bluuebunny/crossref_metadata_2025 huggingface dataset:
Antiviral Drug Resistance and the Need for Development of New HIV-1 Reverse Transcriptase Inhibitors
Authors: Asahchop Eugene L. , Wainberg Mark A. , Sloan Richard D. , Tremblay Cécile L.
Published: June 2012

Highly active antiretroviral therapy (HAART) consists of a combination of drugs to achieve maximal virological response and reduce the potential for the emergence of antiviral resistance. Despite being the first antivirals described to be effective against HIV, reverse transcriptase inhibitors remain the cornerstone of HAART. There are two broad classes of reverse transcriptase inhibitor, the nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Since the first such compounds were developed, viral resistance to them has inevitably been described; this necessitates the continuous development of novel compounds within each class. In this review, we consider the NRTIs and NNRTIs currently in both preclinical and clinical development or approved for second-line therapy and describe the patterns of resistance associated with their use as well as the underlying mechanisms that have been described. Due to reasons of both affordability and availability, some reverse transcriptase inhibitors with a low genetic barrier are more commonly used in resource-limited settings. Their use results in the emergence of specific patterns of antiviral resistance and so may require specific actions to preserve therapeutic options for patients in such settings.
Activity of Ceftaroline-Avibactam Tested against Gram-Negative Organism Populations, including Strains Expressing One or More β-Lactamases and Methicillin-Resistant Staphylococcus aureus Carrying Various Staphylococcal Cassette Chromosome
mec
Types
Authors: Castanheira Mariana , Sader Helio S. , Farrell David J. , Mendes Rodrigo E. , Jones Ronald N.
Published: June 2012

Ceftaroline is a new cephalosporin with broad-spectrum activity against Gram-positive and -negative organisms. The prodrug of ceftaroline, ceftaroline fosamil, combined with the β-lactamase inhibitor avibactam (formerly NXL104), was tested against
Enterobacteriaceae
strains producing Ambler class A, B, C, and D enzymes, including strains producing multiple enzymes, as well as
Pseudomonas aeruginosa
,
Acinetobacter
spp., and methicillin-susceptible and methicillin-resistant
Staphylococcus aureus
(MRSA) strains. Isolates were collected from 1999 to 2008 from global surveillance programs, and susceptibility testing was performed by reference broth microdilution methods. Ceftaroline-avibactam exhibited potent activity against
Enterobacteriaceae
producing various β-lactamase types (MIC
90
, 0.25 to 2 μg/ml, except for metalloenzymes), including 99 strains carrying multiple enzymes (2 to 4 β-lactamases; MIC
90
, 2 μg/ml). All isolates were inhibited by ceftaroline-avibactam at ≤4 μg/ml. Ceftaroline-avibactam (MIC
90
, 0.5 to 1 μg/ml) was more active than meropenem (MIC
90
, >8 μg/ml) and other comparators when tested against KPC-producing strains.
S. aureus
strains, including MRSA with four staphylococcal cassette chromosome
mec
(SCC
mec
) types, were dominantly (99.1%) inhibited by ceftaroline-avibactam at ≤2 μg/ml, and the ceftaroline MIC was not adversely affected by the addition of the β-lactamase inhibitor (MIC
50/90
, 1 and 2 μg/ml for ceftaroline with and without avibactam). Ceftaroline-avibactam demonstrated limited activity against
Acinetobacter
spp. and
P. aeruginosa
(MIC
50
s, 32 and 16 μg/ml, respectively). These results document that ceftaroline-avibactam has potent activity against
Enterobacteriaceae
that produce KPC, various ESBL types (CTX-M types), and AmpC (chromosomally derepressed or plasmid-mediated enzymes), as well as against those producing more than one of these β-lactamase types, and its development as a therapeutic option for the treatment of infections caused by multidrug-resistant
Enterobacteriaceae
as well as MRSA is warranted.
Four-Hour Microbiological Assay of Gentamicin in Serum
Authors: Warren Edward , Snyder Robert J. , Washington John A.
Published: June 2012

Since the microbiological assay of the antibiotic content of serum generally requires 18 to 24 hr of incubation, results of such procedures may not become available in time to make appropriate adjustments in subsequent dosages of antibiotic. A 4-hr bioassay for determining concentrations of gentamicin in serum has been developed in which
Staphylococcus aureus
ATCC 6538P is used as the test organism. Poured plates have yielded satisfactory results after storage at 4 C for 5 days. Results of the 4-hr procedure agree closely with those of a conventional 18-hr disc-plate assay performed with the same test organism.
Structure-Activity Relationships Among a Group of 7-[α-(
N, N
′-Substituted-Amidinothio)-Acetamido] Cephalosporanic Acids
Authors: Misiek M. , Pursiano T. A. , Crast L. B. , Leitner F. , Price K. E.
Published: June 2012

Structure-activity relationships were examined for a number of 7-[α-(
N,N
′-substituted-amidinothio)-acetamido] cephalosporanic acids, including several wherein the amidino group was cyclized into six, seven, and eight-membered rings and a series wherein alkyl, cycloalkyl, alkenyl, and alkynyl radicals were substituted on the nitrogens of the noncyclized amidino group. Derivatives containing an unsubstituted cyclized amidino group had comparable antibacterial activity in vitro and in general had a spectrum of activity broader than that of cephalothin, especially against cephalothin-resistant strains of
Escherichia, Klebsiella
, and
Proteus
. When administered parenterally, the cephalosporin with the six-membered cyclized amidino group was as effective as cephalothin in experimental infections of mice produced by cephalothin-sensitive gram-negative organisms and more efficacious in infections caused by cephalothin-resistant strains. Among the cephalosporins with noncyclized amidino groups, those with an ethyl substituent on one of the nitrogens and a C
2
-C
4
alkyl radical, particularly propyl on the other, were the most active. They not only had a better profile of activity in vitro than cephalothin and the cephalosporin derivatives having a cyclized amidino group, but were also more efficacious in infections of mice.
Antibacterial Activity of Lividomycin Toward R Factor-Resistant Strains of
Escherichia coli
Authors: Yamaguchi Masahito , Kobayashi Fujio , Mitsuhashi Susumu
Published: June 2012

