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1.  Antiviral activity of 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl-5-iodocytosine against human cytomegalovirus in human skin fibroblasts. 
2'-Deoxy-2'-fluoro-beta-D-arabinofuranosyl-5-iodocytosine (FIAC) was shown to be a selective anti-human cytomegalovirus agent in vitro with a 50% antiviral effective dose of 0.6 microM (J. M. Colacino and C. Lopez, Antimicrob. Agents Chemother. 26:505-508, 1983) and a 50% cell growth inhibitory dose of 8 microM. Antiviral activity was more readily reversed with 10-fold excess thymidine, whereby the 50% effective dose was increased to 11.3 microM. FIAC-induced cytotoxicity was more readily reversed with 10-fold excess of deoxycytidine, whereby the 50% inhibitory dose was increased to greater than 100 microM. Thymidine was unable to reverse completely the antiviral activity of FIAC. Although, the extent of phosphorylation of thymidine, deoxycytidine, and deoxyuridine was 6-, 4-, and 4-fold greater, respectively, in human cytomegalovirus-infected cell lysates than in uninfected cell lysates, the extent of phosphorylation of FIAC was only 1.3-fold greater in human cytomegalovirus-infected cell lysates than in uninfected cell lysates. By comparison, the extent of FIAC phosphorylation was 500 times greater in herpes simplex virus type 1-infected cells than in uninfected cell lysates. Methotrexate was 400 times more effective against human cytomegalovirus replication than it was against herpes simplex virus type 1 replication, indicating that thymidylate synthetase may be important for human cytomegalovirus replication. However, 10 microM FIAC did not inhibit thymidylate synthetase activity in uninfected or virus-infected cells as determined by their metabolism of [6-3H]deoxyuridine in the presence or absence of drug. FIAC at 1 microM suppresses and FIAC at 10 microM completely inhibits human cytomegalovirus DNA replication as indicated by Southern blot analysis. This inhibition was reversible. FIAC incorporation into the DNA of human cytomegalovirus strain AD169-infected cells was stimulated relative to that in nondividing, uninfected cells.
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PMCID: PMC180228  PMID: 3010842
2.  Cilastatin does not alter superoxide dismutase activity. 
Cilastatin inhibits dehydropeptidase-I, a zinc metaloenzyme that metabolizes imipenem. Because zinc stabilizes the mammalian superoxide dismutase, we postulated that cilastatin would also inhibit the dismutase. Cilastatin concentrations at levels threefold higher than those expected in urine, however, did not inhibit the superoxide dismutase activity.
PMCID: PMC176359  PMID: 3867330
3.  Stability of imipenem in Mueller-Hinton agar stored at 4 degrees C. 
The purpose of the present study was to measure the stability of imipenem in Mueller-Hinton agar stored at 4 degrees C over time. MICs for Staphylococcus aureus ATCC 25923, Streptococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 27853 were determined in triplicate daily for up to 15 days. The calculated mean time to observe a shift of one dilution in MIC endpoints was 4.33 +/- 1.25 days. For routine work, imipenem agar dilution plates should be prepared within 48 to 72 h of the test.
PMCID: PMC176367  PMID: 3867331
4.  Comprehensive evaluation of ciprofloxacin-aminoglycoside combinations against Enterobacteriaceae and Pseudomonas aeruginosa strains. 
The in vitro activities of antibiotic combinations containing ciprofloxacin and either gentamicin, sisomicin, netilmicin, amikacin, or tobramycin were evaluated by checkerboard assay (agar dilution method). A total of 220 strains of Enterobacteriaceae and Pseudomonas aeruginosa (11 species, 20 strains each) were tested. Synergistic or antagonistic effects were observed in less than 1% of the tests performed; they appeared to represent method-dependent fluctuations rather than true antibiotic interactions. No significant differences among the five aminoglycosides tested were seen. Time-kill experiments performed with three representative strains of Escherichia coli and Serratia marcescens showed additive combination effects with respect to the kill rates and inhibition of bacterial regrowth. Exposure of Serratia strains to either ciprofloxacin or gentamicin before the addition of the second drug had little influence on the combination effects observed. No antagonistic drug interactions were seen in vivo when combination therapy with ciprofloxacin and gentamicin was evaluated in a model of E. coli thigh muscle infection in neutropenic mice. Comparable therapeutic effects were obtained, regardless of whether the two compounds were administered simultaneously or sequentially at 1- or 2-h intervals.
