bluuebunny/crossref_metadata_2025 huggingface dataset:
Antibacterial Activity of a New Parenteral Cephalosporin—HR 756: Comparison with Cefamandole and Ceforanide
Authors: Counts George W. , Turck Marvin
Published: June 2012

HR 756, a new parenteral cephalosporin that is beta-lactamase resistant, was tested against 271 bacterial isolates. Both agar and broth dilution testing were employed, using two media and two inoculum sizes of bacteria. Antibacterial activity of the drug was compared to that of cefamandole (CFM) and ceforanide (CFN). In agar, HR 756 was more active than CFM and CFN against all bacteria tested except isolates of
Staphylococcus aureus
, which were better inhibited by CFM. HR 756 exhibited some antipseudomonas activity in agar, although a marked inoculum effect was apparent. A comparison of median minimum inhibitory and bactericidal concentrations in broth showed again that HR 756 was the most active of these three drugs. HR 756 demonstrated enhanced antibacterial activity compared to CFM and CFN against bacteria sensitive to all three drugs as well as against more resistant isolates of
Serratia marcescens, Enterobacter
species, and indole-positive
Proteus
. As with other cephalosporins, results for most bacteria were affected by inoculum size, medium, and type of dilution test employed in in vitro studies.
In Vitro Antiherpesviral Activity of 5-Alkyl Derivatives of 1-β-
d
-Arabinofuranosyluracil
Authors: Machida Haruhiko , Sakata Shinji , Kuninaka Akira , Yoshino Hiroshi , Nakayama Chikao , Saneyoshi Mineo
Published: June 2012

Several 5-alkyl derivatives of 1-β-
d
-arabinofuranosyluracil (araU) were tested for antiherpesviral activity and inhibitory action on cell growth in human embryonic lung fibroblasts. 1-β-
d
-Arabinofuranosylcytosine, 9-β-
d
-arabinofuranosyladenine, and 5-iododeoxyuridine (IUdR) were included as reference materials. Among the 5-alkyl derivatives of araU, arabinosylthymine was the most active, followed by 5-ethyl- and 5-propyl-araU. 5-Ethyl-araU was as active as IUdR and more active than 9-β-
d
-arabinofuranosyladenine against herpes simplex virus (HSV) type 1 and did not inhibit cell growth at a concentration as high as 1,000 μg/ml. 5-Butyl- and 5-methoxymethyl-araU, as well as araU, exhibited relatively low activity. The araU derivatives tested were as active against HSV WT-34, an isolate from a patient with keratitis, as against HSV type 1. Against an IUdR-resistant isolate, HSV WT-20, arabinosylthymine was less inhibitory than IUdR. Deoxyribonucleic acid synthesis in HSV type 1-infected cells was markedly inhibited by arabinosylthymine, IUdR, and 5-ethyl-araU, whereas cellular deoxyribonucleic acid synthesis in uninfected cells was significantly inhibited by IUdR but not by arabinosylthymine or 5-ethyl-araU.
Antibiotic Susceptibility of
Haemophilus vaginalis (Corynebacterium vaginale)
to 21 Antibiotics
Authors: McCarthy Laurence R. , Mickelsen Patricia A. , Smith E. Grover
Published: June 2012

A total of 56 strains of
Haemophilus vaginalis
were tested for their in vitro susceptibility to 21 antimicrobial agents by an agar dilution method. All strains were inhibited by 1 μg or less of penicillin, ampicillin, carbenicillin, and vancomycin per ml. The cephalosporins were less active; 4 μg of cefazolin per ml, 16 μg of cephalothin per ml, or 128 μg of cephalexin per ml was required to inhibit all strains. Kanamycin, gentamicin, tobramycin, and neomycin were relatively inactive against
H. vaginalis
. All strains were inhibited by 4 μg of streptomycin per ml and 2 μg of chloramphenicol per ml. Only 57% of the strains were inhibited by 4 μg of tetracycline per ml, whereas 43% were inhibited by 16 to 64 μg/ml. The combination sulfamethoxazole/trimethoprim was relatively inactive against
H. vaginalis
. All strains tested exhibited minimal inhibitory concentrations of ≥128 μg when tested against colistin, nalidixic acid, and sulfadiazine. Erythromycin and clindamycin were the most active of the antibiotics tested; for all strains the minimal inhibitory concentrations were ≤0.06 μg/ml.
Effects of Amphotericin B and Its Methyl Ester on the Antiviral Activity of Polyinosinic:Polycytidylic Acid
Authors: Borden Ernest C. , McBain Jack A. , Leonhardt Peggy H.
Published: June 2012

Since the macrolide polyene antibiotics, amphotericin B (AmB) and its methyl ester (AmBME), augment interferon production by polyriboinosinic:polyribocytidylic acid [poly(I):poly(C)] in vitro, experiments were undertaken to determine how AmB and AmBME affect the antiviral activity of poly(I):poly(C) and interferon. AmBME increased the direct antiviral activity of poly(I):poly(C) 10
2
-to 10
4
-fold in L929, Flow 6000, and T98G cells. Viral replication, measured by either direct plaque formation or virus yield, was markedly reduced. Serum interferon levels in mice induced by poly(I):poly(C) were enhanced by concomitant treatment with AmB. However, the therapeutic effects of poly(I):poly(C) in encephalomyocarditis and Semliki Forest virus infections were not augmented by combined treatment with poly(I):poly(C) and AmB. In vitro, the antiviral effects of exogenous interferon were markedly inhibited by AmB and AmBME. This inhibition may have contributed to the adverse effects of the macrolide polyenes in encephalomyocarditis and Semliki Forest virus infections in vivo. These findings further substantiate the effectiveness of macrolide polyenes in augmenting cellular penetration of macromolecules. However, therapeutic application may be limited by the complex interactions which occur between compounds administered in vivo.
Mecillinam-Ampicillin Synergism in Experimental
Enterobacteriaceae
Meningitis
Authors: Scheld W. M. , Fink F. N. , Fletcher D. D. , Sande M. A.
Published: June 2012

