bluuebunny/crossref_metadata_2025 huggingface dataset:
Lysostaphin Cream Eradicates
Staphylococcus aureus
Nasal Colonization in a Cotton Rat Model
Authors: Kokai-Kun John F. , Walsh Scott M. , Chanturiya Tanya , Mond James J.
Published: April 2003

The anterior nares are a primary ecologic niche for
Staphylococcus aureus
, and nasal colonization by this opportunistic pathogen increases the risk of development of
S. aureus
infection. Clearance of
S. aureus
nasal colonization greatly reduces this risk. Mupirocin ointment is the current standard of care for clearance of
S. aureus
nasal colonization, but resistance to this antibiotic is emerging. Lysostaphin is a glycylglycine endopeptidase which specifically cleaves the cross-linking pentaglycine bridges in the cell walls of staphylococci. Lysostaphin is extremely staphylocidal (MIC at which 90% of isolates are inhibited, 0.001 to 0.064 μg/ml) and rapidly lyses both actively growing and quiescent
S. aureus
. This study demonstrates that a single application of 0.5% lysostaphin (actual dose, ∼150 μg of lysostaphin), formulated in a petrolatum-based cream, dramatically reduces
S. aureus
nasal colonization in 100% of animals tested and eradicates
S. aureus
nasal colonization in 93% of animals in a cotton rat model. A single dose of lysostaphin cream is more effective than a single dose of mupirocin ointment in eradicating
S. aureus
nasal colonization in this animal model. The lantibiotic peptide nisin, which has potent in vitro antistaphylococcal activity, was ineffective in reducing staphylococcal nasal carriage in this model. Nasal colonization was not reduced after three treatments with 5% nisin (∼1,500 μg/dose) in any of the treated animals. Lysostaphin formulated in cream may prove to be a superior alternative to mupirocin ointment for clearance of
S. aureus
nasal colonization.
Daptomycin Dose-Effect Relationship against Resistant Gram-Positive Organisms
Authors: Cha Raymond , Grucz Richard G. , Rybak Michael J.
Published: April 2003

Daptomycin exhibits in vitro bactericidal activity against clinically significant gram-positive bacteria. We employed pharmacodynamic modeling to determine a once-daily dosing regimen of daptomycin that correlates to pharmacodynamic endpoints for different resistant gram-positive clinical strains. An in vitro pharmacodynamic model with an initial inoculum of 6 log
10
CFU/ml was used to simulate daptomycin regimens ranging in dose from 0 to 9 mg/kg of body weight/day, with corresponding exposures reflecting free-daptomycin concentrations in serum. Bacterial density was profiled over 48 h for two methicillin-resistant
Staphylococcus aureus
(MRSA-67 and -R515), two glycopeptide intermediate-resistant
S. aureus
(GISA-992 and -147398), and two vancomycin-resistant
Enterococcus faecium
(VREF-12366 and -SF12047) strains. A sigmoid dose-response model was used to estimate the effective dose required to achieve 50% (ED
50
) and 80% (ED
80
) bacterial density reduction at 48 h. Daptomycin MICs for study isolates ranged from 0.125 to 4 μg/ml. Model fitting resulted in an
r
2
of >0.80 for all tested isolates. Control growths at 48 h ranged from 7.3 to 8.5 log
10
CFU/ml. Sigmoid relationships were not superimposable between categorical resistant species: ED
50
and ED
80
values were 1.9 and 3.1, 4.2 and 5.6, and 5.4 and 6.8 mg/kg for MRSA, GISA, and VREF isolates, respectively. Doses required to achieve ED
50
and ED
80
values correlated with MIC differences between tested organisms. Corresponding area under the concentration-time curve from 0 to 24 h/MIC exposure ratios demonstrated a wide range of ED
80
values among the tested isolates. Doses ranging between 3 and 7 mg/kg produced significant bactericidal activity (ED
80
) against these multidrug-resistant
S. aureus
and
E. faecium
isolates.
In Vitro Pharmacodynamic Evaluation of the Mutant Selection Window Hypothesis Using Four Fluoroquinolones against
Staphylococcus aureus
Authors: Firsov Alexander A. , Vostrov Sergey N. , Lubenko Irene Y. , Drlica Karl , Portnoy Yury A. , Zinner Stephen H.
Published: April 2003

