bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-level colonization of hospitalized patients with methicillin-resistant coagulase-negative staphylococci and emergence of the organisms during surgical antimicrobial prophylaxis
Authors: Kernodle D S , Barg N L , Kaiser A B
Published: June 2012

By use of techniques that have been developed to detect small numbers of methicillin-resistant staphylococci, we cultured samples from the nares and subclavian and inguinal areas of 29 patients before and after cardiac surgery and 10 patients before and after coronary angioplasty. Methicillin-resistant coagulase-negative staphylococci were recovered before the surgical or angioplasty procedure from 74% of patients. The quantitative recovery of methicillin-resistant isolates before cardiac surgery or coronary angioplasty was compared with the number of methicillin-resistant staphylococci detected at the same site 3 days after the procedure. In cardiac surgery patients (who received antibiotic prophylaxis), 17 of the 28 sites (61%) in which low-level colonization with methicillin-resistant strains was detected preoperatively contained high levels of methicillin-resistant staphylococci postoperatively. In contrast, coronary angioplasty patients (who did not receive antibiotic prophylaxis) did not have any of the 14 sites containing low levels of methicillin-resistant strains before angioplasty emerge to harbor high levels of methicillin-resistant staphylococci after angioplasty. Methicillin-resistant coagulase-negative staphylococci from each site in which high levels of methicillin-resistant staphylococci emerged postoperatively were paired with preoperative isolates from the same site. Identical antibiograms and plasmid profile patterns were demonstrated for seven of the pre- and postoperative isolate pairs, suggesting that the high levels of methicillin-resistant coagulase-negative staphylococci detected on the skin or in the nares after cardiac surgery were derived from methicillin-resistant organisms present at the site preoperatively in much smaller numbers.
Comparison of difloxacin, enoxacin, and cefazolin for the treatment of experimental Staphylococcus aureus endocarditis
Authors: Boscia J A , Kobasa W D , Kaye D
Published: June 2012

This study compared difloxacin administered orally, enoxacin administered orally, and cefazolin administered intramuscularly for the treatment of experimental Staphylococcus aureus endocarditis. Difloxacin significantly reduced bacterial counts of vegetations compared with enoxacin. This study demonstrated that difloxacin was significantly more effective than enoxacin and as effective as cefazolin for the treatment of S. aureus endocarditis in rabbits.
In vitro susceptibilities of common pediatric pathogens to LY163892
Authors: Shelton S , Nelson J D
Published: June 2012

LY163892 is a carbacephem antibiotic for oral administration with an antibacterial spectrum similar to that of cefaclor and amoxicillin-clavulanic acid. It has greater stability than cefaclor and greater activity against beta-lactamase-producing Haemophilus influenzae and Escherichia coli. LY163892 is less active than amoxicillin against streptococci and less active than amoxicillin-clavulanic acid against Branhamella catarrhalis but comparable against other pathogens.
Comparative toxicities of cephalosporin antibiotics in a rabbit kidney cell line (LLC-RK1)
Authors: Williams P D , Laska D A , Tay L K , Hottendorf G H
Published: June 2012

The rabbit kidney cell line LLC-RK1 was tested for its ability to discriminate the toxicities of six cephalosporin antibiotics according to their in vivo nephrotoxic potentials in rabbits. With the exception of cephalothin, which was markedly toxic to kidney cells in vitro, a good correlation between in vitro toxicity and in vivo nephrotoxicity was obtained, yielding the following toxicity rank order: ceftazidime less than cefazolin approximately cefoperazone less than cephaloglycin approximately cephaloridine. The addition of a kidney microsomal S9 fraction to the cell cultures desacetylated cephalothin as occurs in vivo and detoxified this antibiotic, providing it with the proper toxicity relative to the other cephalosporins. When compared with parent structures, desacetylated derivatives of other cephalosporins such as cephapirin were similarly found to be less toxic to LLC-RK1 cells. The acetylated cephalosporin cephaloglycin was not detoxified by the kidney S9 fraction and was desacetylated three to four times slower than cephalothin by renal esterases. Thus, the rate and extent of desacetylation of cephalosporins may play a role in their in vivo nephrotoxic potential. Our results further suggest that LLC-RK1 cells will provide a useful model for evaluating the potential nephrotoxicity of new cephalosporin antibiotics before in vivo studies.
In vitro and in vivo Phlebovirus inhibition by ribavirin
Authors: Sidwell R W , Huffman J H , Barnett B B , Pifat D Y
Published: June 2012

Ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) was markedly inhibitory in vitro to Adames and Balliet strains of Punta Toro virus (PTV), a Phlebovirus related to Rift Valley fever and sandfly fever viruses. By using inhibition of viral cytopathic effect in LLC-MK2 cells with both virus strains, the 50% effective dose was 4 to 10 micrograms/ml and the virus rating was 1.3. The Adames strain of PTV infection in mice was established for evaluation of the in vivo antiviral efficacy of ribavirin. The drug was administered subcutaneously (s.c.) twice daily for 5 to 7 days beginning 4 h pre-virus inoculation, 24 h post-virus inoculation, or 36 h post-virus inoculation, with increased survivors, reduced hepatic icterus, reduction of serum glutamic oxalic acid transaminase and serum glutamic pyruvic acid transaminase, and inhibition of infectious virus from sera and livers of infected mice. The minimum effective dose was 4.7 mg/kg per day, with a maximum tolerated dose of 75 mg/kg per day. When the same treatment schedule beginning 4 h pre-virus inoculation, 4 h post-virus inoculation, or 24 h post-virus inoculation was used, orally administered ribavirin was effective at doses as low as 6.3 mg/kg per day. Single s.c. ribavirin treatments at doses of 175 to 700 mg/kg administered from 4 to 48 h post-virus inoculation were also effective. No effect was seen when ribavirin was administered s.c. to mice infected intracerebrally with the PTV strain Balliet, even though treatment was begun 36 h before virus exposure.
Pharmacokinetics of carumonam after single and multiple 1- and 2-g dosage regimens
Authors: Bérubé D , Vallée F , Panneton A C , Bergeron M G , LeBel M
Published: June 2012

