrobial agents. Ciprofloxacin was substantially more active than nalidixic acid or cinoxacin against all gram-negative bacteria tested. Virtually all strains of Enterobacteriaceae were inhibited by the new drug at concentrations of less than or equal to 0.125 micrograms/ml. Ciprofloxacin was more active than norfloxacin against Klebsiella sp., Enterobacter sp., and Serratia marcescens, and it was the most active agent against Pseudomonas aeruginosa (MIC90, 0.5 micrograms/ml). The new drug also demonstrated significant activity against gram-positive cocci, inhibiting all strains of staphylococci at concentrations of less than or equal to 1.0 microgram/ml. Ciprofloxacin was bactericidal at concentrations near the MIC against most isolates tested. Although stepwise increases in resistance were seen with Escherichia coli and P. aeruginosa during serial passage on plates containing incremental concentrations of the drug, significant resistance did not emerge during incubation of strains in broth containing concentrations of ciprofloxacin above the MBC.

Anti-Bacterial Agents↗
PubMed1984

Ribosomal resistance of clinical enterococcal to streptomycin isolates.

The mechanism of high-level resistance to streptomycin was studied in 12 clinical isolates of Streptococcus faecalis. Six strains produced streptomycin-modifying enzymes. Each of three enzyme-negative strains tested demonstrated ribosomal resistance to streptomycin. Lack of ribosomal susceptibility is a significant cause of high-level streptomycin resistance among clinical enterococcal isolates.

Drug Resistance, Microbial↗
PubMed1984

In vitro activity of U-63196E, a new cephalosporin, against clinical bacterial isolates.

The in vitro activity of U-63196E, a new cephalosporin, was compared with those of other extended-spectrum cephalosporins and penicillins against clinical bacterial isolates. Against Pseudomonas aeruginosa, the activity of U-63196E was comparable to those of cefoperazone and piperacillin, each of which inhibited 90% of strains at concentrations of less than or equal to 16 micrograms/ml. The new drug also demonstrated activity against a variety of other bacterial species, but it was generally less active than cefotaxime, moxalactam, and cefoperazone against members of the family Enterobacteriaceae and staphylococci. The presence of any 1 of 10 plasmid-mediated beta-lactamases in a series of otherwise isogenic laboratory strains of P. aeruginosa resulted in a significant reduction in the activity of U-63196E in comparison with its activity against the parent strain, which lacks these enzymes. Combinations of U-63196E with tobramycin demonstrated bacteriostatic synergism against 11 of 20 clinical isolates of P. aeruginosa.

Anti-Bacterial Agents↗
PubMed1984

Activity of cefotaxime against enterococci.

The third-generation cephalosporins as a group are characterized by spectra of activity that are the broadest of the currently available antibiotics (Farber and Moellering, 1982). These agents provide excellent coverage of infections due to Enterobacteriaceae. They also exhibit good (but variable) activity against a number of "nonfermentors" such as Pseudomonas aeruginosa, and many of them are likewise active against anaerobes, including Bacteroides fragilis (Farber and Moellering, 1982). As a class, the third generation cephalosporins are less active against gram-positive organisms, but in spite of this they have been clinically effective against infections due to S. aureus and many other gram-positive cocci (Saito, 1982). Enterococci, however, have proven to be a difficult organism for the third-generation cephalosporins. None of the presently available compounds exhibits very good activity against these organisms in vitro (Fass, 1983). Given this fact and the broad spectrum of activity of these compounds against other organisms, there is a significant potential for enterococcal superinfection in patients treated with the third-generation cephalosporins. Indeed, serious enterococcal infection has clearly been documented in patients treated with some third-generation cephalosporins (Moellering, 1982; Yu, 1981). Although none of the presently available third-generation cephalosporins exhibits therapeutically useful activity against enterococci, currently available data suggest that there may be differences among these compounds in their ability to cause (or prevent) this complication. For instance, there are more published reports of enterococcal superinfection in patients treated with moxalactam than in patients receiving the other third-generation cephalosporins.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood↗
PubMed1984

Intra-abdominal Citrobacter infections: association with biliary or upper gastrointestinal source.