Forty-eight R factors conferring resistance to both kanamycin (KM) and streptomycin (SM) were demonstrated from 1,270
Escherichia coli
strains of clinical origin. Among these R factors isolated, 42 also conferred resistance to the new antibiotic lividomycin (LV). Extracts of
E. coli
ML1410 carrying one such factor (R
M81
) inactivated LV as well as KM and SM. But extracts of
E. coli
ML1410 carrying an R factor (R
M82
or R
M83
) sensitive to LV could not inactivate LV. LV inactivation required both adenosinetriphosphate (ATP) and Mg
2+
. Inactivated LV was reactivable by alkaline phosphatase. Isotopic studies with labeled ATP and elemental analysis of the reaction product indicate that it is a monophosphorylated derivative of LV.
In Vitro Studies of the Combined Effect of Ampicillin and Sulfonamides on
Nocardia asteroides
and Results of Therapy in Four Patients
Authors: Orfanakis Mike G. , Wilcox Howard G. , Smith Charles B.
Published: June 2012

The minimal inhibiting concentrations (MIC) of ampicillin, trisulfapyrimidines, and various combinations of these drugs were determined for four clinical isolates of
Nocardia asteroides
on Mueller-Hinton agar. The combination of ampicillin and sulfonamides was found to be synergistic for three of the four isolates when an inoculum of 10
3
to 10
4
organisms per ml was used. (Synergism was defined as occurring when the MIC of each of the drugs in combination was one-quarter or less of the MIC of each drug alone.) All four isolates were inhibited by concentrations of the drugs in combination that were clinically achievable. Combined therapy with ampicillin and sulfonamides was used in four immunologically suppressed renal transplant patients who had pulmonary infection with
N. asteroides
. Clinical improvement was noted within 2 weeks in all patients, and the pulmonary infiltrates cleared by 6 months in three patients. One patient died from an unrelated illness 10 days after starting therapy. The disease was arrested in two patients who were maintained on full immunosuppressive therapy.
Survey for Methicillin-Resistant Staphylococci
Authors: Bran Jose L. , Levison Matthew E. , Kaye Donald
Published: June 2012

The incidence of isolation of
Staphylococcus aureus
strains resistant to methicillin is increasing in England and other European countries, whereas there have been only isolated reports of resistance in the United States. We thought this contrast might be related to the use of special sensitive screening techniques (i.e., incubation at 30 C, prolonged incubation, use of 5% sodium chloride-agar medium, and use of a large inoculum) in these other countries. A survey was undertaken in a hospital in Philadelphia to detect methicillin-resistant
S. aureus
. In spite of using large inocula, 5% sodium chloride-agar medium, and prolonged incubation at 30 C, no strains of
S. aureus
resistant to methicillin were found.
Detection of a Cephalosporin C Acetyl Esterase in the Carbamate Cephalosporin Antibiotic-Producing Culture,
Streptomyces clavuligerus
Authors: Brannon D. R. , Fukuda D. S. , Mabe J. A. , Huber F. M. , Whitney J. G.
Published: June 2012

The possible role of a cephalosporin C acetyl esterase in the formation of the β-lactam antibiotic A16886A, 7-(5-amino-5-carboxyvaleramido)-3-carbamoyloxy-methyl-3-cephem-4-carboxylic acid, by
Streptomyces clavuligerus
was studied. Addition of
dl
-valine-
14
C-1
to a fermentation of
Cephalosporium acremonium
gave cephalosporin C-
14
C-9
(I). The formation of deacetylcephalosporin C-
14
C-9
from I occurred at a greater rate in broths of
S. clavuligerus
than in the broths of
C. acremonium
, or in the autoclaved broths of
S. clavuligerus
. Diisopropylfluorophosphate partially inhibited the deacetylation of I in
S. clavuligerus
broth. An intracellular cephalosporin C esterase in
S. clavuligerus
could not be demonstrated. Although A16886A has been chemically synthesized from deacetylcephalosporin C, this reaction could not be demonstrated with
S. clavuligerus
.
Incorporation of Labeled Precursors into A16886B, a Novel β-Lactam Antibiotic Produced by
Streptomyces clavuligerus
Authors: Whitney J. G. , Brannon D. R. , Mabe J. A. , Wicker K. J.
Published: June 2012

The incorporation of C-14 from amino acids into A16886B, 7-(5-amino-5-carboxyvaleramido)-7-methoxy-3-carbamoyloxymethyl-3-cephem-4- carboxylic acid, by
Streptomyces clavuligerus
is reported. As with cephalosporin C biosynthesis by the mold
Cephalosporium acremonium
, labels from cysteine, valine, and α-amino-adipic acid were incorporated. Unlike cephalosporin C, in A16886B label from lysine was incorporated into the α-aminoadipic acid side chain. Label from methionine-
14
C-methyl
was incorporated into the methoxyl group. The relative percentage of incorporation of
3
H and
14
C from doubly labeled cystine suggests the improbability of the C-7 methoxyl group arising from an intermediate containing a double bond between C-6 and C-7.
Effect of Exogenous Penicillin on Penicillin Biosynthesis
Authors: Gordee Elizabeth Z. , Day L. E.
Published: June 2012