To study the hypothesis of the mutant selection window (MSW) in a pharmacodynamic context, the susceptibility of a clinical isolate of methicillin-resistant
Staphylococcus aureus
exposed to moxifloxacin (MOX), gatifloxacin (GAT), levofloxacin (LEV), and ciprofloxacin (CIP) was tested daily by using an in vitro dynamic model that simulates human pharmacokinetics. A series of monoexponential pharmacokinetic profiles that mimic once-daily administration of MOX (half-life, 12 h), GAT (half-life, 7 h), and LEV (half-life, 6.8 h) and twice-daily administration of CIP (half-life, 4 h) provided peak concentrations (
C
max
) that either equaled the MIC, fell between the MIC and the mutant prevention concentration (MPC) (i.e., within or “inside” the MSW), or exceeded the MPC. The respective ratios of the area under the curve (AUC) over a 24-h dosing interval (AUC
24
) to the MIC varied from 13 to 244 h, and the starting inoculum was 10
8
CFU/ml (6 × 10
9
CFU per 60-ml central compartment). With all four quinolones, the greatest increases in MIC were observed at those AUC
24
/MIC values (from 24 to 62 h) that corresponded to quinolone concentrations within the MSW over most of the dosing interval (>20%). Less-pronounced increases in MIC were associated with the smallest simulated AUC
24
/MIC values (15 to 16 h) of GAT and CIP, whose
C
max
exceeded the MICs. No such increases were observed with the smallest AUC
24
/MIC values (13 to 17 h) of MOX and LEV, whose
C
max
were close to the MICs. Also, less pronounced but significant increases in MIC occurred at AUC
24
/MIC values (107 to 123 h) that correspond to quinolone concentrations partly overlapping the MIC-to-MPC range. With all four drugs, no change in MIC was seen at the highest AUC
24
/MIC values (201 to 244 h), where quinolone concentrations exceeded the MPC over most of the dosing interval. These “protective” AUC
24
/MIC ratios correspond to 66% of the usual clinical dose of MOX (400 mg), 190% of a 400-mg dose of GAT, 220% of a 500-mg dose of LEV, and 420% of two 500-mg doses of CIP. Thus, MOX may protect against resistance development at subtherapeutic doses, whereas GAT, LEV, and CIP provide similar effects only at doses that exceed their usual clinical doses. These data support the concept that resistant mutants are selectively enriched when antibiotic concentrations fall inside the MSW and suggest that in vitro dynamic models can be used to predict the relative abilities of quinolones to prevent mutant selection.
Antimicrobial and Immunologic Activities of Clarithromycin in a Murine Model of
Mycoplasma pneumoniae
-Induced Pneumonia
Authors: Hardy Robert D. , Rios Ana Maria , Chavez-Bueno Susana , Jafri Hasan S. , Hatfield Jeanine , Rogers Beverly B. , McCracken George H. , Ramilo Octavio
Published: April 2003

Because macrolide antibiotics are hypothesized to possess immunomodulatory activity independent of their antimicrobial activity, we evaluated the immunomodulatory effect of clarithromycin in a murine model of lung inflammation induced by either live or UV-killed
Mycoplasma pneumoniae
. BALB/c mice were intranasally inoculated once with live or UV-killed
M
.
pneumoniae
. Clarithromycin (25 mg/kg of body weight) or placebo was subcutaneously administered once daily in both groups of mice. In mice infected with live
M
.
pneumoniae
, clarithromycin treatment significantly reduced quantitative
M
.
pneumoniae
bronchoalveolar lavage (BAL) culture, pulmonary histopathologic scores (HPS), and airway resistance-obstruction (as measured by plethysmography) compared with placebo. Concentrations of tumor necrosis factor alpha, gamma interferon, interleukin-6 (IL-6), mouse KC (functional IL-8), JE/MCP-1, and MIP-1α in BAL fluid were also significantly decreased in mice infected with live
M
.
pneumoniae
given clarithromycin. In contrast, mice inoculated with UV-killed
M
.
pneumoniae
had no significant reduction in HPS, airway resistance-obstruction, or BAL cytokine or chemokine concentrations in response to clarithromycin administration. Clarithromycin therapy demonstrated beneficial effects (microbiologic, histologic, respiratory, and immunologic) on pneumonia in the mice infected with live
M
.
pneumoniae
; this was not observed in the mice inoculated with UV-killed
M
.
pneumoniae
.
Moxifloxacin Efficacy and Vitreous Penetration in a Rabbit Model ofStaphylococcus aureusEndophthalmitis and Effect on Gene Expression of Leucotoxins and Virulence Regulator Factors
Authors: Bronner Stéphane , Jehl François , Peter Jean-Daniel , Ploy Marie-Cécile , Renault Corinne , Arvis Pierre , Monteil Henri , Prevost Gilles
Published: April 2003