PMCID: PMC176353  PMID: 2936301
5.  Comparative in vitro activities of selected antimicrobial agents against Aeromonas species and Plesiomonas shigelloides. 
The in vitro antimicrobial susceptibilities of fecal isolates of Aeromonas caviae, Aeromonas hydrophila, Aeromonas sobria, and Plesiomonas shigelloides were tested by agar dilution. This in vitro study suggested that ciprofloxacin, enoxacin, norfloxacin, tetracycline, and trimethoprim-sulfamethoxazole might be effective oral agents for treatment of diarrhea involving Aeromonas spp. or P. shigelloides.
PMCID: PMC180112  PMID: 4004196
6.  In vitro activity of ciprofloxacin combined with azlocillin. 
A ciprofloxacin plus azlocillin broth microdilution checkerboard was evaluated against 125 aerobic gram-negative and gram-positive bacteria. Synergism (sigma FIC less than or equal to 0.5) occurred among 56% of Pseudomonas aeruginosa, 30% of Acinetobacter species, and 40% of Staphylococcus aureus studied. Antagonism (sigma FIC greater than or equal to 2) was present in less than 1% of the organisms.
PMCID: PMC180346  PMID: 2935078
7.  Comparative in vitro activities of selected antimicrobial agents against Edwardsiella tarda. 
MICs of 14 antimicrobial agents for 29 strains of Edwardsiella tarda were determined by an agar dilution method. Of the agents tested, ciprofloxacin, enoxacin, and norfloxacin were the most active on a weight basis. All strains were also susceptible to clinically achievable concentrations of ampicillin, chloramphenicol, tetracycline, trimethoprim, sulfamethoxazole, trimethoprim plus sulfamethoxazole, cefotaxime, and gentamicin. Ninety percent of the strains demonstrated high-level resistance to polymyxin B and colistin.
PMCID: PMC180198  PMID: 4026271
8.  Activities of the modified polyene N-D-ornithyl amphotericin methyl ester and the azoles ICI 153066, Bay n 7133, and Bay l 9139 compared with those of amphotericin B and ketoconazole in the therapy of experimental blastomycosis. 
We studied the efficacy of new experimental antifungal drugs, which represent molecular modifications of present active agents, in a murine model of blastomycosis. Ketoconazole, previously the best azole drug studied and which is protective when administered orally, was superior to a new oral imidazole, Bay l 9139, and a new oral triazole, Bay n 7133. A new oral triazole, ICI 153066, was markedly more effective than ketoconazole and is the only oral drug studied which came close to producing complete sterilization of all visceral infection in all animals treated. Amphotericin B, a polyene given parenterally, was shown to be more efficacious than any drug studied. It completely sterilized the infection. A modified polyene, N-D-ornithyl amphotericin methyl ester, was only slightly less effective on a milligram-per-kilogram basis.
PMCID: PMC176278  PMID: 3994350
9.  In vitro activity and mechanism of action of A21978C1, a novel cyclic lipopeptide antibiotic. 
The in vitro activity of A21978C1, a novel cyclic polypeptide antibiotic, was compared with those of vancomycin, teichomycin, and several beta-lactam antibiotics against gram-positive bacteria. The new drug was at least as active as vancomycin against all species of streptococci and staphylococci tested, including methicillin-resistant Staphylococcus aureus and penicillin-resistant pneumococci. Activity of the drug was found to be strongly correlated with the calcium concentration in test media. Against enterococci, A21978C1 was bactericidal at concentrations near the MIC (MIC for 100% of the strains, 2 micrograms/ml), but combining that drug with gentamicin resulted in bactericidal synergism by time-kill methods. Studies were undertaken to examine the mechanism of action of the drug. A21978C1 did not interact with penicillin-binding proteins of bacterial cell membranes. No direct effect of the drug on the synthesis of DNA, RNA, or protein by a susceptible strain of Streptococcus faecalis could be demonstrated. However, A21978C1 inhibited peptidoglycan synthesis in early-log-phase cultures of both Streptococcus faecalis and Staphylococcus aureus.