The addition of phenoxymethylpenicillin (10 mg/ml) at any time during the penicillin fermentation inhibited further accumulation of the antibiotic in broth but had no effect on growth. Benzylpenicillin, 6-aminopenicillanic acid (6-APA), and some semisynthetic penicillins also showed this effect, but penicillin N, penicilloic acid, cephalosporin C, and 7-aminocephalosporanic acid did not limit penicillin accretion. Incorporation of radioactive precursors (cysteine, valine, and sodium phenoxyacetate) into penicillin in the presence of inhibitory concentrations of the antibiotic indicated that penicillin synthesis continued despite the lack of accretion of the antibiotic in broth. The rates of penicillin synthesis in a 48-hr and a 136-hr culture were compared by short-term exposure to Na
2
35
SO
4
, and no significant difference in the biosynthetic rate was observed. Exogenous penicillin in the range of 1 to 15 mg/ml of culture broth had no effect on utilization of acetate or glucose by
Penicillium chrysogenum
. The antibiotic-synthesizing capacity of the organism was not irreversibly inhibited by exogenous penicillin. The degradation of penicillin during the fermentation was also studied. Penicillin V was stable in broth filtrate. Catabolic enzymes such as penicillinase and penicillin-acylase were not demonstrated in whole broth, nor was the accumulation of 6-APA, penicilloic acid, or other degradation products detected. An examination of the intracellular penicillin concentration and the amount of penicillin associated with the mycelium revealed that cells contained significantly more penicillin late in the fermentation than earlier in the cycle. This cell-associated antibiotic may be a regulatory factor in further penicillin synthesis.
Effect of Chemotherapeutic Agents upon Microorganisms Isolated from Cancer Patients
Authors: Goldschmidt Millicent C. , Bodey Gerald P.
Published: June 2012

Attempting to explain the predominance of
Pseudomonas
in leukemic patients, five of the most common gram-negative organisms isolated from sites of infection in cancer patients were exposed to several of the chemotherapeutic agents used in the treatment of this disease (methotrexate, cytosine arabinoside, cyclophosphamide, and 6-mercaptopurine). At concentrations of 125 μg/ml or higher, methotrexate inhibited all organisms except
Pseudomonas
. Cytosine arabinoside inhibited
Escherichia
and
Klebsiella
but appeared to stimulate the growth of
Pseudomonas
slightly at the higher concentrations. Thus, significant differences existed in individual susceptibilities to these agents. Clinical isolates were more resistant than the corresponding laboratory strains not previously exposed to these compounds. The resistance of
Escherichia coli
to cyclophosphamide was decreased 26% when it was grown in mixed culture with
Pseudomonas
. Only
Pseudomonas
was resistant to all of these compounds whether in pure or mixed culture. These observations may help to explain, in part, the predominant role that
Pseudomonas
plays as an infectious agent in leukemic patients.
Antifungal Spectra of Actinomycetes Isolated from Tobacco
Authors: Lukic Anka , Welty R. E. , Lucas G. B.
Published: June 2012

Five species (28 strains) of actinomycetes isolated from tobacco were tested for antagonism against 12 species of storage and field fungi associated with tobacco. Two strains of
Streptomyces albus
were antagonistic against all test fungi. The actinomycetes grew more rapidly, produced more pigment, and had more pronounced antibiotic activity when grown at 36 C than at 28 C. Krasilnikov's synthetic medium, SMK-1, supported the greatest antifungal activity. More of the actinomycetes were antagonistic against more test fungi when grown for 20 days rather than 10 days.
Reversibility of Protein Binding of Penicillins: an In Vitro Study Employing a Rapid Diafiltration Process
Authors: Barza Michael , Vine Hugh , Weinstein Louis
Published: June 2012

The reversibility of human serum protein binding of oxacillin, nafcillin, and cephalothin was investigated by using a diafiltration technique. While the temperature,
p
H, and protein concentration were kept constant, 20% of the serum volume was exchanged every 4 to 5 min. The binding of all three drugs was rapidly reversible, and the percentage of protein binding remained the same throughout the experiment.
In Vitro Antimicrobial Activity of Cinoxacin Against 2,968 Clinical Bacterial Isolates
Authors: Jones R. N. , Fuchs P. C.
Published: June 2012

Cinoxacin demonstrated effective in vitro antimicrobial activity against the
Enterobacteriaceae
, but negligible activity against
Pseudomonas aeruginosa
and gram-positive cocci. The activity of cinoxacin was slightly greater than that of nalidixic acid.
Synergism of Cefazolin-Gentamicin Against Enterococci
Authors: Bourque Michael , Quintiliani Richard , Tilton Richard C.
Published: June 2012

A miniaturized technique for detecting antibiotic synergy by using microliter volumes was perfected. With this microtiter serial dilution method, the effect of the previously untried combination of cefazolin and gentamicin on 10 strains of enterococci was evaluated. At clinically achievable concentrations, the combination of cefazolin and gentamicin was found to be synergistic against all 10 strains when the data were plotted in the form of an isobologram. These results were compared with the conventional method of detecting synergy in vitro, namely, the determination of the rate of killing of the microorganisms with the antibiotics, singly and in combination. Similar results were also observed. These findings indicate that the microtiter serial dilution technique is a useful method for the routine determination of drug synergy. Moreover, in a patient with penicillin hypersensitivity and enterococcal infection, the combination of cefazolin and gentamicin should be considered for possible therapy.
In Vitro Activity of Josamycin and Rosamicin Against
Bacteroides fragilis
Compared with Clindamycin, Erythromycin, and Metronidazole
Authors: Santoro Jerome , Kaye Donald , Levison Matthew E.
Published: June 2012

The inhibitory and bactericidal activities of josamycin and rosamicin against 29 clinical isolates of
Bacteroides fragilis
were compared with those of clindamycin, erythromycin, and metronidazole by a broth dilution technique. Josamycin and rosamicin had similar inhibitory activity to metronidazole and clindamycin. Rosamicin had similar bactericidal activity to clindamycin but was less bactericidal than metronidazole (the most bactericidal agent tested). Josamycin was slightly more bactericidal than erythromycin (the least bactericidal agent tested), but less so than rosamicin and clindamycin.
Nutrition of
Bacillus brevis
ATCC 9999, the Producer of Gramicidin S
Authors: Vandamme E. J. , Demain A. L.
Published: June 2012