The in vitro activities of mecillinam, a new β-amidinopenicillin, and ampicillin, alone and in combination, against an
Escherichia coli
strain and a
Klebsiella pneumoniae
strain were compared, and these results were correlated with their respective activities in vivo in experimental meningitis. The mecillinam-ampicillin combination was synergistic in vitro against both strains when tested by a modified checkerboard technique (bacteriostatic synergy). However when quantitative bactericidal synergy studies were made, the relative bactericidal rate of the combination was more rapid than that of either drug alone (“bactericidal synergy”) against the
Escherichia coli
isolate only. In a rabbit model of
Enterobacteriaceae
meningitis, in vivo bactericidal activity correlated with results obtained in vitro. Both drugs were administered by continuous intravenous infusion for 8 h. Serum and cerebrospinal fluid antibiotic levels were similar to those achieved in humans. Cerebrospinal fluid bacterial concentrations (colony-forming units [CFU] per milliliter) were quantitatively titrated at 2-h intervals. Both drugs, alone or the combination, were ineffective against the
K. pneumoniae
strain in vivo (change in titer <1 log in 8 h). In contrast, the combination produced a markedly enhanced bactericidal effect against the
E. coli
strain (mean ± standard deviation, decrease of log
10
CFU per milliliter of 3.65 ± 1.02) compared with those of ampicillin alone (decrease of log
10
CFU per milliter of 0.07 ± 0.8) and mecillinam alone (decrease of log
10
CFU per milliliter of 1.6 ± 0.05) (
P
< 0.001). When bactericidal synergism can be demonstrated for mecillinam-ampicillin in vitro in a case of gram-negative-bacillary meningitis this combination may be useful in the therapy of the illness.
LY-127935: a novel beta-lactam antibiotic with unusual antibacterial activity
Authors: Trager G M , White G W , Zimelis V M , Panwalker A P
Published: June 2012

The in vitro activity of LY-127935, a new beta-lactam antibiotic, was examined by using 370 clinical bacterial strains. In comparison with several other beta-lactam agents, LY-127935 was the most inhibitory against the Enterobacteriaceae. It was remarkably active against multi-drug-resistant strains of Enterobacter spp., Serratia spp., and Pseudomonas aeruginosa. LY-127935 had four- to eightfold greater activity than did cefoxitin against Bacteroides fragilis. Production of beta-lactamase by Enterobacteriaceae did not influence the minimal inhibitory concentration of LY-127935. However, the beta-lactamase-producing strains of B. fragilis and Haemophilus influenzae had generally higher minimal inhibitory concentrations. LY-127935 was the least active agent tested against gram-positive aerobic cocci. Variations in pH, salt content, protein content, or inocula size had little influence on susceptibility to LY-127935. Although combination studies with LY-127935 and gentamicin demonstrated synergy for P. aeruginosa, the rates of killing for the combination and for gentamicin alone were similar.
LY127935, a novel oxa-beta-lactam: an in vitro comparison with other beta-lactam antibiotics
Authors: Wise R , Andrews J M , Bedford K A
Published: June 2012

The in vitro activities of LY127935 (LY) were compared with those of other beta-lactam antibiotics. LY was highly active (minimal inhibitory concentration [MIC] range 0.06 to 0.25 micrograms/ml) against the common Enterobacteriaceae (including Providencia stuartiia, Enterobacter, and Serrati marcescens), 8 to 16 times more active than cefoxitin, cefuroxime, or cefazolin, and from one-half to one-eighth as active as cefotaxime (HR756). The activity of LY against Pseudomonas aeruginosa (with MICs of 4 and 64 micrograms/ml for 50 and 90% of test strains, respectively) was essentially similar to that of cefotaxime, but was only one-half as active as CGP 7174/E. LY, cefoxitin, and cefotaxime were essentially equally active against Bacteroides fragilis--each was more active than cefuroxime and cefazolin. Against Staphylococcus aureus, LY (50% MIC and 90% MIC of 4 and 16 micrograms/ml, respectively) was less active than cefotaxime, cefoxitin, or cefuroxime and one-eighth as active as cefazolin. The composition and pH of the culture medium had little effect on the activity of LY, although 7.2 appeared to be the optimum pH.
Correlation of aminoglycoside dosages with serum concentrations during therapy of serious gram-negative bacillary disease
Authors: Reymann M T , Bradac J A , Cobbs C G , Dismukes W E
Published: June 2012

We prospectively evaluated serum aminoglycoside (AMG) concentrations in 120 patients who received gentamicin or tobramycin for serious gram-negative bacillary disease. AMG serum concentrations were assayed by microbiological and radioimmunoassay techniques. Correlation between the two assay methods was good. When AMG doses were based on total body weight, there was no significant correlation between AMG dosage administered and serum concentrations in patients with either normal or abnormal renal function. The use of ideal body weight for calculation of AMG dosage improved this correlation significantly except in hemodialysis patients. AMG-induced nephrotoxicity occurred in 13 patients. No significant association was noted between the occurrence of toxicity and the specific AMG given or with other commonly recognized risk factors. Among study groups, peak AMG serum concentrations failed to exceed the minimal inhibitory concentration of the infecting organism in 17 to 33% of the cases. Serum inhibitory levels of greater than or equal to 1:8 were not associated with improved survival. There was no significant difference in mortality between the gentamicin- and tobramycin-treated groups. We advise base-line serum AMG levels in seriously ill patients with gram-negative bacillary disease and additional bacteriological studies in selected situations.
Cochlear toxicity of butikacin (UK-18,892), a new semisynthetic aminoglycoside antibiotic, in guinea pigs
Authors: Carter A J
Published: June 2012