The pharmacokinetics of carumonam after single and multiple intravenous administration of 1- and 2-g dosage regimens were studied in 12 young male volunteers. Plasma and urine samples were collected in serial order for 24 h and assayed by high-pressure liquid chromatography. The mean elimination half-life of carumonam was not significantly affected by either dosage regimen or single dose versus steady state, ranging from 1.3 to 1.5 h. Mean concentrations at the end of the interval were not influenced by a multiple-dose administration. The normalized volume of distribution was independent of the dose, with values ranging from 0.16 to 0.19 liters/kg. After multiple administration, carumonam was cleared from the body more rapidly: from 96.2 to 121.7 ml/min after 1 g every 8 h, and from 102.1 to 122.3 ml/min after 2 g every 8 h (P less than 0.05). After 24 h, 75.0 to 80.7% of the dose was excreted unchanged in the urine. The protein binding of carumonam to human plasma remained stable at 28%. Carumonam was well tolerated by the volunteers.
National Committee for Clinical Laboratory Standards agar dilution susceptibility testing of anaerobic gram-negative bacteria
Authors: Brown W J
Published: June 2012

One hundred nine recent clinical isolates of anaerobic gram-negative bacteria were tested in triplicate by the National Committee for Clinical Laboratory Standards agar dilution procedure for their susceptibility to 32 antimicrobial agents. All isolates were inhibited by imipenem, but there were significant numbers of strains resistant to other beta-lactam drugs, and therefore the in vitro response to these antimicrobial agents cannot be predicted. This was particularly true for the bile-resistant or Bacteroides fragilis group. beta-Lactamase production was detected in 82% of the bacteroides with the nitrocefin test. Clavulanic acid combined with amoxicillin and ticarcillin and sulbactam combined with ampicillin resulted in synergistic activity against all beta-lactamase-positive organisms. Ceftizoxime was the most active of the cephalosporins. Two percent of the isolates were resistant to chloramphenicol and metronidazole. Clindamycin resistance was detected in 38% of the B. fragilis group, which is a marked increase from the 4% detected 10 years ago at this institution.
Reduced parasitemia observed with erythrocytes containing inositol hexaphosphate
Authors: Mintzer C L , Deloron P , Rice-Ficht A , Durica D , Struck D K , Roessner C A , Nicolau C , Ihler G M
Published: June 2012

Chemicals entrapped in erythrocytes by hypotonic hemolysis can be assessed for possible antiparasitic activity both in vivo and in vitro, regardless of whether they are able to diffuse into erythrocytes readily. Inositol hexaphosphate, a highly charged compound, produced a dramatic lowering of the percentage of cells infected by Babesia microti in vivo and both B. microti and Plasmodium falciparum in vitro. Several possible mechanisms for this observation are discussed.
Potent antipneumocystis and antitoxoplasma activities of piritrexim, a lipid-soluble antifolate
Authors: Kovacs J A , Allegra C J , Swan J C , Drake J C , Parrillo J E , Chabner B A , Masur H
Published: June 2012

Piritrexim, a lipid-soluble antifolate, was evaluated for its activity against Pneumocystis carinii and Toxoplasma gondii. The concentration of piritrexim needed to inhibit 50% of the catalytic activity of P. carinii dihydrofolate reductase (DHFR) was 19.3 nM, and that for T. gondii DHFR was 17.0 nM, concentrations that were 40- to over 1,000-fold less than those needed for the inhibition of activity by trimethoprim and pyrimethamine, the antifolates conventionally used in treating these organisms. Piritrexim was able to inhibit replication of T. gondii in a mouse peritoneal macrophage model at concentrations of 0.1 to 1.0 microM. Leucovorin, a reduced folate that can bypass the inhibition of DHFR by antifols in mammalian cells but not in protozoa, did not affect the ability of piritrexim to inhibit T. gondii replication. The addition of sulfadiazine, which alone was ineffective, to piritrexim allowed inhibition of T. gondii replication at lower concentrations of piritrexim than when piritrexim was used alone. These results suggest that piritrexim, alone or combined with a sulfonamide, may be a highly potent antitoxoplasma and antipneumocystis agent that could provide major pharmacologic and clinical advantages over available agents.
Routes of quinolone permeation in Escherichia coli
Authors: Chapman J S , Georgopapadakou N H
Published: June 2012

The uptake of quinolone antibiotics by Escherichia coli was investigated by using fleroxacin (RO 23-6240, AM 833) as a prototype compound. The uptake of fleroxacin was reduced and its MIC was increased in the presence of magnesium. Quinolones induced lipopolysaccharide release, increased cell-surface hydrophobicity and outer membrane permeability to B-lactams, and sensitized cells to lysis by detergents. These effects were also antagonized by magnesium and were very similar to those seen with EDTA and gentamicin. MICs of quinolones in portin-deficient strains were increased relative to those of the parent strain, consistent with a porin pathway of entry. However, MICs were further increased in the presence of magnesium; the size of the additional increase showed a positive correlation with quinolone hydrophobicity in an OmpF- OmpC- OmpA- strain. When quinolones were mixed with divalent cations in solution, changes in quinolone fluorescence suggestive of metal chelation were observed. The addition of fleroxacin to a cell suspension resulted in a rapid initial association of fluorescence with cells, followed by a brief decrease and a final time-dependent linear increase in cell-associated fluorescence. We interpret these results as representing chelation of outer membrane-bound magnesium by fleroxacin and other quinolones, dissociation of the quinolone-magnesium complex from the outer membrane, and diffusion of the quinolone through both porins and exposed lipid domains on the outer membrane. For a given quinolone, the contribution of the porin and nonporin pathways to total uptake is influenced by the hydrophobicity of the quinolone.
Molecular cloning and mechanism of trimethoprim resistance in Haemophilus influenzae
Authors: de Groot R , Campos J , Moseley S L , Smith A L
Published: June 2012