The nutrition of the gramicidin S (GS) producer
Bacillus brevis
ATCC 9999 was studied with respect to growth and antibiotic production. In a complex medium containing yeast extract and peptone, only glycerol,
d
-fructose, and
meso
-inositol contributed to growth, whereas other hexoses, pentoses, polyols, polysaccharides, and organic acids were inactive. Glycerol and fructose were inhibitory to GS formation; inositol had no effect. In chemically defined media containing a mixture of five amino acids (glutamine, methionine, proline, arginine, and histidine) necessary for good growth, again only glycerol,
d
-fructose, and
meso
-inositol served as effective carbon sources for growth. With respect to antibiotic formation, inositol was much poorer than glycerol or fructose. In the presence of glycerol and the five amino acids, addition of 0.1%
l
-phenylalanine specifically stimulated GS production. Growth kinetics in this defined medium showed two phases: early and rapid growth at the expense of the amino acid mixture, followed by glycerol utilization after a diauxic lag of 2 to 3 h; inositol utilization suffered a much longer lag period. GS formation was initiated after the diauxic lag. Ammonium sulfate was the best individual nitrogen source, but the combination of the five growth-stimulatory amino acids was more potent for GS production. The level of potassium phosphate influenced GS production. High levels stimulated the growth rate but progressively inhibited GS production. Methionine was the best sulfur source. A defined medium (F3/6) that supported rapid exponential growth (μ = 0.53 h
−1
) followed by progressively slower growth over a 30- to 40-h period was devised containing fructose, six amino acids, and mineral salts. GS formation was initiated as the cells left the exponential growth phase and reached high levels (1,500 mg of GS per liter; 0.19 mg of GS/mg of dry cell weight) after 40 to 50 h of incubation.
Comparative Pharmacokinetics and Metabolism of Cephapirin in Laboratory Animals and Humans
Authors: Cabana B. E. , Harken D. R. Van , Hottendorf G. H.
Published: June 2012

Comparative drug disposition studies in mice, rats, dogs, and humans indicate that cephapirin, a new semisynthetic cephalosporin antibiotic that exhibits broad-spectrum antimicrobial activity, is metabolized to desacetylcephapirin in these species. Pharmacokinetic analyses of the concentrations of cephapirin and desacetylcephapirin in plasma and urine reveal that the rate and extent of deacetylation decreases from rodents to dogs to humans. The kinetic analyses also suggest that the kidney performs a role not only in the excretion but also in the metabolism of cephapirin to desacetylcephapirin.
Specific Action of 4-Nitropyridine 1-Oxide on
Escherichia coli
K-12 Pro
+
Strains Leading to the Isolation of Proline-Requiring Mutants: Mechanism of Action of 4-Nitropyridine 1-Oxide
Authors: Inuzuka Manabu , Toyama Hiromi , Miyano Hiroshi , Tomoeda Munemitsu
Published: June 2012

Possible mechanisms involved in the action of 4-nitropyridine 1-oxide (4NPO) on
Escherichia coli
K-12
pro
+
cells in Penassay broth leading to the selective isolation of
proA
−
and/or
proB
−
mutants but not
proC
−
mutant were studied. Reconstruction experiments between
pro
+
and
pro
−
cells, together with experiments on the bactericidal action of 4NPO on
pro
+
and
pro
−
cells, indicated that 4NPO is more toxic for
pro
+
and
proC
−
cells than for
proA
−
and
proB
−
cells. These results, coupled with data indicating little mutagenicity of 4NPO on
E. coli
cells, led us to conclude that the selection of
proA
−
and/or
proB
−
cells that arose spontaneously in the
pro
+
culture is a possible mechanism for the action of 4NPO. Examination of 4NPO sensitivity of
pro
+
transductants derived from
proA
−
and
proB
−
cells with P1
vir
phage and
pro
+
cells as donor and of
pro
+
spontaneous revertants derived from those
pro
−
cells suggested that 4NPO-sensitive gene(s) should be on, or very close to, the
proA
and
proB
loci and that both products of
proA
and
proB
genes may be involved in the sensitivity of bacteria to 4NPO. The fact that the 4NPO-sensitive allele is dominant over the 4NPO-resistant allele further indicated the possible correlation between gene products of
proA
and
proB
and the 4NPO sensitivity of bacteria. Experiments on metabolic conversion of 4NPO with bacterial cells proved that the major metabolic pathway of the agent is reduction to (possibly via 4-nitroso-) 4-hydroxylamino- and 4-amino-pyridine 1-oxides, and then to 4-aminopyridine. Investigation of the effect of structural modification of 4NPO on the elective selection of Pro
−
mutants in Pro
+
culture further suggested that the structural feature indispensable for the action of the agent is the hydroxyl-amino or its more oxidized state at the 4 position and the
N
-oxide moiety at the 1 position on the pyridine skeleton. Action of 4NPO in minimal medium was found to be bacteriostatic on
pro
+
cells but not on
pro
−
cells, leading to the formation of long nonseptate multinucleate filament cells on
pro
+
cells. Possible biochemical mechanisms of the selective toxicity of 4NPO for
pro
+
and
pro
−
cells are discussed.
Change in Susceptibility of Group B Streptococci to Penicillin G from 1968 Through 1975
Authors: Severin M. J. , Wiley J. L.
Published: June 2012

This report describes a study of 212 isolates of group B streptococci from sore throats over an 8-year period. A small but increasing percentage showed increased resistance to penicillin G when tested in an in vitro system.
Comparison of Activity of Sisomicin and Gentamicin in Mouse Protection Tests with Gram-Negative Bacilli
Authors: Meyers Burt R. , Hirschman Shalom Z.
Published: June 2012