PMCID: PMC176277  PMID: 3994349
10.  Comparison of high-pressure liquid chromatography and bioassay for determination of ciprofloxacin in serum and urine. 
Ciprofloxacin was given orally to 10 healthy volunteers for seven consecutive doses of 250 mg every 12 h. Serum and urine samples were collected at distinct times between 0 and 96 h and analyzed both by high-pressure liquid chromatography and by a microbiological assay. The detection limits were 0.006 and 0.03 microgram/ml, respectively. For each method, imprecision coefficients of variation were less than 6.1% at various concentrations in serum and urine. The means +/- standard deviations of the absolute values of the relative differences between the two methods were 9.3 +/- 6.8% (n = 225) for serum samples and 58.5 +/- 50.4% (n = 70) for urine samples. Comparison of the concentrations in serum measured with high-pressure liquid chromatography and bioassay by regression analysis yielded a slope which was not significantly different from 1.0 (99.9% confidence limits: 0.984 less than slope less than 1.035). In urine, however, the bioassay results were markedly higher than the high-pressure liquid chromatography values (1.327 less than slope less than 1.698), which indicates the presence of antimicrobially active metabolites. The cumulative 12-h urinary recovery after the first and seventh doses averaged 30.2 +/- 8.5 and 26.4 +/- 4.6%, respectively, by high-pressure liquid chromatography, whereas with bioassay 38.2 +/- 5.9 and 45.5 +/- 5.9% activity was recovered. Protein binding appeared to be neither concentration nor pH dependent and averaged 21.9 +/- 4.1%.
PMCID: PMC176276  PMID: 3158274
11.  Comparison of a new cephalosporin, BMY 28142, with other broad-spectrum beta-lactam antibiotics. 
BMY 28142, a new broad-spectrum semisynthetic cephalosporin, was evaluated in vitro and in vivo in comparison with ceftazidime, cefotaxime, moxalactam, and cefoperazone. The activity of BMY 28142 compared favorably with the activities of the other compounds against both Pseudomonas aeruginosa and Staphylococcus aureus and was somewhat greater against members of the family Enterobacteriaceae. The influence of inoculum size on MICs of BMY 28142 was small for most of the isolates tested, except Enterobacter species. With Enterobacter strains, a marked inoculum effect was found with all of the compounds, and the effect was more pronounced in broth than agar. Still, MICs of BMY 28142 in broth did not exceed 16 micrograms/ml. Of 37 Enterobacteriaceae strains resistant to one or more of the comparison beta-lactams, none were resistant, at a low inoculum size (10(4) CFU), to BMY 28142, compared with 3 for moxalactam, 18 for ceftazidime, 23 for cefotaxime, and 34 for cefoperazone; at an inoculum size of 10(6) CFU, the number of resistant strains was 12, 17, 25, 34, and 37, respectively. Binding to human serum proteins approximated 19%. Recovery of 73% of the drug in mouse urine indicated good bioavailability. The in vitro profile was sustained in vivo by the results obtained with experimental infections in mice. BMY 28142 was as effective as ceftazidime against systemic infection with P. aeruginosa and as effective as cefotaxime against systemic infection with S. aureus. Overall, infections with 18 of 20 strains representing nine genera were responsive to BMY 28142 at doses equivalent to or lower than those of the most effective of the comparison compounds.
PMCID: PMC176239  PMID: 3885849
12.  In vitro susceptibility of Mycobacterium fortuitum and Mycobacterium chelonei to cefmetazole. 
The in vitro susceptibility of Mycobacterium fortuitum and Mycobacterium chelonei to cefmetazole was studied by the agar dilution method. At a concentration of 16 micrograms/ml or lower, 44 isolates (96%) of M. fortuitum and 8 isolates (40%) of M. chelonei were inhibited.