The cochleotoxic potential of butikacin (UK-18,892), a new semisynthetic aminoglycoside, has been evaluated in neonatal guinea pigs in comparison with amikacin, gentamicin, and kanamycin A. All compounds produced a dose-related increase of the mean threshold sound intensity required to elicit Preyer's reflex. Butikacin produced a similar level of cochlear toxicity to that of kanamycin A, but tended to be less cochleotoxic than amikacin. Gentamicin was the least cochleotoxic.
In Vitro Activity of LY127935
Authors: Fass Robert J.
Published: June 2012

LY127935 is a unique new β-lactam antibiotic. Its activity against 536 clinical isolates was studied by using microdilution methods of susceptibility testing and compared with the activities of cefamandole, cefoxitin, and cephalothin. The lowest concentrations required to inhibit at least 90% of strains tested (MIC
90
s
) of LY127935 for
Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae
, and
Streptococcus pneumoniae
ranged from 2 to 8 μg/ml. The MIC
90
s
for other staphylococci and streptococci were higher. The MIC
90
s
for
Enterobacteriaceae
and
Pseudomonas
species ranged from 0.12 to 8 μg/ml and 8 to >32 μg/ml, respectively. The MIC
90
s
for anaerobes ranged from 2 to >32 μg/ml. As determined by MIC
90
s
, LY127935 was consistently the least active antibiotic against facultatively anaerobic gram-positive cocci and the most active against aerobic and facultatively anaerobic gram-negative bacilli. Its position with respect to activity against anaerobes varied from being the most active against
Bacteroides fragilis
and
Clostridium perfringens
to the least active against anaerobic cocci. In a population of multidrug-resistant isolates, concentrations of 8 μg or less of LY127935 per ml inhibited 82% of
Enterobacteriaceae
; concentrations of 32 μg or less per ml inhibited 100% of
Enterobacteriaceae
and 40% of
P. aeruginosa
. Increasing the inoculum size by 100-fold did not increase the minimal inhibitory concentrations of LY127935 or cefoxitin but did increase minimal inhibitory concentrations of cefamandole and cephalothin for some
Enterobacteriaceae
. All four drugs were bactericidal; minimal bactericidal concentrations were the same or one concentration higher than minimal inhibitory concentrations for 91 to 96% of strains tested. The broad spectrum and marked in vitro activity of LY127935 make it a promising new antibiotic.
Inactivation of Cephalosporins by
Bacteroides
Authors: Tally Francis P. , O'Keefe J. Paul , Sullivan N. M. , Gorbach Sherwood L.
Published: June 2012

We investigated the relationship between β-lactamases of
Bacteroides fragilis
organisms and their resistance to cephalosporins. Timed killing curves were used to study the in vitro activity of three cephalosporins, cephalothin, cefazolin, and cefamandole, and a semisynthetic cephamycin, cefoxitin. Measurements of residual antibiotic concentrations in culture supernatants were made, and they were compared with the β-lactamase activity of the microorganism. A cephalosporin-susceptible strain was rapidly killed by cephalothin, cefazolin, cefamandole, and cefoxitin. Four cephalosporin-resistant strains were not killed by cephalothin, cefazolin, or cefamandole but were killed by cefoxitin. An inoculum effect was noted with cefazolin and not with cefoxitin. The resistant strains of
Bacteroides
inactivated the three cephalosporins, but there was no inactivation of cefoxitin. A constitutive β-lactamase was detected in all the isolates of the
B. fragilis
group that were resistant to the cephalosporins. There was no distinction of the species based on isoelectric focusing of the enzyme. These data suggest that inactivation by β-lactamase may be the mechanism for resistance of
B. fragilis
to the cephalosporins and would explain the enhanced in vitro activity of cefoxitin.
Rapid assay for determination of trimethoprim and sulfamethoxazole levels in serum by spectrofluorometry
Authors: Lichtenwalner D M , Suh B , Lorber B , Sugar A M
Published: June 2012

A rapid spectrofluorometric method for determining the levels of both trimethoprim and sulfamethoxazole from the same specimen of serum is described. The method involves stepwise extraction of the specimen first with chloroform at an alkaline pH (pH 9.0) for trimethoprim followed by n-butyl chloride at an acidic pH (pH 2.0) for sulfamethoxazole. To quantitate trimethoprim, the chloroform layer was subjected to fluorometry by exciting the specimen at 295 nm and measuring the relative intensity at 330 nm. To determine sulfamethoxazole levels, the n-butyl chloride layer was subjected to fluorometry by exciting the specimen at 285 nm and measuring the relative intensity at 330 nm. Relative intensities were linear (r greater than 0.99) over the concentration ranges of 0.5 to 40 microgram/ml for trimethoprim and 1 to 400 microgram/ml for sulfamethoxazole. Values obtained by this spectrofluorometric procedure were in excellent agreement with those obtained by a conventional fluorometric assay for trimethoprim and a colorimetric assay for sulfamethoxazole. Elevated levels of endogenous metabolic products and numerous other drugs, including a number of antimicrobial agents, did not interfere with the method. Although salicylates interfere with the determination of sulfamethoxazole, an appropriate correction can be made. This method can also be used to determine the drug levels in cerebrospinal fluid.
High-level, plasmid-borne resistance to gentamicin in Streptococcus faecalis subsp. zymogenes
Authors: Horodniceanu T , Bougueleret L , El-Solh N , Bieth G , Delbos F
Published: June 2012