The clinical records of 46 patients with intra-abdominal and/or bacteremic infections caused by Citrobacter organisms were reviewed to determine whether the isolation of Citrobacter organisms from these sites could be used to determine its portal of entry. The isolation of Citrobacter organisms from intra-abdominal or pleural fluid cultures was associated with a biliary tract or upper gastrointestinal source in 36 of 41 patients. The biliary tract or small bowel was likewise the portal of entry for 8 to 13 patients with Citrobacter septicemia. Thus, the isolation of these organisms from the blood, pleural space, or abdominal cavity strongly suggests that the upper gastrointestinal (or biliary) tract is the site of significant pathologic disease. Of the antibiotics tested, moxalactam, cefotaxime, and amikacin were most effective against Citrobacter.

Adolescent↗
PubMed1983

Rationale for use of antimicrobial combinations.

In most cases antimicrobial combinations are employed to broaden the spectrum of coverage. This clinical application is likely to be successful as long as the combinations are not antagonistic. Most examples of antibiotic antagonism are those in which a bacteriostatic agent renders a bactericidal agent "static." Another type of antagonism occurs when cefoxitin (which has a propensity to induce beta-lactamase production) is combined with another beta-lactam antibiotic. Combination drug therapy prevents emergence of resistant strains in mycobacterial infections and in infections due to methicillin-resistant staphylococci and certain other resistant organisms. Synergistic combinations should allow the use of lower concentrations of drugs in combination and thus diminish the incidence of dose-related antibiotic toxicity, but the concept has met with only limited success so far. Three types of antimicrobial combination or interaction result in enhanced (synergistic) antimicrobial activity. These types include combinations of agents that inhibit bacterial cell wall synthesis with aminoglycosidic aminocyclitols, the use of beta-lactamase inhibitors in combination with beta-lactam antibiotics, and the administration of agents that act on sequential steps in one of the bacterial metabolic or synthetic pathways. Combinations of two beta-lactam antibiotics that bind to complementary penicillin-binding proteins may represent an analogous situation. Amdinocillin binds specifically to penicillin-binding protein 2, and in vitro studies have clearly demonstrated synergism when amdinocillin is combined with other penicillins and cephalosporins that have higher affinity for other penicillin-binding proteins.

Anti-Bacterial Agents↗
PubMed1983

Studies on the mechanism of intrinsic resistance to beta-lactam antibiotics in group D streptococci.

Six penicillin-binding proteins (PBPs) were detected in clinical isolates of each one of three group D streptococci: Streptococcus bovis, S. faecalis and S. faecium. When examined in whole organisms, the PBPs of S. faecium, the most penicillin-resistant species of group D streptococci, generally had lower affinities for the antibiotic than those of S. faecalis (intermediate penicillin resistance), which in turn were of lower affinity than those of S. bovis (penicillin-sensitive). On the other hand, no quantitative correlation could be established between the binding of penicillin to any one PBP or group of PBPs, and the penicillin MIC value for the corresponding micro-organism. Examination of the amounts of antibiotic bound and the rates of binding to PBPs of equal numbers of protoplasts and whole bacteria of S. faecalis and S. faecium, indicated that there was no permeability barrier to benzylpenicillin in the cell walls of these species. The lower antibacterial effectiveness of cephalothin compared with ampicillin in group D streptococci was paralleled by the higher concentrations of cephalothin needed in competition assays to inhibit the lower molecular size PBPs of these bacteria.

Ampicillin↗
PubMed1983

Retrospective study of the toxicity of preparations of vancomycin from 1974 to 1981.