Bacterial endophthalmitis is a serious complication of ocular surgery and of eye trauma; the leading causative organisms areStaphylococcus aureusstrains. Tissue damage is due both to the host inflammatory response and to toxin synthesis by bacteria. Systemic treatment remains difficult because most antibiotics show poor ocular penetration. Moxifloxacin (MXF), a novel fluoroquinolone, was evaluated for its penetration into the vitreous of normal rabbit eyes and of eyes of rabbits infected for 24 h with methicillin-susceptible and methicillin-resistantS. aureus(MSSA and MRSA) following a single intravenous administration of 5 or 20 mg/kg. MXF penetration was rapid and efficient regardless of the dose, ranging from 28 to 52%. An inflammatory state of the vitreous significantly increased penetration after the 20-mg/kg dose, with penetration reaching 52%. Concentrations determined in the vitreous cavity following a 20-mg/kg administration showed a 3.5-fold decrease of the bacterial density within 5 h for MSSA (MIC, 0.125 μg/ml) and a 1.6-fold decrease for MRSA (MIC, 4 μg/ml) strains, respectively. By using a semiquantitative reverse transcription-PCR method, the expression ofluk-PVandhlgCB, but nothlgA, encoding staphylococcal leukotoxins, was detected in the vitreous without MXF treatment. A slight decrease in the expression of leucotoxins andsarA,agr, andsigBvirulence regulatory factors was observed 1 h following the administration of 5 mg of MXF per kg.
Pharmacodynamics of a Novel Des-F(6)-Quinolone, BMS-284756, against
Streptococcus
pneumoniae
in the Thigh Infection Model
Authors: Nicolau David P. , Mattoes Holly M. , Banevicius Maryanne , Xuan Dawei , Nightingale Charles H.
Published: April 2003

BMS-284756 is a novel quinolone that lacks the six-position fluorine typical of existing compounds. Despite this structural change, BMS-284756 maintains potent antibacterial activity against gram-negative and gram-positive aerobic and anaerobic pathogens. The objective of this study was to define the pharmacodynamic profile of BMS-284756 against
Streptococcus
pneumoniae
. Protein binding in mice was assessed by the ultrafiltration method. For pharmacodynamic studies, neutropenic ICR mice were used, as well as an immunocompetent mouse species, CBA/J, in order to evaluate the impact of white blood cells on infection outcome. Mice were infected with 10
5
to 10
6
CFU per thigh, and therapy was initiated after 2 h. Animals received BMS-284756 orally over a range of 1.25 to 100 mg/kg/day divided into one to four doses. At 0 and 24 h postinfection, thighs were harvested for bacterial density measurement. Survival was assessed during 96 h of therapy and again at 3 days after therapy. Pharmacokinetic studies were also conducted with infected mice. Protein binding was determined to be 80%. The MICs for clinical isolates (
n
= 8) ranged from 0.03 to 2 μg/ml. The change in bacterial density and survival was correlated with the pharmacodynamic parameters percentage of time that the drug concentration in serum remains above the MIC, AUC (area under the concentration-time curve)/MIC ratio, and peak/MIC ratio, and the best predictor of response was the AUC/MIC ratio for both outcome measures. Total AUC/MIC ratios of 100 to 200 appear to result in maximal bactericidal effects. While a total AUC/MIC ratio exposure value of 100 (free AUC/MIC ratio, ∼20) resulted in nearly 100% survival at the conclusion of therapy, a total AUC/MIC ratio of 200 (free AUC/MIC ratio, ∼40) was required to ensure survival at 3 days posttherapy. These data demonstrate (i) the in vivo bactericidal activity of BMS-284756 against
S
.
pneumoniae
, (ii) that protein binding has a profound impact on the in vivo pharmacodynamic assessment of BMS-284756, and (iii) that an AUC/MIC ratio of 200 (free AUC/MIC ratio, ∼40) appears to best characterize the required dynamic exposure for optimization of bactericidal activity and maximal survival.
Shiga-Like Toxin II Impairs Hepatobiliary Transport of Doxorubicin in Rats by Down-Regulation of Hepatic P Glycoprotein and Multidrug Resistance-Associated Protein Mrp2
Authors: Hidemura Kazuhiko , Zhao Ying Lan , Ito Katsuki , Nakao Akimasa , Tatsumi Yasuaki , Kanazawa Hiroaki , Takagi Kenzo , Ohta Michio , Hasegawa Takaaki
Published: April 2003