PMCID: PMC176257  PMID: 3857020
13.  Cefotaxime and desacetylcefotaxime pharmacokinetics in infants and children with meningitis. 
The pharmacokinetics and cerebrospinal fluid (CSF) penetration of cefotaxime (Ctx) and desacetylcefotaxime (dCtx) were evaluated in 13 infants and children with meningitis after dose 6 of Ctx in a multiple-dose intermittent intravenous infusion regimen (50 mg/kg every 6 h). Model-dependent and noncompartmental pharmacokinetic parameters were determined and were found to be congruous. The disposition of both Ctx and dCtx was described adequately by a one-compartment, open model. Noncompartmental pharmacokinetic parameters are reported. The mean Ctx serum concentration at 0.25 h postinfusion was 121.2 micrograms/ml, and the mean CSF concentration at 1 h postinfusion was 6.2 micrograms/ml. The CSF/serum ratio was variable (0 to 20%), with a mean penetration of 10.1%. The mean Ctx elimination half-life, apparent steady-state volume of distribution, and total body clearance were 0.8 h, 0.361 liter/kg, and 0.289 liter/h per kg, respectively. For Ctx, 61% of the dose was excreted unchanged in the urine during the 6-h postinfusion period, and the estimated renal clearance was 0.174 liter/h per kg. No significant correlations were observed between Ctx pharmacokinetic parameters and demographic parameters. The mean peak concentration of dCtx in serum (21.6 micrograms/ml) occurred at approximately 1.5 h postinfusion, and the mean concentration in CSF at 1 h postinfusion was 5.6 micrograms/ml. The CSF/serum ratio was extremely variable (0 to 103%), and the mean penetration was 28.8%. The mean apparent elimination half-life for dCtx was 2.1 h. In infants and children with normal renal function, a 50-mg/kg dose of Ctx administered every 6 h should provide adequate concentrations in serum and CSF in the majority of patients with meningitis.
PMCID: PMC180330  PMID: 4083862
14.  Comparison of the in vitro activities of teicoplanin and vancomycin against Clostridium difficile and their interactions with cholestyramine. 
The in vitro activity of teicoplanin was compared with that of vancomycin against fecal isolates of Clostridium difficile. All strains were susceptible to both antibiotics, but teicoplanin was fourfold more active than vancomycin. Cholestyramine was found to bind teicoplanin almost completely, reducing its activity to nondetectable levels.
PMCID: PMC180345  PMID: 2935077
15.  In vitro activity of CI-934, a quinolone carboxylic acid active against gram-positive and -negative bacteria. 
CI-934 is a totally synthetic difluorinated quinolinecarboxylic acid with an ethyl-amino-methyl pyrrolidine side chain, which has broad-spectrum antibacterial activity, including particular potency directed against streptococci and staphylococci. The CI-934 MIC (micrograms per milliliter) for 90% of the strains tested was 0.4 (range, 0.2 to 0.8) for a group of streptococci (pneumococci, viridans streptococci, Streptococcus faecalis, and Lancefield groups A, B, and C), 0.2 (0.05 to 0.2) for staphylococci (including methicillin-resistant Staphylococcus aureus), 0.025 (less than or equal to 0.003 to 0.025) for Haemophilus influenzae and Neisseria gonorrhoeae, 1.6 (0.1 to 25) for Enterobacteriaceae, 25 (3.1 to 25) for Pseudomonas aeruginosa, and 1.6 (0.05 to 3.1) for non-Bacteroides anaerobe species. CI-934 was equally active in vitro against multi-drug-resistant and -sensitive isolates, and cross-resistance was not apparent. Potency increased with alkalinity and was somewhat lower in urine. CI-934 was bactericidal. Inhibitory activity was generally unaffected by anaerobiosis, light, changes in inoculum size or cation concentration, or addition of human serum or sodium cholate.
PMCID: PMC180325  PMID: 3866513
16.  Comparative activities of piperacillin, ceftazidime, and amikacin, alone and in all possible combinations, against experimental Pseudomonas aeruginosa infections in neutropenic rats. 
This study compared the efficacy of therapy with the double beta-lactam combination of ceftazidime plus piperacillin with that of single-agent therapy with ceftazidime, piperacillin, or amikacin alone and with that of two aminoglycoside-beta-lactam combinations against Pseudomonas aeruginosa peritonitis and bacteremia in neutropenic rats. Rats made severely granulocytopenic with cyclophosphamide became bacteremic secondary to peritonitis which was induced by intraperitoneal challenge with P. aeruginosa. Antibiotic therapy with single agents (amikacin, 20 mg/kg of body weight, intramuscularly; ceftazidime, 20 mg/kg of body weight, subcutaneously; piperacillin, 200 mg/kg of body weight, intramuscularly) or with the various combinations of agents was begun 2 h after bacterial challenge and was continued every 6 to 8 h for 62 h. Therapeutic efficacy was judged on the basis of survival 72 h after bacterial challenge, rate of mortality, incidence of bacteremia, and the emergence of resistant organisms. Based on these criteria, therapy with the double beta-lactam combination had no advantage over single-agent therapy and was in all cases clearly inferior to beta-lactam-aminoglycoside combinations.