We studied 10 trimethoprim-resistant (Tmpr) Haemophilus influenzae isolates for which agar dilution MICs were 10 to greater than 200 micrograms/ml. Trimethoprim resistance was transferred from two Tmpr H. influenzae isolates to a Tmps strain by conjugation or transformation. Wild-type Tmpr strains and Tmpr transcipients did not contain detectable plasmid DNA. The trimethoprim resistance gene was cloned into a cosmid vector, and recombinant plasmids were transduced into Escherichia coli. A 0.50-kilobase intragenic probe derived from a 12.9-kilobase fragment which encoded trimethoprim resistance hybridized with whole-cell DNA from Tmps and Tmpr strains. Southern blot analysis of restricted DNA from isogenic Tmps and Tmpr H. influenzae indicated that acquisition of trimethoprim resistance involved a rearrangement or change in nucleotide sequence. Hybridization was not seen with DNA derived from Tmpr E. coli containing dihydrofolate reductase I, II, and III genes or with Tmpr Neisseria meningitidis, Neisseria gonorrhoeae, and Pseudomonas cepacia. Southern hybridization with 12 multiply resistant encapsulated H. influenzae strains confirmed that the trimethoprim resistance gene was chromosomally mediated. Dihydrofolate reductase activity was significantly greater in cell sonicate supernatants of Tmpr strains in comparison with isogenic Tmps recipients. Differences were not found in the trimethoprim inhibition profile of dihydrofolate reductase activity in Tmps and Tmpr strains. We conclude that the mechanism of trimethoprim resistance in H. influenzae is overproduction of chromosomally located dihydrofolate reductase.
Effect of temperature on inoculum as a potential source of error in agar dilution plate count bactericidal measurements
Authors: Woolfrey B F , Gresser-Burns M E , Lally R T
Published: June 2012

The effect of increased temperature on Staphylococcus aureus during the inoculation step of the agar dilution plate count method was investigated as a possible cause of artificially high persister counts. For some isolates, exposure of the inoculum to increased temperature resulted in higher persister counts and diminution or loss of the paradoxical effect. The persister patterns for three representative S. aureus isolates are presented to illustrate the strain- and temperature-dependent nature of the phenomenon. For any isolate, the net effect appears to be caused by an interplay of temperature-induced inoculum loss and temperature-induced cell division cycle blockage. A modification of the agar dilution plate count inoculation step to circumvent such problems is described.
In vitro activities of two oxazolidinone antimicrobial agents, DuP 721 and DuP 105
Authors: Neu H C , Novelli A , Saha G , Chin N X
Published: June 2012

The antibacterial activities of DuP 105 and DuP 721, new oxazolidinone antimicrobial agents, were compared with those of beta-lactams and glycopeptides. Ninety percent of Staphylococcus aureus and Staphylococcus epidermidis isolates, including methicillin-resistant isolates, were inhibited by 4 micrograms of DuP 105 and 1 microgram of DuP 721 per ml. DuP 721 inhibited hemolytic streptococcus groups A, B, C, F, and G at a concentration of less than or equal to 1 microgram/ml, and it inhibited viridans group streptococci at a concentration of 2 micrograms/ml. Both agents inhibited Listeria monocytogenes, Corynebacterium group JK species, anaerobic cocci, and Clostridium spp. including Clostridium difficile. They did not inhibit members of the family Enterobacteriaceae or Pseudomonas aeruginosa, but the MIC for 90% of Bacteroides fragilis isolates was 8 micrograms of DuP 721 per ml.
Improved sodium hydroxide digestion method without homogenization for extraction of gentamicin from renal tissue
Authors: Brown S A , Sugimoto K , Smith G G , Garry F B
Published: June 2012

Recovery of gentamicin from renal cortical tissue (assayed by fluorescence polarization immunoassay) was highest (P less than 0.05) when using a sodium hydroxide (NaOH) digestion procedure without homogenization (90.0 +/- 5.4%), followed by homogenization with NaOH digestion (85.8 +/- 7.7%) and homogenization with trichloroacetic acid precipitation (84.4 +/- 3.3%). Simple homogenization recovered the least gentamicin (59.0 +/- 5.2%; P less than 0.05).
Effect of cardiopulmonary bypass on vancomycin and netilmicin disposition
Authors: Klamerus K J , Rodvold K A , Silverman N A , Levitsky S
Published: June 2012

The effect of cardiopulmonary bypass (CPB) on the disposition of vancomycin (15 mg/kg) and of netilmicin (3 mg/kg) was studied in 10 adults. The concentration-time profile of the drug in serum and renal clearance were characterized pre-CPB, during CPB, and post-CPB. Vancomycin and netilmicin exhibited initial decreases in mean concentrations in serum of 4.0 mg/liter (16.8%) and 2.2 mg/liter (29.1%), respectively, upon initiation of CPB. Netilmicin concentrations in serum rebounded to a mean of 0.6 mg/liter (15.4%) within 90 min on CPB and then continuously decreased. Vancomycin concentrations in serum demonstrated a rebound increase of 2.3 mg/liter (23.5%) at the end of CPB when the aorta was unclamped. Mean renal clearance throughout CPB was decreased for vancomycin (58.4 to 43.4 ml/min per m2) and netilmicin (53.4 to 31.5 ml/min per m2). The rebound in vancomycin concentration in serum strongly correlated with the length of time between unclamping the aorta and coming off CPB (r = 0.94), as well as with the increase in temperature upon rewarming (r = 0.92).
Spectinomycin disk zone diameter as a predictor of outcome in clinical treatment of gonorrhea
Authors: McChesney D G , Boslego J W , Khan W N
Published: June 2012