The efficacy of sisomicin and gentamicin was compared in mouse protection studies against strains of
Escherichia coli, Klebsiella
sp.,
Enterobacter aerogenes, Serratia marcescens, Proteus mirabilis
, and
Pseudomonas aeruginosa
. There was no significant difference in mortality of the mice in any of the protocol groups when five different dosages of sisomicin and gentamicin given by three separate schedules were compared for each bacterial inoculum in each antibiotic protocol. The mean protective dose values of sisomicin were at least one-half those of gentamicin for each protocol against
Pseudomonas aeruginosa
.
Comparative Pharmacology of Josamycin and Erythromycin Stearate
Authors: Strausbaugh Larry J. , Bolton W. Kline , Dilworth John A. , Guerrant Richard L. , Sande Merle A.
Published: June 2012

Two macrolide antibiotics, josamycin and erythromycin stearate, were administered orally to healthy, adult male volunteers for a comparative study of their pharmacological properties. In comparable doses, josamycin and erythromycin produced similar plasma concentrations, with similar half-lives and elimination constants. An initial loading dose of 1.5 g of josamycin produced greater peak concentrations of antibiotic throughout a 10-day period with a regimen of every 6 h. In addition, josamycin tended to reach higher peak and trough concentrations after regimens of every 6 or 8 h were maintained for 2 days. Josamycin penetrated into saliva, sweat, and tears, and it was better tolerated in fasting subjects than was erythromycin stearate.
Evolution of Transferable Antibiotic Resistance in Coliform Bacteria from Remote Environments
Authors: Burt Sharon J. , Woods D. R.
Published: June 2012

The influence of a mission hospital on the evolution of antibiotic resistance in coliform bacteria from a remote antibiotic-free Xhosa community and environment is described.
Pharmacokinetics of Cefamandole in the Presence of Renal Failure and in Patients Undergoing Hemodialysis
Authors: Appel Gerald B. , Neu Harold C. , Parry Michael F. , Goldberger Mark J. , Jacob Ginette B.
Published: June 2012

The pharmacology of cefamandole in seven patients with stable renal insufficiency and in eight patients undergoing hemodialysis was determined. All patients had creatinine clearances less than 5 ml/min. The half-life of cefamandole in those patients with stable chronic renal failure was 7.7 ± 2.2 h. The mean venous level 1 h after intravenous injection of a 1-g dose was 85.3 ± 32.0 μg/ml. The mean venous half-life of cefamandole during hemodialysis was 6.1 h. The venous serum level after 5.5 of hemodialysis was 50.4 ± 20.8 μg/ml. The mean coefficient of extraction was 0.155, and the mean clearance was 34.7 ml/min. The time interval between doses of cefamandole administered intravenously should be lengthened to 24 h in the presence of stable renal failure. No major change in dosage schedule is necessary for patients undergoing dialysis.
Correlation of Resistance to Proflavine and Penicillin in
Escherichia coli
Authors: McKellar Robin C. , McKenzie Colin N. , Kushner Donn J.
Published: June 2012

A number of proflavine (PF)-resistant mutants of
Escherichia coli
B were also resistant to penicillin and cephalothin. Mutants resistant to 1.0 mM PF were 10 times more penicillin resistant than were the PF-susceptible, wild-type cells. Single-step mutants selected for resistance to either PF or penicillin were also resistant to the other drug. None of the resistant mutants tested possessed β-lactamase activity. These results suggest that resistance to PF and penicillin in
E. coli
B may be due to permeability changes in the cell envelope.
Effect of Ribavirin on Murine Cytomegalovirus Infection
Authors: Dowling John N. , Postic Bosko , Guevarra Lucille O.
Published: June 2012

Ribavirin (1-β-
d
-ribofuranosyl-1,2,4-triazole-3-carboxamide), a new synthetic nucleoside, inhibited murine cytomegalovirus in cell culture. This was shown by the inhibition of viral cytopathic effect and plaque formation, as well as reduction in the yield of virus. Despite this in vitro antiviral effect, ribavirin did not protect mice from mortality produced by a high inoculum of cytomegalovirus. When a lower inoculum was used to initiate a chronic infection, the administration of ribavirin for 9 days had no effect on the titer of cytomegalovirus in the salivary gland, kidney, liver, and spleen. Thus, ribavirin was ineffective in the treatment of both acute and chronic murine cytomegalovirus infections.
Chemically Defined Medium for Susceptibility Testing of Antimicrobial Agents
Authors: Dougherty Paula F. , Yotter David W. , Matthews Thomas R.
Published: June 2012

A defined medium was developed that supports growth of many of the bacterial and fungal pathogens frequently isolated in clinics.
Lysis of Enterobacteria by Cefoxitin, Cefuroxime, and Cephalothin
Authors: Goodwin C. S. , Hill Joyce P.
Published: June 2012

Cefoxitin, cefuroxime, and cephalothin were added to dense populations of beta-lactamase-producing enterobacteria, and the subsequent turbidity changes were monitored continuously. Viable counts and antibiotic assays were made at intervals after the addition of antibiotic, and the morphological appearances of the organisms were observed. Cephalothin caused lysis of most of the organisms tested, but even at high concentrations, after a few hours the antibiotic was destroyed and the organisms recommenced logarithmic growth. Cefoxitin produced lysis of all the strains of
Escherichia coli
and
Klebsiella
species tested, with supression of regrowth. With cephalothin and cefoxitin the viable counts after the addition of antibiotic correlated with the turbidity measurements. Cefuroxime infrequently caused lysis that suppressed multiplication, and the organisms became long and filamentous while the turbidity readings increased; the viable counts did not correlate with the turbidity measurements. Cefuroxime and cefoxitin were not destroyed by the beta-lactamases of any of the strains of enterobacteria that were studied.
Production of Megacins C and Cx: Presumptive Evidence of Extrachromosomal Control
Authors: Donoghue Helen D.
Published: June 2012