Each of three isolates of Streptococcus faecalis subsp. zymogenes harbored three R plasmids and a hemolysin-bacteriocin plasmid. The plasmids carried by one of these strains were physically characterized after their conjugative transfer. In each strain one of the plasmids carried genetic markers for resistance to gentamicin, kanamycin, sisomicin, netilmicin, and tobramycin.
Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique
Authors: Desjardins R E , Canfield C J , Haynes J D , Chulay J D
Published: June 2012

A rapid, semiautomated microdilution method was developed for measuring the activity of potential antimalarial drugs against cultured intraerythrocytic asexual forms of the human malaria parasite Plasmodium falciparum. Microtitration plates were used to prepare serial dilutions of the compounds to be tested. Parasites, obtained from continuous stock cultures, were subcultured in these plates for 42 h. Inhibition of uptake of a radiolabeled nucleic acid precursor by the parasites served as the indicator of antimalarial activity. Results of repeated measurements of activity with chloroquine, quinine, and the investigational new drug mefloquine demonstrated that the method is sensitive and precise. Several additional antimalarial drugs and compounds of interest were tested in vitro, and the results were consistent with available in vivo data. The use of P. falciparum isolates with known susceptibility to antimalarial drugs also permitted evaluation of the cross-resistance potential of each compound tested. The applications and expectations of this new test system within a drug development program are discussed.
Gentamicin antibacterial activity in the presence of human polymorphonuclear leukocytes
Authors: Vaudaux P , Waldvogel F A
Published: June 2012

Complete protection of Staphylococcus aureus Wood 46 from gentamicin bactericidal activity was documented for microorganisms located within polymorphonuclear leukocytes. The highest, still ineffective gentamicin concentration tested in the phagocytic assay was 80 times higher than the minimal concentration required to kill uningested organisms. Extracellular gentamicin activity was unaffected by the phagocytic process as demonstrated by microbiological and enzymatic assays, and liberation of intracellular S. aureus by lysis of neutrophils showed the bacteria to be fully susceptible to the antibiotic. These results were corroborated by studies performed with [14C]gentamicin; binding of the labeled antibiotic by resting neutrophils, or by neutrophils ingesting live, killed S. aureus or endotoxin-coated paraffin particles, showed no statistical differences and never exceeded 20% of the extracellular concentration. These results show that intraleukocytic S. aureus are protected from the bactericidal action of gentamicin and suggest that this protection can be explained by poor intracellular penetration of the antibiotic.
Antibacterial activities, nephrotoxicity, and ototoxicity of a new aminoglycoside, Win 42122-2
Authors: Came P E , O'Connor J R , Dobson R A , Wagner R B , Fabian R J
Published: June 2012

Win 42122-2 is a new aminoglycoside antibiotic obtained from a mutant strain of Micromonospora purpurea. In vitro and in vivo comparisons of Win 42122-2 with gentamicin and amikacin revealed that Win 42122-2 generally was less active than gentamicin against Pseudomonas and many Enterobacteriacae, especially Klebsiella and indole-negative Proteus. Against most gentamicin-susceptible isolates, Win 42122-2 was more active than amikacin. Gentamicin-resistant clinical isolates were usually resistant to Win 42122-2, although it was active against certain gentamicin-resistant organisms, depending upon the aminoglycoside-modifying enzymes harbored by the organism. However, Win 42122-2 was markedly less toxic than gentamicin in subacute nephrotoxicity studies in rats, ototoxicity experiments in guinea pigs, and ataxia determinations in cats. This series of antibacterial determinations and toxicity evaluations indicated that the reduced toxicity of the antibiotic may be sufficient to provide an improved therapeutic ratio over gentamicin and other aminoglycosides, even though Win 42122-2 is less potent than gentamicin against some bacteria.
Reversal by Calcium Ions of the Growth Inhibition of
Debaryomyces nicotianae
Caused by Antifungal Polyene Antibiotics
Authors: Berdicevsky Israela , Grossowicz Nathan
Published: June 2012

Only
Debaryomyces nicotianae
strain 77, of seven different yeast strains tested, was found to be resistant to heptamycin and other antifungal heptaenes when grown in a rich medium. This strain, however, like the other six, was completely susceptible to these antibiotics in a minimal medium. Addition of yeast extract to the minimal medium abolished the heptamycin effect; calcium ions fully duplicated the effect of yeast extract; Mg
2+
and Mn
2+
were also effective but less so than Ca
2+
. Ca
2+
also counteracted the activity of the heptaenes ascosin and trichomycin. Complete reversal of the polyene inhibition by Ca
2+
was obtained if the cation was added simultaneously with the antibiotic; addition of Ca
2+
2 hr after the polyene was without effect. Addition of Ca
2+
in the absence of the polyene caused a slight, if any, growth stimulation of
D. nicotianae
77. Cholesterol also counteracted polyene activity; this was due to the formation of a complex with the antibiotic which prevented the polyene from reaching the site of action—the cytoplasmic membrane. No evidence for complex formation between heptamycin and calcium was found. The importance of Ca
2+
in membrane structure, as evidenced from heptaene studies, is discussed.
Fatty Acids and Derivatives as Antimicrobial Agents
Authors: Kabara Jon J. , Swieczkowski Dennis M. , Conley Anthony J. , Truant Joseph P.
Published: June 2012