We investigated the effect of Shiga-like toxin II (SLT-II), derived from
Escherichia coli
O157:H7, on the hepatobiliary excretion of doxorubicin, a substrate for P glycoprotein and the multidrug resistance-associated protein Mrp2, and on the expression of P glycoprotein and Mrp2 in rats. Histopathological examination did not show any liver injury in SLT-II-treated rats. A significant delay in the disappearance of doxorubicin from plasma after its intravenous administration (5 mg/kg of body weight) was observed in rats treated 24 h earlier with SLT-II (2 μg/animal). When rats received an infusion of doxorubicin (2.6 μg/min) 24 h after intravenous injection of SLT-II, the steady-state concentration of doxorubicin in plasma increased and the bile flow decreased, whereas the concentration in liver did not alter. SLT-II significantly increased the unbound fraction of doxorubicin in plasma but did not alter the concentration in liver tissue. SLT-II significantly decreased the biliary excretion rate and biliary clearance of doxorubicin based on the total concentration and concentration of the unbound fraction in plasma and liver. Western blot analysis revealed that SLT-II down-regulated P glycoprotein and Mrp2 in the liver, which could explain the observed decrease in the biliary excretion of doxorubicin by SLT-II. A tumor necrosis factor alpha (TNF-α) production inhibitor, pentoxifylline, could not protect SLT-II-induced decreases in the biliary clearance of doxorubicin and down-regulation of both transporters. It is unlikely that TNF-α plays a major role in the SLT-II-induced decrease in the hepatobiliary transport of doxorubicin and the down-regulation of both transporters.
Pharmacokinetics-Pharmacodynamics of Cefepime and Piperacillin- Tazobactam against
Escherichia coli
and
Klebsiella pneumoniae
Strains Producing Extended-Spectrum β-Lactamases: Report from the ARREST Program
Authors: Ambrose P. G. , Bhavnani S. M. , Jones R. N.
Published: April 2003

The frequency of resistance to β-lactams among nosocomial isolates has been increasing due to extended-spectrum β-lactamase (ESBL)-producing enteric bacilli. Although clinical outcome data are desirable, assessment of clinical efficacy has been limited due to the lack of a statistically meaningful number of well-documented cases. Since time above the MIC (
T
>MIC) is the pharmacokinetic-pharmacodynamic (PK-PD) measure that best correlates with in vivo activity of β-lactams, a stochastic model was used to predict the probability of PK-PD target attainment ranging from 30 (P30) to 70% (P70)
T
>MIC, for standard dosing regimens of both piperacillin-tazobactam and cefepime against
Escherichia coli
and
Klebsiella pneumoniae
ESBL phenotypes. The P70/30
T
>MIC for cefepime at 2 g every 12 h against
E. coli
and
K. pneumoniae
was 0.99/1.0 and 0.96/1.0 and for a regimen of 1 g every 12 h was 0.96/1.0 and 0.93/0.99, respectively. For piperacillin-tazobactam at 3.375 g every 4 h against
E. coli
and
K. pneumoniae
, the P70/30
T
>MIC was 0.77/0.96 and 0.48/0.77 and for a regimen of 3.375 g every 6 h was 0.28/0.91 and 0.16/0.69, respectively. These data suggest that the probability of achieving
T
>MIC target attainment rates is generally higher with cefepime than with piperacillin-tazobactam for present-day ESBL-producing strains when one uses contemporary dosing regimens.
Correlation between E-Test, Disk Diffusion, and Microdilution Methods for Antifungal Susceptibility Testing of Fluconazole and Voriconazole
Authors: Matar Madonna J. , Ostrosky-Zeichner Luis , Paetznick Victor L. , Rodriguez Jose R. , Chen Enuo , Rex John H.
Published: April 2003