The MICs for 41 Neisseria gonorrhoeae strains from patients receiving spectinomycin treatment were determined by the agar dilution method and compared with the zones of inhibition produced by disks containing 100 micrograms of spectinomycin. Our data demonstrated a good correlation between the two methods. Moreover, a zone of inhibition of less than or equal to 15 mm was a good predictor of clinical treatment failures with spectinomycin.
Randomized clinical trial of rifampin-trimethoprim and sulfamethoxazole-trimethoprim in the treatment of localized urinary tract infections
Authors: Stein G E , Gurwith D , Gurwith M
Published: June 2012

To investigate whether 10 days of rifampin-trimethoprim (RIF-TMP) or 6 weeks of sulfamethoxazole-trimethoprim (SMX-TMP) would decrease the relapse rate in patients with acute uncomplicated upper urinary tract infections in comparison with 10 days of SMX-TMP, we randomized 189 patients to receive RIF-TMP or SMX-TMP in a ratio of 1:2. After the site of infection was established by the antibody-coated bacterium (ACB) test, patients with upper-tract infections who received SMX-TMP were again randomized and received either a total of 6 weeks or 10 days of therapy. All patients who received RIF-TMP were treated for 10 days. Clinical and microbiological evaluations were repeated at 2 and 6 weeks posttreatment. Eighty-five patients (54 ACB positive) received 10 days of RIF-TMP, 71 patients (45 ACB positive) received 10 days of SMX-TMP, and 18 patients (18 ACB positive) received 6 weeks of SMX-TMP. The overall recurrence rates in patients who received 10 days of therapy were 32% for RIF-TMP and 23% for SMX-TMP (P = 0.13). There were 12 (14%) relapses in the RIF-TMP group compared with 2 (3%) relapses in the SMX-TMP group (P = 0.01). In patients with upper-tract infections, the relapse rates were not statistically significantly different (P = 0.13). There were two (11%) recurrences (one relapse and one reinfection) in the 6-week treatment group. This 6% relapse rate was not different from the 4% relapse rate observed in patients with upper-tract infections who received 10 days of SMX-TMP. The number of patients who discontinued treatment because of an adverse effect in the 6-week SMX-TMP treatment group was significantly greater than those in the 10-day SMX-TMP treatment group (P=0.003) and the RIF-TMP treatment group (P=0.05). Ten days of SMX-TMP was as effective as 6 weeks of SMP-TMP or 10 days of RIF-TMP in the treatment of uncomplicated upper urinary tract infections and caused the fewest untoward effects.
Ciprofloxacin activity in cyst fluid from polycystic kidneys
Authors: Elzinga L W , Golper T A , Rashad A L , Carr M E , Bennett W M
Published: June 2012

Renal cyst infection in patients with polycystic kidney disease (PKD) is often unresponsive to standard antimicrobial therapy, in part because of the failure of most antibiotics to adequately penetrate cyst fluid. Ciprofloxacin, a new quinolone antibiotic, possesses in vitro activity against most pathogens likely to be encountered in renal cyst infection. To study the potential usefulness of ciprofloxacin for the treatment of cyst infection, fluid from 70 cysts was obtained from seven patients with polycystic kidney disease who were receiving the drug. Cysts were categorized as nongradient or gradient by the sodium concentration in the fluid. The ciprofloxacin concentration within cysts was measured, and the cyst fluid bactericidal activity against likely cyst fluid pathogens was determined. The mean (+/- standard error) ciprofloxacin concentration was 12.7 +/- 2.9 micrograms/ml. Preferential accumulation of ciprofloxacin occurred in gradient cysts; these levels exceeded levels in serum by more than fourfold. Cyst fluid bactericidal activity titers were uniformly high against Escherichia coli and Proteus mirabilis, while less activity was observed against Streptococcus faecalis, Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis.
Enhanced phagocytosis, killing, and serum sensitivity of Escherichia coli and Staphylococcus aureus treated with sub-MICs of imipenem
Authors: Adinolfi L E , Bonventre P F
Published: June 2012

The influence of pretreatment of Escherichia coli and Staphylococcus aureus with sub-MICs of the new beta-lactam antibiotic imipenem on phagocytosis and killing by murine peritoneal macrophages and the susceptibility of these organisms to serum bactericidal activity were studied. The effects of imipenem, a round form inducer in gram-negative rods, and piperacillin, a filamentous form inducer, were compared. Bacteria grown in the presence of sub-MICs of imipenem or piperacillin were incubated for 30 min with macrophage monolayers in the absence of antibiotic. Phagocytosis, killing, and survival within macrophages were evaluated by microbiological and fluorescence microscope assays. Bacteria grown in the presence of a sub-MIC of imipenem were phagocytized and killed in numbers significantly higher than untreated or piperacillin-treated bacteria were. Intracellular bacteria pretreated with a sub-MIC of imipenem were also readily killed by lymphokine-activated macrophages. Prior treatment with a sub-MIC of imipenem resulted in an increased susceptibility of E. coli but not S. aureus to the bactericidal activity of immune serum. Imipenem treatment and immune serum acted synergistically to enhance phagocytosis and killing. The data indicate that exposure of E. coli and S. aureus to a sub-MIC of imipenem enhances the susceptibility of these potential pathogens to cellular and humoral host defense mechanisms.
Concentrations of erythromycin, 2'-acetyl erythromycin, and their anhydro forms in plasma and tonsillar tissue after repeated dosage of erythromycin stearate and erythromycin acistrate
Authors: Gordin A , Männistö P T , Antikainen R , Savolainen S , Ylikoski J , Kokkonen P , Rauramaa V
Published: June 2012