The structural relationships of 30 straight-chain fatty acids and derivatives and their bactericidal properties were studied with 8 gram-negative and 12 grampositive organisms. Chain length, unsaturation (
cis, trans
), and functional group were all variables considered in this study. Our data indicate that C
12
(lauric acid) is the most inhibitory saturated fatty acid against gram-positive organisms. Monoenoic acid (C
18:1
) was more inhibitory than saturated fatty acid, but was less active than dienoic derivatives (C
18:2
). Other unsaturated compounds were less active than C
18:2
. Alcohols and glyceryl esters were active only against gram-positive organisms. In general, esterification of the carboxyl group led to a compound which was less active; monoglycerides were the sole exception. Amine derivatives, contrary to results with fatty acids, esters, and amides, showed activity against both gram-positive and gram-negative organisms.
Tilorone Hydrochloride: an Oral Interferon-Inducing Agent
Authors: Stringfellow Dale A. , Glasgow Lowell A.
Published: June 2012

Tilorone hydrochloride characteristically induces an unusually delayed and prolonged interferon response not commonly associated with other synthetic inducers. Maximum circulating interferon levels of 8,000 to 10,000 units/ml were detected 12 hr postinoculation and persisted for up to 30 hr after administration of tilorone. The fact that both oral and intraperitoneal injections of tilorone induce a similar response suggests that this delay is not based on the time required for adsorption from the gastrointestinal tract. In vitro, tilorone failed to induce detectable levels of interferon in either mouse peritoneal lymphocyte or macrophage cell cultures. Furthermore, interferon production could not be detected in the upper gastrointestinal tract after oral administration of tilorone. The striking suppression of interferon production in X-irradiated mice suggested that lymphatic tissue may be a source of interferon in response to tilorone. This concept was not supported, however, by experiments utilizing antilymphocyte serum (ALS). Tilorone induced comparable levels of interferon in both ALS-treated and control animals which had received normal serum, even though the ALS-treated mice had decreased spleen weights and peripheral lymphocyte counts. These data suggest that a radiosensitive cell population other than lymphocytes may be an important factor in the capacity of the host to produce interferon in response to tilorone. Mice which received repeated injections of tilorone developed a severe state of hyporeactivity. The degree of hyporeactivity was particularly striking when compared to that induced by polyinosinic acid:polycytidylic acid and emphasizes one of the major obstacles confronting interferon inducers as chemotherapeutic agents.
Binding of Antibiotics to Bovine and Ovine Serum
Authors: Ziv G. , Sulman F. G.
Published: June 2012

The degree of binding of 37 antibiotics to bovine and ovine serum, after treatment at therapeutic doses, was determined by equilibrium dialysis and ultrafiltration methods. In general, binding values obtained by the two methods were comparable. The extent of binding varied from 0% for cephaloridine and kanamycin to >95% for novobiocin and fusidic acid. Of the 37 drugs studied, one-fourth were less than 25% bound, one-fourth were more than 75% bound, and the percentage binding of about half of the antibiotics ranged from 25 to 75%. Animal to animal variations in the extent of binding of a particular antibiotic were very small. The capacity of bovine or ovine serum to bind antibiotics was, with a few exceptions, similar to the reported capacity of human serum. At drug concentration ranges usually achieved during therapy, variations in drug levels in serum did not influence the degree of binding except with cephalexin, lincomycin, clindamycin, and chloramphenicol. With these antibiotics, the extent of binding increased two- to sevenfold with the decrease in drug concentration in serum.
Target-Organ Treatment of Neurotropic Virus Diseases: Efficacy as a Chemotherapy Tool and Comparison of Activity of Adenine Arabinoside, Cytosine Arabinoside, Idoxuridine, and Trifluorothymidine
Authors: Allen Lois B. , Sidwell Robert W.
Published: June 2012

A sensitive in vivo system was studied for use in evaluating relatively small quantities of antiviral compounds. Swiss mice were injected intracerebrally with 10 LD
50
of type 1 herpes simplex virus (HSV) or vaccinia virus. Test compounds were injected intracerebrally into mice at a standard time interval after virus inoculation. Significant increases in the number of survivors in drug-treated, infected animals as compared to saline-treated virus controls was the criterion for evaluation of antiviral activity. 9-β-
d
-Arabinofuranosyladenine (Ara-A) was used to determine an optimal time of therapy for this system. Significant survival increases occurred when the drug was injected 3, 6, 12, and 48 hr after HSV inoculation, with maximal effect occurring after the 6-hr treatment interval. Determination of brain virus titer of 6-hr Ara-A- and saline-treated mice at various intervals indicated that treatment with the drug delayed development of detectable levels of HSV by 1 day. 1-β-
d
-Arabinofuranosylcytosine (Ara-C), trifluorothymidine (TFT), and 5-iodo-2′-deoxyuridine (IDU) were also evaluated with the use of the 6-hr treatment time against HSV and vaccinia virus. Ara-A and TFT increased the number of survivors among mice infected with either virus, whereas Ara-C increased the survivors among HSV-infected, but not vaccinia virus-infected, mice. IDU was inactive against both viruses.
In Vitro Antibiotic Susceptibility of Pseudomonads Other than
Pseudomonas aeruginosa
Recovered from Cancer Patients
Authors: Moody Marcia R. , Young Viola M. , Kenton Dolores M.
Published: June 2012