A retrospective chart review of 98 patients treated with 100 courses of intravenous vancomycin was undertaken to better define its toxicity. Most of the patients carried diagnoses of Staphylococcus aureus or Staphylococcus epidermidis infection. Auditory toxicity was not seen, and fever and rash occurred in only 1 to 3% of the subjects. Phlebitis was noted in 13% of the cases and required discontinuation of therapy in 2%. Therapy was complicated by neutropenia (polymorphonuclear leukocyte count, less than or equal to 1,000 cells per cm3) in 2% of the patients but was rapidly reversible. Nephrotoxicity was uncommon (5%) and reversible in subjects receiving vancomycin alone, even when the therapy was continued. However, 35% of the patients receiving vancomycin with an aminoglycoside developed significant elevations in serum creatinine. Although this high incidence may have been due to the patient population selected or to the aminoglycoside therapy alone, the possibility of additive toxicity between vancomycin and the aminoglycosides should be considered.

Adolescent↗
PubMed1983

Multiply resistant viridans streptococci: susceptibility to beta-lactam antibiotics and comparison of penicillin-binding protein patterns.

A unique group of viridans streptococci has been found in South Africa. These organisms were isolated in close temporal and physical proximity to the isolation of penicillin-resistant pneumococci. The strains were resistant to penicillin, oxacillin, the cephalosporins (all generations), piperacillin, azlocillin, and mezlocillin but were susceptible to vancomycin. Penicillin-binding proteins of two penicillin-resistant South African strains of Streptococcus mitis differed markedly from those of two penicillin-susceptible strains but were identical to those seen in a penicillin-resistant strain isolated in Boston. Although both susceptible strains were identified as S. mitis with identical biochemical profiles, their penicillin-binding protein patterns differed from each other. This finding may have significance with regard to the need for additional taxonomic classification of the viridans streptococci.

Anti-Bacterial Agents↗
PubMed1983

Resistance to penicillin-streptomycin synergy among clinical isolates of viridans streptococci.

Viridans streptococci are thought to be highly susceptible to penicillin and streptomycin. We recently encountered a unique group of 15 isolates from South Africa epidemiologically related to the isolation of penicillin-resistant pneumococci. These organisms were highly resistant to penicillin (PCN) (minimal inhibitory concentration, 1 to 32 micrograms/ml) and streptomycin (SM) (minimal inhibitory concentration, greater than or equal to 2,000 micrograms/ml). Two additional organisms with high-level streptomycin resistance were identified when 168 clinical isolates from Boston were screened. Time-kill studies with four organisms resistant to high levels of SM demonstrated lack of synergy between PCN and SM but marked synergy between PCN and gentamicin. Adenylylating, acetylating, and phosphorylating activity could not be detected in three organisms studied, and novobiocin failed to cure the SM resistance. Protein synthesis by ribosomes isolated from these organisms was dramatically reduced in the presence of gentamicin but was relatively resistant to inhibition by SM.

Bacterial Proteins↗
PubMed1983

Vancomycin prophylaxis in cardiac operations: determination of an optimal dosage regimen.

Vancomycin is thought to be an acceptable alternative prophylactic antibiotic to the cephalosporins in penicillin allergic patients undergoing cardiopulmonary bypass. We studied the pharmacokinetics of vancomycin in 10 patients undergoing cardiopulmonary bypass. Our results suggest that the commonly used 500 mg dose (7 mg/kg) of vancomycin given preoperatively may provide serum concentrations during cardiopulmonary bypass which are not bactericidal for many S. epidermidis strains. Thus we believe that a higher initial dose, at least 15 mg/kg, should be given.

Cardiopulmonary Bypass↗
PubMed1982

Principles of antibiotic therapy.

Many host factors influence both the presentation and response to therapy of clinical infections. Since the selection of an appropriate antibiotic depends significantly upon results of in vitro susceptibility testing, great care should be taken to obtain suitable specimens for culture and susceptibility studies. The likelihood that antibiotic therapy will be successful depends upon whether the drug will reach the infected site at the desired concentration and for an optimal duration of time. Local factors such as pH, oxygen tension, and the presence of inactivating substances may affect antibiotic activity. At present, many of our recommendations for dose, dosage intervals, and duration of therapy are largely empiric. Enhanced understanding of the pharmacokinetics of antimicrobial agents should provide the basis for more rational therapy in the future. The remainder of this symposium will present the data from which such recommendations can be drawn.

Anti-Bacterial Agents↗