The activities of fluconazole and voriconazole against isolates of
Candida
spp. (
n
= 400) were tested by the E-test, disk diffusion, and the National Committee for Clinical Laboratory Standards (NCCLS) M27-A2 broth microdilution-based reference methods. More than 96% of isolates found to be susceptible to fluconazole by the reference method were identified as susceptible by the agar-based methods. Lesser degrees of correlation with the reference method were seen for isolates identified as resistant by the agar-based methods. Interpretive categories are not available for voriconazole, but results qualitatively similar to those for fluconazole were seen. The agar-based E-test and disk diffusion methods are reliable alternatives to the NCCLS M27-A2 reference microdilution method for isolates that test susceptible to fluconazole.
In Vitro and In Vivo Activities of AM-112, a Novel Oxapenem
Authors: Jamieson Conor E. , Lambert Peter A. , Simpson Iain N.
Published: April 2003

AM-112 [(1′R,5R,6R)-3-(4-amino-1,1-dimethyl-butyl)-6-(1′-hydroxyethyl)oxapenem-3-carboxylate] is a novel oxapenem compound which possesses potent β-lactamase-inhibitory properties. Fifty-percent inhibitory concentrations (IC
50
s) of AM-112 for class A enzymes were between 0.16 and 2.24 μM for three enzymes, compared to IC
50
s of 0.008 to 0.12 μM for clavulanic acid. Against class C and class D enzymes, however, the activity of AM-112 was between 1,000- and 100,000-fold greater than that of clavulanic acid. AM-112 had affinity for the penicillin-binding proteins (PBPs) of
Escherichia coli
DC0, with PBP2 being inhibited by the lowest concentration of AM-112 tested, 0.1 μg/ml. Ceftazidime was combined with AM-112 at 1:1 and 2:1 ratios in MIC determination studies against a panel of β-lactamase-producing organisms. These studies demonstrated that AM-112 was effective at protecting ceftazidime against extended-spectrum β-lactamase-producing strains and derepressed class C enzyme producers, reducing ceftazidime MICs by 16- and 2,048-fold. Similar results were obtained when AM-112 was combined with ceftriaxone, cefoperazone, or cefepime in a 1:2 ratio. Protection of ceftazidime with AM-112 was maintained against
Enterobacter cloacae
P99 and
Klebsiella pneumoniae
SHV-5 in a murine intraperitoneal sepsis model. The 50% effective dose of ceftazidime against
E. cloacae
P99 and
K. pneumoniae
SHV-5 was reduced from >100 and 160 mg/kg of body weight to 2 and 33.6 mg/kg, respectively, when it was combined with AM-112 at a 1:1 ratio. AM-112 demonstrates potential as a new β-lactamase inhibitor.
Molecular Evaluation of Antibiotic Susceptibility:
Tropheryma whipplei
Paradigm
Authors: Masselot F. , Boulos A. , Maurin M. , Rolain J. M. , Raoult D.
Published: April 2003

Tropheryma whipplei
, the agent of Whipple's disease, grows fastidiously only in cell cultures without plaque production, and only three strains have been passaged. The formation of bacterial clumps in the supernatant precludes enumeration of viable bacteria and MIC determination. We evaluated the bacteriostatic effects of fluoroquinolones against two
T. whipplei
isolates by measuring the inhibition of the DNA copy number increase by real-time quantitative PCR. The analysis of the
T. whipplei
genome database allowed the identification not only of the
gyrA
gene but also the
parC
gene encoding the alpha subunit of the natural fluoroquinolone targets DNA gyrase (GyrA) and topoisomerase IV (ParC), respectively. The
parC
gene was detected in actinobacteria for the first time. High ciprofloxacin MICs (4 and 8 μg/ml) were correlated with the presence in
T. whipplei
GyrA and ParC sequences with an alanine residue at positions 83 and 80 (
Escherichia coli
numbering), respectively. Alanines at these positions have previously been associated with increased fluoroquinolone resistance in
E. coli
and mycobacteria. However, the MIC of levofloxacin was low (0.25 μg/ml). The same
T. whipplei
GyrA and ParC sequences were found in two other cultured strains and in nine uncultured tissue samples from Whipple's disease patients, allowing one to speculate that
T. whipplei
is naturally relatively resistant to fluoroquinolones.
Wolbachia pipientis
Growth Kinetics and Susceptibilities to 13 Antibiotics Determined by Immunofluorescence Staining and Real-Time PCR
Authors: Fenollar Florence , Maurin Max , Raoult Didier
Published: April 2003