Exposure of growing cultures of
Bacillus megaterium
C4A
−
to ethidium bromide or an elevated growth temperature was found to eliminate megacin C production. Ethidium bromide resulted in a cure rate of up to 13%. Growth at 43°C gave a cure rate of up to 99%. Megacin C production was lost spontaneously at a rate of 4% or less. There was a greater rate of spontaneous loss of megacin Cx production by
B. megaterium
337, up to 14%. Growth at 43°C resulted in a cure rate of up to 24% in this organism. Reversion to the Meg
+
state by cured clones has never been demonstrated. These observations support the hypothesis that production of megacins C and Cx is plasmid mediated. Meg
−
clones adsorbed more megacin than either parent strain and were more susceptible to megacin action.
Laboratory Evaluation of FR10024, a New Cephalosporin Derivative
Authors: Nishida Minoru , Murakawa Takeo , Kamimura Toshiaki , Okada Naohiko , Fukada Shigemi , Sakamoto Hiroshi , Nakamoto Shoji , Yokota Yoshiko , Kono Yoko
Published: June 2012

FR10024 is a broad-spectrum antibiotic. The in vitro antibacterial activity of FR10024 against clinical isolates of
Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae
, and
Proteus mirabilis
is greater than that of any of the cephalosporins developed to date. Indole-positive
Proteus, Enterobacter
, and
Citrobacter
are resistant to FR10024, as is true for the other cephalosporins. However, more than half of the strains of
Enterobacter
and
Citrobacter
tested were susceptible to FR10024 at an inoculum of 10
6
cells/ml. A single subcutaneous injection of FR10024 to mice with peritoneal infections due to
S. aureus
and several species of gram-negative bacilli gave a protective effect inferior to that of cefazolin but appeared to be superior to that of cephalothin. When given in two divided doses, however, the protective effect of FR10024 was enhanced and almost equaled that of cefazolin. The serum levels and rates of urinary recovery of FR10024 varied in different animal species. The mean peak serum level of FR10024 in humans after a single intramuscular injection of 500 mg was two times higher than that of cephalothin. The serum half-life after intramuscular injections of 250 and 500 mg was slightly shorter than that of cephalothin. After receiving 250 mg of FR10024 intramuscularly the urinary recovery rate was 87.7% in healthy volunteers. The biliary excretion rate of FR10024 was particularly high. The 24-h excretion of FR10024 in rats was 63.3%, this being six to seven times higher than that for cefazolin, which has the highest biliary excretion of the other known cephalosporins. When FR10024 was injected intramuscularly (20 mg/kg), it was found that the hepatic levels of FR10024 in rats were the highest of all the cephalosporins, including cefazolin, but the levels of FR10024 in other tissues were not as high as those of cefazolin.
Comparative In Vitro Activity of Nafcillin, Oxacillin, and Methicillin in Combination with Gentamicin and Tobramycin Against Enterococci
Authors: Watanakunakorn Chatrchai , Glotzbecker Cheryl
Published: June 2012

The in vitro activity of nafcillin, oxacillin, and methicillin alone and in combination with gentamicin and tobramycin against 30 strains of enterococci was investigated. The penicillinase-resistant penicillins were less active than penicillin and ampicillin against the enterococci. Nafcillin was more active than oxacillin and methicillin. Sixty-six percent of strains were inhibited by nafcillin at 6.25 μg/ml, but none was inhibited by oxacillin and methicillin at the same concentration. At 12.5 μg/ml, 83, 16, and 0% were inhibited by nafcillin, oxacillin, and methicillin, respectively. By using a variety of criteria and analyses, it was shown that none of the antibiotic combinations studied demonstrated enhanced killing of all strains of enterococci. Nafcillin-gentamicin was the best combination, and enhanced killing was demonstrated against most strains. Oxacillin was more effective than methicillin when combined with gentamicin. Tobramycin was probably less effective than gentamicin in combination with the penicillinase-resistant penicillins against enterococci.
Pharmacokinetics of Cefamandole in Patients with Normal and Impaired Renal Function
Authors: Mellin Hans-Eberhard , Welling Peter G. , Madsen Paul O.
Published: June 2012

The pharmacokinetics of cefamandole, a new cephalosporin, were investigated in 23 patients with urinary tract infections and normal or varying degrees of impairment of renal function. A daily dose of 1.5 to 3.0 g administered intramuscularly was tolerated well and resulted in very high urine concentrations. The pharmacokinetics of the antibiotic were compared with isotopically labeled [
131
I]hippurate and [
125
I]iothalamate, which were used for determination of effective renal plasma flow and glomerular filtration rate, respectively. It was shown that cefamandole was excreted by glomerular filtration as well as by active tubular secretion. Probenecid inhibited the tubular secretion of cefamandole. The serum half-life of cefamandole in patients with normal renal function was approximately 1.5 h and increased in patients along with increasing impairment of renal function. Our studies indicate that a dosage regimen of 1 g of cefamandole every 8 h in patients with normal renal function results in urine concentrations sufficiently high for treatment of most common urinary tract infections. In patients with impaired renal function, the dosage interval should be increased or the dosage lowered according to the serum creatinine values.
Experimental Herpes Simplex Virus Type 1 Encephalitis: Treatment with 5-Trifluoromethyl-2′-Deoxyuridine
Authors: Clough D. W. , Parkhurst J. Rodney
Published: June 2012