The increase in occurrence of infections due to opportunistic gram-negative bacilli in patients with impaired host defenses emphasizes the need for information on the antibiotic susceptibility of the organisms that colonize such patients. During a 20-month period, more than 100 pseudomonads which were not
Pseudomonas aeruginosa
were recovered from cancer patients at the Baltimore Cancer Research Center. These included
P. fluorescens, P. putida, P. multivorans
(
cepacia
),
P. maltophilia, P. stutzeri, P. alcaligenes
, and
P. pseudoalcaligenes
. Susceptibility tests with 12 antibiotics indicated that the intraspecies antibiograms for many of these species were more uniform than those of
P. aeruginosa
. The stability of susceptibility patterns allowed the antibiograms to be used as aids in the preliminary differentiation of these organisms. Variable antibiogram patterns were noted among certain species, i.e.,
P. fluorescens, P. stutzeri
, and
P. multivorans
, whereas each of the other species had essentially one pattern. These in vitro studies showed that some of the
Pseudomonas
species other than
P. aeruginosa
were resistant to a number of antibiotics. Among these were antibiotics that are in general use for
P. aeruginosa
infections. Such differences in antibiotic susceptibilities emphasize the necessity for careful speciation of this group of microorganisms to assure proper epidemiological documentation of colonization and infection, as well as to ensure therapy with an antimicrobial agent to which the organism is susceptible in vitro.
Hyperbaric Oxygen Exposures at 3 and 4 Atmospheres Absolute Pressure for Experimental Gas Gangrene: Succinate Protection Against Oxygen Toxicity
Authors: Hill Gale B.
Published: June 2012

The concurrent effect of succinate administration to protect against oxygen toxicity and of hyperbaric oxygen (HBO) exposures to treat model gas gangrene in mice was tested to determine whether succinate would interfere with the therapeutic efficacy of HBO. HBO (seven 90-min exposures) at 3 atmospheres absolute pressure (ATA) had been shown to reduce significantly the mortality of mice injected with
Clostridium perfringens
suspended in 10 μg of Adrenalin. When succinate was tested with this system, mortality of HBO-exposed infected animals was again significantly reduced (79% control mortality versus 17% HBO-exposed mortality), indicating that succinate does not interfere with the action of HBO. Exposures to 4 ATA of O
2
were evaluated in the same model clostridial infection with succinate used to prevent oxygen toxicity. Five 30-min exposures at 4 ATA reduced the mortality of infected animals (62% control versus 6% HBO-exposed mortality). Intraperitoneal succinate injections (10 mmoles/kg) were given 20 to 25 min prior to four of the seven 3-ATA exposures and before three of the five 4-ATA exposures. The intermittent succinate injections gave significant protection against the development of oxygen toxicity in infected and noninfected mice at both O
2
pressures. These studies support the potential clinical use of succinate or other oxygen-protective agents (i) to shorten HBO exposure times by using higher pressures to deliver the necessary O
2
dose, (ii) to increase the O
2
dose for difficult clinical situations by using maximal exposures at 4 ATA or more prolonged exposures at 2 to 3 ATA, and (iii) to continue HBO exposures in patients who require treatment but develop symptoms of oxygen toxicity.
Clinical Significance of In Vitro Synergism Between Antibiotics in Gram-Negative Infections
Authors: Klastersky J. , Cappel R. , Daneau D.
Published: June 2012

Five combinations of antibiotics (ampicillin/gentamicin, cephalothin/gentamicin, carbenicillin/gentamicin, polymyxin/carbenicillin, and carbenicillin/cephalothin) were investigated in vitro and in 148 severe infectious episodes caused by gram-negative bacilli in patients with disseminated cancer. The use of combinations that were synergistic in vitro against the offending microorganism (synergy was defined as occurring when the minimal inhibitory concentration of each of the drugs in the combination was one-quarter or less of the minimal inhibitory concentration of each drug alone) was associated with a significantly better response to antibacterial therapy (
P
< 0.01) than the use of combinations that were not synergistic against the causative agent.
Practical Quantitative Assay for 5-Fluorocytosine in Serum and Other Body Fluids
Authors: Blaker Robert G. , Doutt Barbara J.
Published: June 2012

A method is described for assaying 5-fluorocytosine levels in serum or other body fluids. It is simpler and less expensive than the standard cylinder plate assay and is therefore more practical for routine diagnostic laboratory testing.
Comparison of Colistin-Carbenicillin, Colistin, and Carbenicillin in
Pseudomonas
Sepsis in Monkeys
Authors: Saslaw Samuel , Carlisle Harold N. , Moheimani Mohammad
Published: June 2012

Intravenous inoculation of 6.2 × 10
10
to 6.7 × 10
10
Pseudomonas aeruginosa
organisms into rhesus monkeys 5 days after intratracheal inoculation of 2.0 to 2.5 mg of vincristine sulfate resulted in fatal sepsis in 8 of 10 untreated monkeys. When similarly infected monkeys were treated intramuscularly with 2.5 mg of colistin or 50 mg of carbenicillin per kg per day, all three monkeys in each treatment group survived; one of three monkeys receiving both antibiotics at the above doses died. Six of seven monkeys treated with 1.25 mg of colistin per kg per day and three of seven treated with 25 mg of carbenicillin per kg per day died; four of nine monkeys receiving both antibiotics at these doses died. A combination of the data obtained at both dose levels tested shows that 6 of 10, 3 of 10, and 5 of 12 monkeys, respectively, died after treatment with colistin, carbenicillin, and the colistin-carbenicillin combination. Antibacterial activity of serum from both infected and normal monkeys was not appreciably different when the two antibiotics were given singly or in combination. Under the conditions of this study and with the doses employed, the response of monkeys treated with the antibiotic combination did not differ significantly from that of monkeys treated with a single agent.
Independent Antibiotic Actions of Hetacillin and Ampicillin Revealed by Fast Methods
Authors: Faine S. , Harper M.
Published: June 2012