Wolbachia
spp. are strict intracellular bacteria that infect a wide range of arthropods and filarial nematodes. Filarial nematodes are important causes of human diseases. There is increasing evidence that
Wolbachia
spp. influence important functions in the biology of the hosts, specifically, infertility. Preliminary experiments with humans and animals have suggested that antibiotics with activity against
Wolbachia
may help to treat filariasis. In this study, we determined using a real-time quantitative PCR assay the growth kinetics of a strain of
Wolbachia pipientis
from a mosquito grown in Aa23 cells. The doubling time was estimated to be 14 h. We then determined the susceptibilities of this strain to 13 antibiotics by two methods: an immunofluorescent-antibody test and a real-time quantitative PCR assay. Both techniques gave similar results. Doxycycline and rifampin were the most effective compounds, with MICs of 0.125 and 0.06 to 0.125 μg/ml, respectively. Fluoroquinolones were less effective, with MICs of 2 to 4 μg/ml for ciprofloxacin, 2 μg/ml for ofloxacin, and 1 μg/ml for levofloxacin. β-Lactams (penicillin G, amoxicillin, ceftriaxone) were not effective at concentrations up to 128 μg/ml. The MIC of erythromycin was >32 μg/ml, whereas that of telithromycin was 8 μg/ml. Other antibiotic compounds were bacteriostatic only at high concentrations, including gentamicin, co-trimoxazole, and thiamphenicol. The real-time PCR assay was a convenient and reliable technique for determination of the antibiotic susceptibilities of
Wolbachia
. It may help in the future to simplify antibiotic susceptibility testing of strict intracellular pathogens.
Trends in Antimicrobial Susceptibilities among
Enterobacteriaceae
Isolated from Hospitalized Patients in the United States from 1998 to 2001
Authors: Karlowsky James A. , Jones Mark E. , Thornsberry Clyde , Friedland Ian R. , Sahm Daniel F.
Published: April 2003

Longitudinal surveillance of
Enterobacteriaceae
for antimicrobial susceptibility is important because species of this family are among the most significant and prevalent human pathogens. To estimate rates of in vitro antimicrobial susceptibility among hospitalized patients in the United States, data from The Surveillance Network were studied for 14 agents tested against 10 species of
Enterobacteriaceae
(
n
= 384,279) isolated from intensive-care-unit (ICU) patients and non-ICU inpatients from 1998 to 2001. Cumulative susceptibility (percent) data for all species of
Enterobacteriaceae
isolated from ICU patients and non-ICU inpatients, respectively, were ranked as follows: ampicillin-sulbactam (45.5 and 57.2) ≪ ticarcillin-clavulanate (74.8 and 83.5) < trimethoprim-sulfamethoxazole (87.0 and 84.5) ≅ cefotaxime (82.9 and 92.6) = ceftazidime (82.3 and 91.0) = ceftriaxone (86.5 and 93.9) = piperacillin-tazobactam (83.5 and 90.5) < levofloxacin (89.3 and 90.6) = ciprofloxacin (91.0 and 91.7) < gentamicin (91.8 and 94.3) < cefepime (95.0 and 97.9) < amikacin (98.5 and 99.2) < imipenem (100 and 100) = meropenem (100 and 100). Of those agents studied only susceptibilities to ciprofloxacin (94 to 89%) and levofloxacin (93 to 89%) decreased in a stepwise manner from 1998 to 2001. Decreased fluoroquinolone susceptibility was most pronounced for
Escherichia coli
,
Proteus mirabilis
, and
Enterobacter cloacae
. For all species of
Enterobacteriaceae
, trimethoprim-sulfamethoxazole resistance was more commonly observed in isolates with a single-drug resistance phenotype while gentamicin and fluoroquinolone resistances were more common in isolates resistant to at least one additional class of antimicrobial agent. Ongoing surveillance of
Enterobacteriaceae
will be particularly important to monitor changes in fluoroquinolone susceptibility, as well as changes in the prevalence of isolates resistant to multiple classes of antimicrobial agents.
Surveillance for Antimicrobial Susceptibility among Clinical Isolates of
Pseudomonas aeruginosa
and
Acinetobacter baumannii
from Hospitalized Patients in the United States, 1998 to 2001
Authors: Karlowsky James A. , Draghi Deborah C. , Jones Mark E. , Thornsberry Clyde , Friedland Ian R. , Sahm Daniel F.
Published: April 2003