The concentrations of erythromycin, 2'-acetylerythromycin (2'-AE) and their anhydro forms in plasma and tonsillar tissue were analyzed after a 3-day repeated-dosage regimen of erythromycin stearate (ES; 500 mg twice a day [b.i.d]) and erythromycin acistrate (EA), a new erythromycin prodrug, at two doses (400 and 500 mg b.i.d.). The tonsils of 40 patients were removed at 112 to 329 min after intake of the last dose. Blood samples were collected at the time of tonsillectomy and at 0, 2, and 6 h after the last dose. At all time points, EA produced severalfold more total antibiotic (erythromycin + 2'-AE) concentrations in plasma compared with ES. There were two nonabsorbers in the ES group, but none in the two EA groups. The mean total antibiotic levels in tonsillar tissue after EA treatment exceeded the levels after treatment with ES by a factor of 3 (for EA at 400 mg b.i.d.) and 4.5 (for EA at 500 mg b.i.d.). The ratios of erythromycin concentration in tonsil to that in plasma at the time of tissue removal were quite similar for all groups (means, 0.51 to 0.54). In the EA groups, 2 of 26 (8%) patients had no measurable erythromycin in the tonsillar tissue samples, whereas in the ES group, 3 of 14 (21%) patients had no measurable erythromycin in the same tissue. The degree of hydrolysis of 2'-AE to erythromycin was about 25% in plasma at the time of tonsillectomy for both EA groups and about 40% in tonsillar tissue. There were negligible amounts of anhydro forms in plasma after EA administration, whereas in the ES group, anhydroerythromycin levels were, from time to time, even higher than erythromycin levels. Very high levels of anhydro forms were detected in tonsillar tissue after ES treatment, whereas only low levels were found after EA administration.
Phosphonylmethoxyethyl purine derivatives, a new class of anti-human immunodeficiency virus agents
Authors: Pauwels R , Balzarini J , Schols D , Baba M , Desmyter J , Rosenberg I , Holy A , De Clercq E
Published: June 2012

A study of the structure-activity relationship of a series of newly synthesized phosphonylmethoxyalkyl purine and pyrimidine derivatives revealed that several adenine derivatives substituted at the N9 position by a 2-phosphonylmethoxyethyl (PME) group inhibited human immunodeficiency virus (HIV)-induced cytopathogenicity and HIV antigen expression in vitro at concentrations significantly below the toxicity threshold for the host cells. In terms of anti-HIV potency in MT-4 cells, the PME 2,6-diaminopurine derivative (50% effective dose [ED50], 1 microM) ranked first, followed by the PME adenine derivative (ED50, 2 microM [MT-4]) and the PME 2-monoaminopurine derivative (ED50, 45 microM). Antiretroviral activity was also demonstrated in ATH8 and H9 cells, which were de novo infected with HIV, and extended to C3H mouse fibroblasts infected with Moloney murine sarcoma virus. Unlike 2',3'-dideoxyadenosine, these compounds were not found to be degraded by deaminases derived from bovine intestine.
Carumonam versus ceftazidime for urinary tract infections
Authors: Edelstein H , Oster S , Cassano K , McCabe R
Published: June 2012

Carumonam is a new monobactam antibiotic with potent activity against gram-negative aerobes. To study the efficacy and safety of carumonam for treatment of complicated and uncomplicated urinary tract infections, 54 patients were randomized to therapy with either carumonam or ceftazidime. Of 42 patients who could be evaluated, 82% of the carumonam-treated patients and 80% of the ceftazidime-treated patients were cured clinically. At 5 to 9 days posttherapy, microbiologic criteria indicated that 13 carumonam-treated patients (48%) and 8 ceftazidime-treated patients (53%) were cured. Patients with indwelling bladder catheters at the end of therapy had a markedly worse microbiologic outcome than those without catheters. Enterococcus sp. reinfection was common in both groups. Possible adverse clinical and laboratory reactions occurred in six carumonam-treated patients (21%) and four ceftazidime-treated patients (27%). Most reactions occurred at the end of therapy and resolved with discontinuation of the study drug. In this small study, carumonam appeared as safe and as effective as ceftazidime for the treatment of complicated and uncomplicated urinary tract infections.
Glucokinase-deficient mutant of Penicillium chrysogenum is derepressed in glucose catabolite regulation of both beta-galactosidase and penicillin biosynthesis
Authors: Barredo J L , Alvarez E , Cantoral J M , Diez B , Martin J F
Published: June 2012

One glucokinase-deficient mutant (glk1) of Penicillium chrysogenum AS-P-78 was isolated after germ tube-emitting spores were mutated with nitrosoguanidine and selected for growth on lactose-containing medium in the presence of inhibitory concentrations of D-2-deoxyglucose (3 mM). Penicillin biosynthesis was greatly reduced (55%) in D-glucose-grown cultures of the parental strain, but this sugar had no repressive effect on the rate of penicillin biosynthesis in the mutant glk1. This mutant was deficient in ATP-dependent glucokinase and showed a greatly reduced uptake of D-glucose. The parental strain P. chrysogenum AS-P-78 showed in vitro ATP-dependent phosphorylating activities of D-glucose, D-2-deoxyglucose, and D-galactose. The glk1 mutant was deficient in the in vitro phosphorylation of D-glucose and D-2-deoxyglucose but retained a normal D-galactose-phosphorylating activity. D-Glucose repressed both beta-galactosidase and isopenicillin-N-synthase but not acyl coenzyme A:6-aminopenicillanic acid acyltransferase in the parental strain. The glucokinase-deficient mutant was simultaneously derepressed in carbon catabolite regulation of beta-galactosidase and isopenicillin-N-synthase, suggesting that a common regulatory mechanism is involved in carbon catabolite regulation of both sugar utilization and penicillin biosynthesis.
Antibacterial activity of HRE 664, a new parenteral penem
Authors: Cullmann W , Stieglitz M
Published: June 2012