5-Trifluoromethyl-2′-deoxyuridine (F
3
dThd) was evaluated for its neurotoxicity and for its ability to increase the life span of mice injected intracerebrally with herpes simplex virus type 1 (HSV-1) and F
3
dThd simultaneously. F
3
dThd showed no neurotoxicity at the highest concentration tested (100 mg/kg). Mice injected intracerebrally with HSV-1 died within 5 days postinfection. However, all mice injected concurrently with HSV-1 and 100 mg of F
3
dThd per kg lived through the termination of the experiment (60 days). Protection of mice from HSV-1 encephalitis by F
3
dThd has been shown to be dose dependent, with 100, 75, 50, and 25 mg of F
3
dThd per kg yielding a survival rate of 100, 90, 50, and 10%, respectively. HSV-1 titers in mouse brains receiving HSV-1 and 100 mg of F
3
dThd per kg concurrently were 100- to 1,000-fold lower at 2 to 4 days postinfection than control mice receiving HSV-1 alone. F
3
dThd was shown not to stimulate interferon production. Encephalitis caused by a ribonucleic acid virus, encephalomyocarditis virus, was not modified by F
3
dThd treatment.
Bacteriostatic and Bactericidal Activities of Selected Beta-Lactam Antibiotics Studied on Agar Plates
Authors: Masuda Gohta , Tomioka Susumu , Uchida Hiroshi , Hasegawa Mitsuto
Published: June 2012

A novel and time-saving method for assessing bactericidal activities of β-lactam antibiotics on agar plates is described. Minimal inhibitory concentrations (MICs) were determined by the agar dilution method. A potent β-lactamase solution was sprayed onto the plates to inactivate the antibiotic. After further incubation at 37°C overnight, the minimal concentration at which no visible growth occurred on the plates was defined as minimal bactericidal concentration (MBC). With undiluted culture as the inoculum, strains of
Staphylococcus aureus, Escherichia coli
, and
Klebsiella pneumoniae
showed a marked increase in MBC values compared with the values of MIC. There was a marked decrease in both the MICs and MBCs with diminution of inoculum size. The two concentrations were almost the same when the inoculum size was decreased to a 10
−4
dilution. In contrast, MIC and MBC for enterococci showed no marked decrease with decrease in inoculum size. Although the present study was performed with β-lactamase-unstable penicillins and cephalosporins, the method can be applicable with any β-lactam antibiotic if optimal and potent enzymes are available.
Effect of Penicillin on Streptomycin Production by
Streptomyces griseus
Authors: Barabás Gy. , Szabó G.
Published: June 2012

The correlation between the biosynthesis of the cell wall and the formation of streptomycin (SM) in
Streptomyces griseus
, influenced by a specific inhibitor of cell wall synthesis, was investigated. Penicillin, in subinhibitory concentrations (1 to 5 μg/ml), was added to cultures of
S. griseus
in different stages of its life cycle. The inhibitor decreased SM production, when young cultures were treated; however, there was an increase in SM formation when penicillin was added to older cultures. The explanation for these findings is discussed in detail.
Chemically Defined Antimicrobial Susceptibility Test Medium for
Pseudomonas aeruginosa
Authors: Jorgensen J. H. , Lee J. C. , Jones P. M.
Published: June 2012

A chemically defined growth medium containing physiological concentrations of magnesium and calcium ions was utilized in a microdilution procedure for antimicrobial drug susceptibility testing of
Pseudomonas aeruginosa
. Determinations of growth end points were simplified by use of sodium citrate as a sole carbon source and bromothymol blue as a pH indicator. Growth of the test organisms was detectable by a change in the indicator color from green to blue after alkalinization of the medium due to citrate utilization. Minimal inhibitory concentrations of amikacin, carbenicillin, gentamicin, and tobramycin were determined on 100 recent clinical isolates of
Pseudomonas
. Parallel determinations using the microdilution procedure and a conventional tube-broth dilution technique incorporating Mueller-Hinton broth with identical magnesium and calcium content generally agreed within one twofold dilution. Modal minimal inhibitory concentrations for susceptible strains using the microdilution method were: amikacin, 6 μg/ml; carbenicillin, 50 μg/ml; gentamicin, 1.5 μg/ml; tobramycin, 1.5 μg/ml. This modified microdilution technique allowed rapid, definitive minimal inhibitory concentration determinations, using growth end points defined by a color indicator change.
Inhibition of Cellular and Viral Protein Synthesis by 3-Methyleneoxindole
Authors: Abreu Sergio L. , Lucas-Lenard Jean
Published: June 2012

The effect of 3-methyleneoxindole (MO) on mengovirus and L-cell protein synthesis was investigated. MO was found to inhibit mengovirus multiplication and the incorporation of radioactive amino acids into both viral and cellular proteins. These results suggest that the antiviral effect of this compound is not specific but rather stems from its inhibition of the cellular translational machinery upon which mengovirus depends. We have also found that MO inhibits natural messenger ribonucleic acid (mengovirus and globin messenger ribonucleic acid) translation in cell-free extracts from Ehrlich ascites tumor cells but has no significant effect on polyuridylic acid translation. Additional data which suggest that MO inhibits protein synthesis at the level of initiation are shown.
Comparison of the Effects of Mecillinam and 6-Aminopenicillanic Acid on
Proteus mirabilis, Escherichia coli
, and
Staphylococcus aureus
Authors: Lorian Victor , Atkinson Barbara
Published: June 2012