Fast methods for measuring inhibition of growth of
Escherichia coli
or
Staphylococcus aureus
by hetacillin or ampicillin showed that the rate of inhibition was a function of the antibiotic concentration. When ampicillin concentrations were measured rapidly, hetacillin was shown to have a half-life of 20 min at 37 C and
p
H 6.7. Hetacillin was much less susceptible to penicillinase (β-lactamase) than was ampicillin. An inhibitory effect of hetacillin was shown in the presence of β-lactamase, which destroyed ampicillin activity very rapidly.
Experimental Therapy of Cladosporiosis and Sporotrichosis with 5-Fluorocytosine
Authors: Block Edward R. , Jennings Anne E. , Bennett John E.
Published: June 2012

Cladosporium trichoides
and
Sporothrix schenckii
are fungi known to be pathogenic for man. No effective chemotherapy is available for cladosporiosis, and systemic sporotrichosis can be very resistant to antifungal chemotherapy. Experimental infections of mice with these fungi resembled their respective infections in man and provided a model for evaluating a new antifungal agent, 5-fluorocytosine (5-FC). Our results with four isolates of
C. trichoides
demonstrated a statistically significant dose-related therapeutic effect with 5-FC. Mortality was significantly reduced in all treatment groups, and survivors showed no clinical sign of disease despite positive brain cultures. Results with a single isolate of
S. schenckii
were less encouraging. Fatality rate was significantly decreased in all treatment groups, but no trend was noted with increasing 5-FC dosage. Survivors manifested the signs of active disease, and all liver and spleen cultures were positive for
S. schenckii
. These results indicated that (i) 5-FC may be the first drug useful in the treatment of cladosporiosis, and (ii) 5-FC may have only limited therapeutic benefit in systemic sporotrichosis.
Susceptibility of
Bacteroides fragilis
to Six Antibiotics Determined by Standardized Antimicrobial Disc Susceptibility Testing
Authors: Sutter Vera L. , Kwok Yung-Yuan , Finegold Sydney M.
Published: June 2012

The susceptibility of 100 or more strains of
Bacteroides fragilis
to six antibiotics was determined by standardized agar dilution and disc diffusion tests. Good correlation of results of the two methods was obtained with chloramphenicol, clindamycin, lincomycin, penicillin, and vancomycin. Correlation of results with erythromycin was not as good. A great deal of overlapping of zone diameters among strains classed as susceptible, intermediate, and resistant occurred with both erythromycin and lincomycin, making interpretation of disc diffusion tests difficult. All strains tested were susceptible to chloramphenicol; 94% were susceptible to clindamycin at concentrations readily achieved with ordinary dosage, and all strains were inhibited by 6.2 μg/ml, a level which is achieved with somewhat more intensive therapy. Only 7% were shown to be susceptible to erythromycin and 13% to lincomycin under the conditions of our testing procedure. Only a small percentage of the strains were susceptible to penicillin, and none was susceptible to vancomycin.
Mechanism by Which Hydnocarpic Acid Inhibits Mycobacterial Multiplication
Authors: Jacobsen Peter L. , Levy Louis
Published: June 2012

Recent work in this laboratory has shown that hydnocarpic acid (HA), a principal constituent of chaulmoogra oil, inhibits multiplication in vitro of a number of mycobacterial species. This activity of HA was not shared by several straight-chain fatty acids and by dihydrochaulmoogric acid. A study of the interaction of HA with biotin has been undertaken, based on a structural analogy between biotin and the cyclopentenyl fatty acid. The multiplication of a strain of
Mycobacterium intracellulare
susceptible to 2 μg of HA/ml was measured turbidimetrically in Dubos medium, in the presence and absence of biotin and several other compounds. Biotin and, to a lesser extent, adenine plus guanine, palmitic acid, and linoleic acid antagonized growth inhibition by HA. Desthiobiotin, thioctic acid, and succinic acid did not block inhibition of bacterial multiplication by HA. HA may act by blocking the coenzymatic activity of biotin, or it may inhibit microbial biotin synthesis. Resumption of multiplication of
M. intracellulare
after a period of inhibition by HA in broth culture was found to be accompanied by reduction of the effective concentration of the drug; this could have resulted from metabolism of HA or production of an antagonist to HA by the organisms. Also, those organisms that multiplied in the presence of HA were found to represent HA-resistant mutants of
M. intracellulare
.
In Vitro Microassay for Biological Activity of Cyclophosphamide Metabolites
Authors: Laux David , Lausch Robert N.
Published: June 2012

A rapid tissue culture assay for detecting the activated metabolites of cyclophosphamide in serum is described. Serum obtained shortly after drug administration was added to microtest wells containing a known number of previously planted target cells. The presence and amount of drug was directly correlated with the degree of inhibition of target cell replication. Either transformed or untransformed cells could be used as the target cells. No inhibition of cell growth was observed if cyclophosphamide was added directly to target cells without prior in vivo activation.

The appearance and persistence of activated drug in hamster serum was followed by using in vitro microassay. Cyclophosphamide administered intraperitoneally was metabolized to its active form very rapidly, reaching peak activity in 15 min. After 2 h, activity was no longer detectable. Drug given subcutaneously was activated less rapidly and persisted for a longer period of time. The kinetics of drug activation, as determined by tissue culture assay, appeared to be similar to that obtained by chemical assay for other species.
Cytosine Arabinoside Therapy for Herpes Simplex Encephalitis—Clinical Experience with Six Patients
Authors: Chow Anthony W. , Ronald Allan , Fiala Milan , Hryniuk William , Weil Marvin L. , Geme Joseph St. , Guze Lucien B.
Published: June 2012