The antibacterial activity of the new penem compound HRE 664 was evaluated in 451 clinical isolates, including ampicillin-resistant members of the family Enterobacteriaceae, Acinetobacter spp., Haemophilus influenzae, Staphylococcus aureus, and beta-hemolytic streptococci, and compared with those of piperacillin, ceftazidime, ceftriaxone, aztreonam, imipenem, and the penem compound Sch 34343. The new agent HRE 664 exhibited antibacterial activity comparable to that of the penem Sch 34343 and imipenem. The MICs of the new agent HRE 664 for 90% of the strains tested ranged from 1 to 4 micrograms/ml against Enterobacteriaceae and were 0.06 micrograms/ml for Staphylococcus aureus and 0.125 micrograms/ml for beta-hemolytic streptococci.
Comparative in vitro activities of pristinamycin, its components, and other antimicrobial agents against anaerobic bacteria
Authors: Laforest H , Fourgeaud M , Richet H , Lagrange P H
Published: June 2012

Using an agar dilution technique, we compared the activities of pristinamycin and its components PIA and PIIA with those of penicillin G, cefoxitin, chloramphenicol, metronidazole, and clindamycin against 200 strains of anaerobic bacteria isolated from suppurative lesions. The antimicrobial activity of pristinamycin was similar to that of chloramphenicol. On the basis of these results and because of its antistaphylococcal and antistreptococcal activities and its absence of toxicity, pristinamycin might be a valuable therapeutic agent for treating mixed aerobic-anaerobic cutaneous infections.
Uridine reverses the toxicity of 3'-azido-3'-deoxythymidine in normal human granulocyte-macrophage progenitor cells in vitro without impairment of antiretroviral activity
Authors: Sommadossi J P , Carlisle R , Schinazi R F , Zhou Z
Published: June 2012

We evaluated the effects of natural purine and pyrimidine nucleosides on protection from or reversal of 3'-azido-3'-deoxythymidine (AZT) cytotoxicity in human bone marrow progenitor cells by using clonogenic assays. The selectivity of the "protection" or "rescue" agents was examined in evaluating the antiretroviral activity of AZT in combination with these modulating agents and of AZT alone. Following exposure of human granulocyte-macrophage progenitor cells for 2 h to 5 microM AZT (70% inhibitory concentration), increasing concentrations of potential rescue agents were added. Cells were cultured, and colony formation was assessed after 14 days. At concentrations of up to 50 microM no natural 2'-deoxynucleosides, including thymidine, were able to reverse the toxic effects of AZT. Dose-dependent reversal was observed with uridine and cytidine, and essentially complete reversal was achieved with 50 microM uridine. In the protection studies, 100 microM thymidine almost completely antagonized the inhibition of granulocyte-macrophage colony formation produced by 1 microM AZT (50% inhibitory concentration), and 50 microM uridine effected 60% protection against a toxic concentration of AZT (5 microM) (70% inhibitory concentration). The antiretroviral activity of AZT in human peripheral blood mononuclear cells, assessed by revere transcriptase assays, was substantially decreased in the presence of thymidine, whereas no impairment of suppression of viral replication was observed in the presence of uridine in combination with AZT at a molar ratio (uridine/AZT) as high as 10,000. This demonstration of the capacity of uridine to selectively rescue human bone marrow progenitor cells from the cytotoxicity of AZT suggests that use of uridine rescue regimen with AZT may have potential therapeutic benefit in the treatment of acquired immunodeficiency syndrome.
Inhibition of Escherichia coli growth and diaminopimelic acid epimerase by 3-chlorodiaminopimelic acid
Authors: Baumann R J , Bohme E H , Wiseman J S , Vaal M , Nichols J S
Published: June 2012

The diaminopimelic acid (DAP) analog, 3-chloro-DAP, was synthesized and tested as the racemic acid for antibacterial activity and for inhibition of DAP epimerase. 3-Chloro-DAP was a potent inhibitor of DAP epimerase purified from Escherichia coli (Ki = 200 nM), and it is argued that 3-chloro-DAP is converted to a tight-binding transition state analog at the active site of this enzyme. Furthermore, 3-chloro-DAP inhibited growth of two E. coli mutants. In one of the mutants known for supersusceptibility to beta-lactams, inhibition was not seen until the mid-log phase of growth, while in the other mutant, a DAP auxotroph, inhibition occurred much earlier. Growth inhibition was reversed by DAP in both strains. In the auxotroph, the reversal was specific for meso-DAP, indicating that DAP epimerase was the target for 3-chloro-DAP. Thus we suggest a novel mechanism of bacterial growth inhibition which depends on DAP epimerase inhibition by a DAP analog.
In vitro activity of PD 127,391, an enhanced-spectrum quinolone
Authors: Wise R , Ashby J P , Andrews J M
Published: June 2012