Single strains of
Proteus mirabilis, Escherichia coli
, and
Staphylococcus aureus
were grown on filter membranes placed on agar containing concentration series of mecillinam (FL 1060), 6-aminopenicillanic acid (6-APA), or ampicillin.
P. mirabilis
and
E. coli
were also exposed to combinations of mecillinam or 6-APA with ampicillin. Colony-forming units were counted, and cells were examined by interference phase-contrast and transmission electron microscopy. Mecillinam and 6-APA were very effective in reducing the viability of the two gram-negative species, but they were less effective against
S. aureus
. Combinations of mecillinam and 6-APA with ampicillin acted synergistically against the gram-negative bacilli. When the antibiotics were presented consecutively, their effects on viability were usually no greater than the effects of the individual antibiotics acting alone. When
P. mirabilis
and
E. coli
were exposed to mecillinam alone or in combination with ampicillin, the cells became rounded. 6-APA alone or in combination with ampicillin produced elongated polymorphic cells in these species. The most unusual morphological effects were ultrastructural. Mecillinam and, to a lesser extent, 6-APA produced inward growth of numerous pairs of trilamellar membranous structures within the cells. It is possible that these membranes represent the growth initiation of aberrant cross walls. Both mecillinam and 6-APA produced multiple, thick cross walls in
S. aureus
.
Plasmid-Mediated Aminoglycoside Phosphotransferase of Broad Substrate Range That Phosphorylates Amikacin
Authors: Courvalin Patrice , Davies Julian
Published: June 2012

A plasmid-mediated aminoglycoside phosphotransferase that phosphorylates amikacin has been detected in clinical isolates of
Staphylococcus aureus
. This enzyme does not confer detectable amikacin resistance to the strains.
Susceptibility of Anaerobic Bacteria to Metronidazole, Ornidazole, and Tinidazole and Routine Susceptibility Testing by Standardized Methods
Authors: Wüst Jürg
Published: June 2012

A total of 114 strains of anaerobic bacteria were examined for their susceptibility to metronidazole, ornidazole, and tinidazole by measuring the minimum inhibitory concentration (MIC) and minimum bactericidal concentration in different media. All strains, with the exception of the isolates of
Propionibacterium acnes
, were inhibited by 3.1 μg each and killed by 6.3 μg each of all three nitroimidazole compounds per ml. No significant differences in MIC values were found among metronidazole, ornidazole, and tinidazole. Only minor differences were detected by comparing MIC values obtained in brain heart infusion agar with and without sheep blood, brucella agar, and Mueller-Hinton agar (both containing blood). When the strains were tested by the modified broth-disk method proposed by the Anaerobe Laboratory of the Virginia Polytechnic Institute (VPI), there was good correlation with the MIC values (97.4% agreement for metronidazole and 94.7% for ornidazole and tinidazole). For routine testing, use of a 30-μg-class disk of either nitroimidazole derivative is proposed for the broth-disk method, resulting in a final concentration of 6 μg/ml in the test tubes, a concentration easily attainable in body fluids. In contrast to the broth-disk method, there was very poor correlation between inhibition zone diameters by the standardized VPI agar diffusion test and MIC values.
Therapy of Antimicrobial-Resistant Typhoid Fever
Authors: Butler Thomas , Linh Nguyen Ngoc , Arnold Keith , Adickman Michael D. , Chau Duong Minh , Muoi Mach Muoi
Published: June 2012

Antimicrobial-resistant typhoid fever in Saigon was studied by examining in vitro antimicrobial susceptibilities of
Salmonella typhi
strains and conducting a randomized clinical trial of ampicillin and trimethoprim-sulfamethoxazole (TMP-SMZ). Isolates of
S. typhi
were obtained from blood or stool cultures of 90 patients. Of 87 isolates tested for antimicrobial susceptibility, 65 (75%) were resistant (R) to chloramphenicol, streptomycin, sulfonamide, and tetracycline, and 22 (25%) were susceptible (S). The drug resistance was transferable to
Escherichia coli
and was found in 11 different Vi-phage types. All isolates were susceptible to ampicillin and to TMP-SMZ. Agar dilution studies of TMP and SMZ showed synergistic inhibition of growth in all 18 S isolates and in 12 of 48 R isolates tested. The clinical trial of ampicillin and TMP-SMZ showed that both drugs were equally effective. Treatment failure with both drugs was more frequent in patients with S isolates than in patients with R isolates. Therefore, in an area where antimicrobial-resistant typhoid fever exists, patients with R isolates should receive either ampicillin or TMP-SMZ, but patients with S isolates should be treated with chloramphenicol.
Bactericidal Factor Produced by
Haemophilus influenzae
b: Partial Purification of the Factor and Transfer of Its Genetic Determinant
Authors: Venezia R. A. , Matusiak P. M. , Robertson R. G.
Published: June 2012

When aerobically grown on complex media,
Haemophilus influenzae
b and unencapsulated variants, Rb strains, produced a bactericidal factor that was active against other
Haemophilus
species and certain genera of the
Enterobacteriaceae
. A total of 341 clinical isolates of
Haemophilus
were tested for susceptibility to the factor. Ninety-three percent of
H. influenzae
(nontypable), 75% of
H. haemolyticus
, 71% of
H. parainfluenzae
, and 22% of
H. parahaemolyticus
were susceptible.
H. influenaze
b strains were resistant producers of the bactericidal factor and
H. influenzae
f strains were susceptible nonproducers. Only one strain each of
H. aegyptius
and
H. aphrophilus
was isolated and each was susceptible and resistant, respectively. 143 clinical isolates of the
Enterobacteriaceae
were tested and of those 82% of
Escherichia coli
, 85% of
Salmonella
sp., and all
Citrobacter
sp.,
Shigella
sp., and
Yersinia
sp. were sensitive to the bactericidal factor produced by
H. influenzae
b. Attempts to isolate the bactericidal activity from mechanically disrupted, solubilized, or osmotically shocked cells failed to release active bactericidal factor. However, we partially purified the bactericidal factor from the spent culture medium of aerobically grown
H. influenzae
b by a series of extractions. The ability to produce the bactericidal factor was transferable to nonproducer strains without also genetically transforming for type b encapsulation. The converse was also true in that type b capsules were produced by transformed
H. influenzae
Rd strains but no bactericidal factor was detected from these strains. Additionally, nitrosoguanidine-induced mutants of
H. influenzae
b lost the ability to produce bactericidal factor without loss of their type-specific capsule, demonstrating that production of the bactericidal factor was genetically separable from production of the type capsule of
H. influenzae
b.