Pseudomonas aeruginosa
and
Acinetobacter baumannii
are the most prevalent nonfermentative bacterial species isolated from clinical specimens of hospitalized patients. A surveillance study of 65 laboratories in the United States from 1998 to 2001 found >90% of isolates of
P
.
aeruginosa
from hospitalized patients to be susceptible to amikacin and piperacillin-tazobactam; 80 to 90% of isolates to be susceptible to cefepime, ceftazidime, imipenem, and meropenem; and 70 to 80% of isolates to be susceptible to ciprofloxacin, gentamicin, levofloxacin, and ticarcillin-clavulanate. From 1998 to 2001, decreases in antimicrobial susceptibility (percents) among non-intensive-care-unit (non-ICU) inpatients and ICU patients, respectively, were greatest for ciprofloxacin (6.1 and 6.5), levofloxacin (6.6 and 3.5), and ceftazidime (4.8 and 3.3). Combined 1998 to 2001 results for
A
.
baumannii
isolated from non-ICU inpatients and ICU patients, respectively, demonstrated that >90% of isolates tested were susceptible to imipenem (96.5 and 96.6%) and meropenem (91.6 and 91.7%); fewer isolates from both non-ICU inpatients and ICU patients were susceptible to amikacin and ticarcillin-clavulanate (70 to 80% susceptible); and <60% of isolates were susceptible to ceftazidime, ciprofloxacin, gentamicin, or levofloxacin. From 1998 to 2001, rates of multidrug resistance (resistance to at least three of the drugs ceftazidime, ciprofloxacin, gentamicin, and imipenem) showed small increases among
P
.
aeruginosa
strains isolated from non-ICU inpatients (5.5 to 7.0%) and ICU patients (7.4 to 9.1%). From 1998 to 2001, rates of multidrug resistance among
A
.
baumannii
strains isolated from non-ICU inpatients (27.6 to 32.5%) and ICU patients (11.6 to 24.2%) were higher and more variable than those observed for
P
.
aeruginosa
. Isolates concurrently susceptible, intermediate, or resistant to both imipenem and meropenem accounted for 89.8 and 91.2% of
P
.
aeruginosa
and
A
.
baumannii
isolates, respectively, studied from 1998 to 2001. In conclusion, for aminoglycosides and most β-lactams susceptibility rates for
P
.
aeruginosa
and
A
.
baumannii
were constant or decreased only marginally (≤3%) from 1998 to 2001. Greater decreases in susceptibility rates were, however, observed for fluoroquinolones and ceftazidime among
P
.
aeruginosa
isolates.
Baseline Study To Determine In Vitro Activities of Daptomycin against Gram-Positive Pathogens Isolated in the United States in 2000-2001
Authors: Critchley Ian A. , Blosser-Middleton Renée S. , Jones Mark E. , Thornsberry Clyde , Sahm Daniel F. , Karlowsky James A.
Published: April 2003

The activity of daptomycin was assessed by using 6,973 gram-positive bacteria isolated at 50 United States hospitals in 2000 and 2001. Among the isolates of
Streptococcus pneumoniae
(
n
= 1,163) collected, the rate of penicillin resistance was 16.1%; rates of oxacillin resistance among
Staphylococcus aureus
isolates (
n
= 1,018) and vancomycin resistance among
Enterococcus faecium
isolates (
n
= 368) were 30.0 and 59.5%, respectively. Multidrug-resistant (MDR) phenotypes (isolates resistant to three or more different chemical classes of antimicrobial agents) accounted for 14.2% of
S. pneumoniae
isolates, 27.1% of
S. aureus
isolates, and 58.4% of
E. faecium
isolates. For all gram-positive species tested, MICs at which 90% of the isolates tested were inhibited (MIC
90
s) and MIC ranges for directed-spectrum agents (daptomycin, quinupristin-dalfopristin, and linezolid) were identical or highly similar for isolates susceptible or resistant to other agents or MDR. Daptomycin had a MIC
90
of 0.12 μg/ml for both penicillin-susceptible and -resistant isolates of
S. pneumoniae
. Against oxacillin-resistant
S. aureus
daptomycin had a MIC
90
of 0.5 μg/ml, and it had a MIC
90
of 4 μg/ml against both vancomycin-susceptible and -resistant
E. faecium
. The MIC
90
s for daptomycin and other directed-spectrum agents were unaffected by the regional or anatomical origin of isolates or patient demographic parameters (patient age, gender, and inpatient or outpatient care). Our results confirm the gram-positive spectrum of activity of daptomycin and that its activity is independent of susceptibility or resistance to commonly prescribed and tested antimicrobial agents. This study may serve as a baseline to monitor future changes in the susceptibility of gram-positive species to daptomycin following its introduction into clinical use.
Pharmacokinetics of Ritonavir and Delavirdine in Human Immunodeficiency Virus-Infected Patients
Authors: Shelton Mark J. , Hewitt Ross G. , Adams John , Della-Coletta Andrew , Cox Steven , Morse Gene D.
Published: April 2003