The in vitro activity of PD 127,391, a dihalogenated quinolone, was compared with those of ofloxacin, ciprofloxacin, nalidixic acid, gentamicin, and cefuroxime against 525 recent isolates and well-characterized antimicrobial agent-resistant strains. The MICs of PD 127,391 against 90% of members of the family Enterobacteriaceae, Bacteroides fragilis, Haemophilus influenzae, Neisseria sp., and Streptococcus pneumoniae were less than or equal to 0.12 microgram/ml. Some 90% of Pseudomonas aeruginosa and staphylococci were susceptible to 0.25 micrograms of PD 127,391 per ml. Against most strains, PD 127,391 was 2- to 8-fold more active than ciprofloxacin, but it was 64-fold more active than ciprofloxacin against B. fragilis. Strains of members of the family Enterobacteriaceae which were resistant to nalidixic acid were less susceptible to all of the quinolones tested, including PD 127,391. The MIC and minimum lethal concentration of PD 127,391 against three strains of Chlamydia trachomatis were each 0.06 microgram/ml, and the MIC against 90% of 21 strains of Mycobacterium tuberculosis was 1 microgram/ml. PD 127,391 was less active at pH 5, its maximal activity being at pH 7 to 8. The presence of urine at pH 5.9 decreased the bactericidal activity. The protein binding of PD 127,391 was 2 to 7%, and serum had little effect on activity.
Mode of action of a new type of UDP-glucose analog against herpesvirus replication
Authors: Alarcón B , González M E , Carrasco L , Méndez-Castrillón P P , García-López M T , de las Heras F G
Published: June 2012

The mode of action of a new type of UDP-glucose analog against herpes simplex virus type 1 (HSV-1) replication was examined. The analog showed good selectivity and potent activity. At 10 micrograms/ml, P-536 inhibited the formation of infectious HSV-1 by more than 90%, whereas at 100 micrograms/ml it had no cytotoxic effects, as evidenced by phase-contrast microscopy. P-536 showed a wide spectrum of action and was active against HSV-1, adenovirus type 5, vaccinia virus, poliovirus type 1, encephalomyocarditis virus, vesicular stomatitis virus, influenza virus, and measles virus, irrespective of whether these viruses have lipidic envelopes or not. P-536 clearly inhibited protein glycosylation if added at the time when late viral proteins were being synthesized. Moreover, it also interfered with the synthesis of nucleic acids and the phosphorylation of nucleosides. If P-536 was present from the beginning of infection, HSV-1 replication was blocked at an early step and the infected cells continued to synthesize cellular proteins for long periods.
Development of resistance to nalidixic acid and the fluoroquinolones after the introduction of norfloxacin and ofloxacin
Authors: Kresken M , Wiedemann B
Published: June 2012

Since 1975, the group Resistenz of the Paul-Ehrlich-Gesellschaft für Chemotherapie has monitored the development of resistance in isolates of members of the family Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis in the Federal Republic of Germany, West Berlin, Austria, and Switzerland. Despite a marked increase in the use of 4-quinolones, there was no increase in the percentages of nalidixic acid-resistant strains of Enterobacteriaceae between 1975 and 1986. However, different bacterial species showed considerable variation, and there were also considerable differences in the percentages of nalidixic acid-resistant strains of Enterobacteriaceae from different centers. The frequency of resistance to fluoroquinolones was unchanged from 1983 to 1986 and was less than 4% in all species except P. aeruginosa. In this species, there was an increase from about 3 to 10% from 1983 to 1986 for strains for which the MIC was fourfold above the mode MIC of ciprofloxacin, enoxacin, and ofloxacin.
New sensitive bioassay for sulbactam in bovine tissues
Authors: Keeler G H , Stankewich J P , Girard A E , Rash J J
Published: June 2012

A quantitative cylinder plate bioassay for sulbactam has been developed which can detect concentrations as low as 0.01 microgram/g in bovine muscle, fat, kidney, and liver tissues. This procedure may also be applicable to human tissues and fluids. In addition to the improved sensitivity, this method differs from all previously described systems because it is based on inhibition by sulbactam of a cell-free beta-lactamase incorporated in the assay agar. The assay is unaffected by the presence of ampicillin even at concentrations 10 times that of the sulbactam concentration. This report describes the analytical technique as well as the accuracy and precision of the method. The assay can be applied to tissue depletion studies.
Susceptibility to hydrophobic molecules and phospholipid composition in Pasteurella multocida and Actinobacillus lignieresii
Authors: Hart M E , Champlin F R
Published: June 2012

Despite its typically gram-negative cell envelope ultrastructure, Pasteurella multocida is susceptible to the hydrophobic antibiotic novobiocin and is unable to initiate growth on MacConkey agar, a parameter often used to effect is differentiation from other members of the family Pasteurellaceae such as Actinobacillus lignieresii. However, growth on basal medium supplemented with individual selective factors and an agar diffusion assay revealed the bile salts contained in MacConkey agar to be toxic to both organisms. Four P. multocida surface hydrophobicity variants exhibited consistent in vitro susceptibility to the hydrophobic antibiotics novobiocin, rifamycin SV, and actinomycin D as determined by broth dilution. Readily extractable lipid fractions were obtained by chloroform-methanol extraction of freeze-dried whole cells from exponential-phase cultures. No major differences in total cellular readily extractable lipid content were observed among the P. multocida and A. lignieresii strains examined, although hydrophobic P. multocida strains appeared to contain slightly more than did hydrophilic strains. Analytical thin-layer chromatography and quantitation of resolved readily extractable lipid components revealed the major cell envelope phospholipids of both organisms to be phosphatidylethanolamine and phosphatidylglycerol in a molar ratio of approximately 4:1 regardless of cell surface hydrophobicity properties. Similar results were obtained for Pseudomonas aeruginosa, which is notably refractory to hydrophobic molecules. These data support the conclusion that the permeability of the P. multocida cell envelope to structurally unrelated, hydrophobic molecules is not dependent on cell surface hydrophobicity and cannot be explained on the basis of anomalous polar lipid composition.
Antagonistic effect of chloramphenicol in combination with cefotaxime or ceftriaxone
Authors: Asmar B I , Prainito M , Dajani A S
Published: June 2012