Two neonates and four adults with herpes simplex virus (HSV) encephalitis were treated with cytosine arabinoside (Ara-C). A low dose of 40 to 160 mg per m
2
per day was given for 4 to 6 days by continuous intravenous infusion and, except in two cases, by intrathecal administration. In one patient, idoxuridine (IUdR) at the dose of 1 g every 4 h was also administered after 4 days of Ara-C therapy. Both neonates and two of four adults survived. Their clinical improvement was closely related in time to the onset of therapy with Ara-C (cases 1, 2, 3) and with IUdR (case 4). In one adult who died on the 27th day of illness of a massive pulmonary embolus, postmortem examination of the brain did not disclose viral inclusions, and viral culture was negative. In the other patient who died, however, brain culture postmortem was still positive for HSV despite 4 days of Ara-C therapy. Ara-C, in addition to IUdR, may be effective in HSV encephalitis treatment, but double-blind, controlled studies appear to be necessary with these agents.
Rapid, Modified Kirby-Bauer Susceptibility Test with Single, High-Concentration Antimicrobial Disks
Authors: Boyle V. James , Fancher Marilyn E. , Ross Richard W.
Published: June 2012

A rapid (6–7 hr), modified Kirby-Bauer disk-susceptibility method, by which derivatives of tetrazolium dyes are used to enhance delineation between areas of growth and zones of inhibition, has been developed. Inoculated petri plates, prepared by the Kirby-Bauer method, were sprayed, after 6 to 7 hr of incubation (37 C), with aqueous solutions of MTT-tetrazolium or INT-tetrazolium resulting in readily detectable zones of inhibition. Excellent correlation was obtained between the modified test and the standard Kirby-Bauer test when challenged with a variety of gram-negative bacteria and
Staphylococcus aureus
strains. Additionally, the modified test has demonstrated reproducibility comparable to the standard Kirby-Bauer test. It is demonstrated that the modified test is applicable to susceptibility determinations with representative, commercially available antimicrobial disks. This applicability indicates that the modified method could provide rapid in vitro guidelines for in vivo therapy.
Effect of Hydroxyurea on
Staphylococcus epidermidis
and
Micrococcus lysodeikticus
: Thickening of the Cell Wall
Authors: Feiner Rose R. , Coward Joe E. , Rosenkranz Herbert S.
Published: June 2012

Hydroxyurea-sensitive strains of
Staphylococcus epidermidis
and
Micrococcus lysodeikticus
showed marked thickening of cell walls and reduction in deoxyribonucleic acid synthesis when grown in the presence of hydroxyurea.
Evaluation of Cefazolin, a New Cephalosporin Antibiotic
Authors: Reller L. Barth , Karney Walter W. , Beaty Harry N. , Holmes King K. , Turck Marvin
Published: June 2012

Cefazolin sodium was tested in vitro against 308 isolates of
Enterobacteriaceae, Pseudomonas aeruginosa, Neisseria meningitidis, Haemophilus influenzae, Staphylococcus aureus
, and enterococcus. Broth and agar dilution and disk diffusion techniques were used with at least two sizes of inocula of organisms. Cefazolin was also studied in the treatment of 85 hospitalized patients with a variety of serious infections. In concentations of 5 μg or less/ml, cefazolin inhibited and killed more than 90% of isolates of
Enterobacteriaceae
with the exception of indole-positive
Proteus
and
Enterobacter
species. No isolate of
P. aeruginosa
and only a few of
Enterobacter
and enterococci were killed by 25 μg of cefazolin/ml, a concentration readily attainable in serum with a 500-mg dose given intramuscularly. Penicillin-susceptible as well as penicillin-resistant isolates of
S. aureus
were killed by 1 μg or less of cefazolin per ml; however, 25 μg/ml was required to kill 100% of the strains when the inoculum size was increased 100-fold. Cefazolin treatment appeared effective in 82 of 85 patients, including four with endocarditis. Pain was minimal after intramuscular injection, and thrombophlebitis was not observed in those treated intravenously. No patient developed a positive Coombs test, and no evidence of renal toxicity was apparent in clinical studies.
Radioimmunoassay for Measurement of Gentamicin in Blood
Authors: Mahon W. A. , Ezer J. , Wilson T. W.
Published: June 2012

Gentamicin toxicity has been shown to be related to high concentrations in serum. Because there is a narrow range between its therapeutic and toxic levels, serial monitoring of gentamicin is the most reliable method of guiding therapy. Microbiological assays commonly in use do not afford the desired speed and accuracy, and results may be difficult to interpret in the presence of other antimicrobials. Hence, a rapid, sensitive, and highly specific radioimmunoassay for measurement of gentamicin in serum has been developed. Antibody to gentamicin was raised in rabbits by using a gentamicin-albumin conjugate. Tritiated gentamicin (specific activity 1.0 Ci/mM) competes with unlabeled gentamicin for binding sites on the antibody. Dextran-coated charcoal separates the unbound from antibody-bound gentamicin. Serum levels of gentamicin are determined by comparison with a standard curve. This method can detect concentrations as low as 0.01 μg/ml. Results of a 24-tube run can be obtained in 1 h, thus allowing modification of gentamicin dosage to advantage.
Silver Sulfadiazine: Effect on the Ultrastructure of
Pseudomonas aeruginosa
Authors: Coward Joe E. , Carr Howard S. , Rosenkranz Herbert S.
Published: June 2012

Pseudomonas aeruginosa
exposed to silver sulfadiazine (AgSu) were examined in an electron microscope. The treated cells were distorted in shape, and structures (blebs) protruded from the cell surface. These “blebs” appeared to arise from the cell wall. A strain of
P. aeruginosa
resistant to AgSu did not display these changes. Upon exposure of
P. aeruginosa
to silver nitrate, none of these changes was seen; rather, such cells are characterized by large, central aggregations of nuclear material. The results are consistent with previous findings which suggested that AgSu acted at the cell surface.