PMCID: PMC180319  PMID: 3909952
18.  In vitro activities of the quinolone antimicrobial agents A-56619 and A-56620. 
The in vitro activities of two new quinolone antimicrobial agents, A-56619 and A-56620, were compared with those of norfloxacin, ciprofloxacin, and other antimicrobial agents. The activity of A-56620 was comparable to that of ciprofloxacin against Escherichia coli, Enterobacter cloacae, and Aeromonas hydrophila (MICs for 90% of the strains were less than or equal to 0.06 micrograms/ml); Acinetobacter anitratus and Staphylococcus aureus (MIC for 90% of the strains was 0.5 micrograms/ml); and most streptococci. Against other gram-negative strains, A-56620 demonstrated activity comparable to that of norfloxacin, but the new drug was two to eight times more active than norfloxacin against gram-positive isolates. A-56620 was more active than A-56619 against most gram-negative organisms tested. Of the members of the family Enterobacteriaceae examined, 88% were inhibited by A-56619 and 99% by A-56620 at concentrations of less than or equal to 1.0 microgram/ml. By time-kill methods, the new quinolones were bactericidal against gram-negative bacilli during the first 6 h of incubation, but against S. aureus and enterococci the drugs were primarily bacteriostatic during this period. The frequency of spontaneous resistance to 10 micrograms of these drugs per ml was less than 10(-8) for all species tested except E. cloacae, but by serial passage through incremental concentrations of the antimicrobial agents, colonies many-fold more resistant than the initial isolate could be selected. However, resistance to concentrations of the drug greater than 100 micrograms/ml remained stable after passage on antibiotic-free media in only 1 of 35 strains tested.
PMCID: PMC180295  PMID: 3935046
19.  Pharmacokinetics and tissue penetration of carumonam, a new synthetic monobactam. 
The pharmacokinetics of the monobactam carumonam (Ro 17-2301) as derived from serial measurement of the concentrations of this agent in serum, blister fluid, and urine were studied in six male volunteers subsequent to intravenous infusion of a single 2-g dose. Drug levels in serum in excess of 75 micrograms/ml were achieved 0.5 h after the end of infusion, declining to 2.9 micrograms/ml at 8 h. The mean serum and blister fluid elimination half-lives were 1.68 and 1.7 h, respectively. The urinary recovery of the drug by 24 h was 80.6% (range, 68.3 to 91.1%). Carumonam penetrated blister fluid well, the mean percentage penetration (as measured by the ratio of areas under curves) being 101.6%.
PMCID: PMC180266  PMID: 4073864
20.  In vitro antistreptococcal activity of the potassium-sparing diuretics amiloride and triamterene. 
The ionophore antimicrobial agents provide evidence that perturbations of the electrolyte balance of bacterial cells exert a growth-inhibitory activity. Several drugs acting on animal cell membranes have also been shown to be active on bacterial cells. In this paper, we report preliminary susceptibility studies showing that the class of potassium-sparing diuretics acting directly on monovalent cation fluxes on animal cells possesses a selective growth-inhibitory activity on hemolytic streptococci.