We evaluated the in vitro interaction at clinically attainable concentrations of cefotaxime and ceftriaxone with chloramphenicol against 26 clinical isolates of gram-negative rods, group B streptococci, and Staphylococcus aureus. Cefotaxime and ceftriaxone were bactericidal against all 26 organisms (MBC, 0.03 to 4 micrograms/ml). Chloramphenicol was bacteriostatic against 24 organisms (MBC, greater than or equal to 32 micrograms/ml) and bactericidal against two Escherichia coli isolates (MBC, 8 micrograms/ml). Checkerboard testing showed chloramphenicol to be antagonistic to the bactericidal activity of cefotaxime and ceftriaxone for all 24 bacteria for which chloramphenicol was bacteriostatic. Time kill curves for selected strains of E. coli and group B streptococci for which chloramphenicol was bacteriostatic showed antagonism of chloramphenicol to both cephalosporins. The combination of chloramphenicol with either cephalosporin was antagonistic in cases in which chloramphenicol was bacteriostatic against the above organisms and should be avoided in the treatment of infections caused by such organisms if bactericidal therapy is desired.
In vitro activities of the newer beta-lactam and quinolone antimicrobial agents against Pseudomonas pseudomallei
Authors: Ashdown L R
Published: June 2012

Imipenem was highly active and bactericidal against all 100 strains of Pseudomonas pseudomallei tested, followed in activity by piperacillin, carumonam, ceftazidime, cefotaxime, and ceftriaxone. The addition of clavulanic acid significantly increased the activities of both amoxicillin and ticarcillin. Ciprofloxacin and norfloxacin showed poor activity against test strains.
Intramuscular ceftriaxone in home parenteral therapy
Authors: Russo T A , Cook S , Gorbach S L
Published: June 2012

Ceftriaxone administered via the intramuscular route was evaluated as home parenteral therapy for 31 patients with a variety of serious but stable infections. Cure was achieved in 30 of the patients. When lidocaine was used for reconstitution of ceftriaxone, the intramuscular route was well tolerated by all patients.
Purification and characterization of the anti-Candida toxin of Pichia anomala WC 65
Authors: Sawant A D , Abdelal A T , Ahearn D G
Published: June 2012

Pichia anomala WC 65 secretes a toxin that is inhibitory to a variety of yeasts, including strains of the animal pathogen Candida albicans. The toxin was purified to homogeneity by ultrafiltration, ethanol precipitation, ion-exchange chromatography with a Mono Q column, and gel permeation chromatography with a Superose 12 column. The toxin had a molecular weight of 83,300 as determined by electrophoresis on sodium dodecyl sulfate-polyacrylamide gradient gels and a molecular weight of 85,290 as determined by gel permeation chromatography. The isoelectric point of the toxin was pH 5.0. The toxin was stable between pH 2.0 and 5.0. Chemical analysis of the purified toxin indicated that the toxin was a glycoprotein composed of about 86% protein and 14% carbohydrate. At high concentrations, the toxin showed a tendency to aggregate, with loss of biological activity against C. albicans, Pichia bimundalis, and Saccharomycodes ludwigii. Purified toxin expressed killing activity against C. albicans in contrast to the static activity of the crude toxin.
Chromosomal beta-lactamase of Klebsiella oxytoca, a new class A enzyme that hydrolyzes broad-spectrum beta-lactam antibiotics
Authors: Arakawa Y , Ohta M , Kido N , Mori M , Ito H , Komatsu T , Fujii Y , Kato N
Published: June 2012

The chromosomally encoded beta-lactamase gene of Klebsiella oxytoca E23004, a strain resistant to cefoperazone and aztreonam, was cloned and expressed in Escherichia coli HB101. The molecular mass and pI of this enzyme were 28 kilodaltons and 7.4, respectively. Although the beta-lactamase of K. oxytoca hydrolyzed many cephalosporins, including broad-spectrum drugs, the nucleotide sequence and deduced amino acid sequence lacked homology with chromosomal class C beta-lactamase genes (ampC) of E. coli or Citrobacter freundii. Rather, about 45% nucleotide sequence homology and 40% deduced amino acid sequence homology were observed between the K. oxytoca beta-lactamase and TEM-1, a class A beta-lactamase which does not efficiently hydrolyze cephalosporins. Values of Km, relative Vmax, and relative Vmax/Km for the K. oxytoca beta-lactamase indicated that the enzyme is a penicillinase but that it can hydrolyze cefoperazone effectively and other broad-spectrum cephems weakly. Hence, the chromosomal beta-lactamase of K. oxytoca E23004 belongs to class A but differences in its amino acid sequence provide a broader spectrum of activity.
Randomized trial comparing ciprofloxacin plus netilmicin versus piperacillin plus netilmicin for empiric treatment of fever in neutropenic patients
Authors: Chan C C , Oppenheim B A , Anderson H , Swindell R , Scarffe J H
Published: June 2012

To assess the efficacy of ciprofloxacin in neutropenic patients, we conducted a randomized prospective trial comparing the combination of ciprofloxacin and netilmicin against piperacillin plus netilmicin as an empiric treatment of fever in cancer patients with neutropenia. Of 214 evaluable episodes, 115 and 99 were randomly assigned to the ciprofloxacin and the piperacillin arms, respectively. The overall response rates were very similar (59 and 62% for the ciprofloxacin and piperacillin arms, respectively). The response for the gram-positive bacteremias was almost identical (around 40%); this low response was due in part to an outbreak of infection by a multiply resistant strain of Staphylococcus epidermidis (for which the ciprofloxacin MIC was greater than or equal to 128 micrograms/ml) which occurred during the second half of the trial. Among gram-negative bacteremias, 9 of 11 infections (82%) responded to the ciprofloxacin combination compared with 3 of 7 (43%) that responded to the piperacillin combination (P = 0.23). The incidences of persistent, profound neutropenia were comparable in both treatments, but the susceptibility of the gram-negative organism to ciprofloxacin and netilmicin was significantly higher than was susceptibility to the other combination. Ciprofloxacin was well tolerated, and patients were able to convert from intravenous to oral therapy in 64 of 115 episodes.