PMCID: PMC180264  PMID: 4073863
21.  Role of an altered penicillin-binding protein in methicillin- and cephem-resistant Staphylococcus aureus. 
About 80% of methicillin- and cefazolin-resistant strains of Staphylococcus aureus isolated clinically in Japan in 1982 retained their resistance even after elimination of penicillinase-encoding plasmids. The penicillin-binding proteins (PBPs) of the penicillinase-free, methicillin- and cephem-resistant subclones of Staphylococcus aureus (MRSA) were compared with those of spontaneous susceptible revertants which had been obtained by the replica method after 10 subcultures in drug-free media. A new PBP fraction (PBP2') having a molecular weight of 78,000 and low binding affinities for various beta-lactam antibiotics was found in MRSA exclusively. The levels of resistance of MRSA strains were reduced markedly by culturing them at 43 degrees C or at pH 5.2 or both. We found that the binding capacity of PBP2' for 14C-labeled penicillin G was decreased by preincubation of the membrane fractions of MRSA strains at 43 degrees C for 60 min and that the amount of PBP2' in MRSA strains grown at pH 5.2 was less than that the amount of PBP2' in MRSA strains grown at pH 7.0. Temperature- and pH-dependent expression of resistance in MRSA is likely to reflect the temperature sensitivity and neutral pH-dependent production of the specific PBP fraction (PBP2'). We suggest that MRSA strains can grow in the presence of beta-lactam antibiotics because of the low affinities of the specific PBP2' fraction for various beta-lactam antibiotics.
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PMCID: PMC180261  PMID: 3878127
22.  In vitro activity of BMY-28142 against pediatric pathogens, including isolates from cystic fibrosis sputum. 
The antibacterial activity of BMY-28142, a new aminothiazole cephalosporin, was measured by standardized broth microdilution and agar dilution methods against 450 gram-positive and gram-negative bacteria isolated from pediatric infections, including acute pulmonary exacerbations of cystic fibrosis. BMY-28142 activity was compared with that of aminoglycosides, beta-lactams, chloramphenicol, trimethoprim-sulfamethoxazole, vancomycin, and clindamycin. The activity of BMY-28142 in combination with other antimicrobial agents against Pseudomonas aeruginosa was also determined. Furthermore, the effects of inoculum and pH on BMY-28142 activity were evaluated. BMY-21842 was active against most of the gram-positive and gram-negative isolates, with the exception of methicillin-resistant Staphylococcus aureus and Pseudomonas cepacia. The combination of BMY-28142 with tobramycin was often synergistic, and combinations of BMY-28142 with either polymyxin B or imipenem were usually antagonistic. BMY-28142 antibacterial activity could be adversely affected at extremes of medium pH and by high inoculum densities.
PMCID: PMC176310  PMID: 3929681
23.  Ceftazidime versus tobramycin-ticarcillin in the treatment of pneumonia and bacteremia. 
A prospective, randomized study was undertaken to compare the efficacy and safety of ceftazidime with those of a combination of ticarcillin and tobramycin in the treatment of 40 nonneutropenic patients with pneumonia or bacteremia. Altogether, 93% of the patients receiving ceftazidime for pneumonia were cured, and 87% of those with bacteremia responded favorably. Of the subjects who were treated with ticarcillin and tobramycin ceftazidime developed significant superinfection, and one individual treated with the aminoglycoside and carboxypenicillin developed reversible azotemia. Ceftazidime appears to be as efficacious as the ticarcillin-tobramycin combination and is probably safer with regard to oto-and nephrotoxicity; however, superinfections did occur more frequently in the group treated with ceftazidime.
PMCID: PMC176304  PMID: 3899005
24.  Tetracycline-resistant Mycoplasma hominis strains contain streptococcal tetM sequences. 
Clinical isolates of Mycoplasma hominis resistant to high levels of tetracycline contained DNA sequences homologous to the streptococcal tetracycline determinant, tetM. In contrast, none of the susceptible M. hominis isolates tested carried this determinant. This is the first description of tetM in an unrelated genus and suggests the spread of tetM from Streptococcus spp. to Mycoplasma spp.
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PMCID: PMC176326  PMID: 2994555
25.  Systemic absorption and persistence of tioconazole in vaginal fluid after insertion of a single 300-mg tioconazole ovule. 
After vaginal insertion of a 300-mg ovule of tioconazole in 10 patients with vaginal candidiasis, the mean concentration in plasma was 21.2 ng/ml (range, 10.6 to 35.8 ng/ml) at 8 h and was not measurable at 24 h in 9 of 10 patients. The mean vaginal concentration at 24 h was 21.4 mg/liter (range, 2.4 to 50 mg/liter) and remained detectable in 7 of 9 and 2 of 9 patients after 48 and 72 h, respectively.
PMCID: PMC180197  PMID: 4026270

Results 1-25 (417)