To evaluate the pharmacokinetic effect of adding delavirdine mesylate to the antiretroviral regimens of human immunodeficiency virus (HIV)-infected patients stabilized on a full dosage of ritonavir (600 mg every 12 h), 12 HIV-1-infected subjects had delavirdine mesylate (400 mg every 8 h) added to their current antiretroviral regimens for 21 days. Ritonavir pharmacokinetics were evaluated before (day 7) and after (day 28) the addition of delavirdine, and delavirdine pharmacokinetics were evaluated on day 28. The mean values (± standard deviations) for the maximum concentration in serum (
C
max
) of ritonavir, the area under the concentration-time curve from 0 to 12 h (AUC
0-12
), and the minimum concentration in serum (
C
min
) of ritonavir before the addition of delavirdine were 14.8 ± 6.7 μM, 94 ± 36 μM · h, and 3.6 ± 2.1 μM, respectively. These same parameters were increased to 24.6 ± 13.9 μM, 154 ± 83 μM · h, and 6.52 ± 4.85 μM, respectively, after the addition of delavirdine (
P
is <0.05 for all comparisons). Delavirdine pharmacokinetic parameters in the presence of ritonavir included a
C
max
of 23 ± 16 μM, an AUC
0-8
of 114 ± 75 μM · h, and a
C
min
of 9.1 ± 7.5 μM. Therefore, delavirdine increases systemic exposure to ritonavir by 50 to 80% when the drugs are coadministered.
Pharmacodynamics of Oritavancin (LY333328) in a Neutropenic-Mouse Thigh Model of
Staphylococcus aureus
Infection
Authors: Boylan Carole J. , Campanale Kristina , Iversen Philip W. , Phillips Diane L. , Zeckel Michael L. , Parr Thomas R.
Published: April 2003

The pharmacokinetics and pharmacodynamics of oritavancin (LY333328), a glycopeptide antibiotic with concentration-dependent bactericidal activity against gram-positive pathogens, in a neutropenic-mouse thigh model of
Staphylococcus aureus
infection were studied. Plasma radioequivalent concentrations of oritavancin were determined by using [
14
C]oritavancin at doses ranging from 0.5 to 20 mg/kg of body weight. Peak plasma radioequivalent concentrations after an intravenous dose were 7.27, 12.56, 69.29, and 228.83 μg/ml for doses of 0.5, 1, 5, and 20 mg/kg, respectively. The maximum concentration of drug in serum (
C
max
) and the area under the concentration-time curve (AUC) increased linearly in proportion to the dose. Neither infection nor neutropenia was seen to affect the pharmacokinetics of oritavancin. Intravenous administration resulted in much higher concentrations in plasma than the concentrations obtained with subcutaneous administration. Single-dose dose-ranging studies suggested a sigmoid maximum effect (
E
max
) dose-response relationship, with a maximal effect evident at single doses exceeding 2 mg/kg. The oritavancin dose (stasis dose) that resulted in a 24-h colony count similar to the pretreatment count was 1.53 (standard error [SE], 0.35) mg/kg. The single oritavancin dose that resulted in 50% of maximal bacterial killing (ED
50
) was 0.95 (SE, 0.20) mg/kg. Dose fractionation studies suggested that single doses of 0.5, 1, 2, 4, and 16 mg/kg appeared to have greater bactericidal efficacy than the same total dose subdivided and administered multiple times during the 24-h treatment period. When using an inhibitory
E
max
model,
C
max
appears to correlate better with bactericidal activity than do the time during which the concentration in plasma exceeds the MIC (T>MIC) and AUC. These data suggest that optimal oritavancin dosing strategies will require regimens that favor high
C
max
concentrations rather than long periods during which unbound concentrations in plasma exceed the MIC.
Differential Mutation Patterns in Thymidine Kinase and DNA Polymerase Genes of Herpes Simplex Virus Type 1 Clones Passaged in the Presence of Acyclovir or Penciclovir
Authors: Suzutani Tatsuo , Ishioka Ken , De Clercq Erik , Ishibashi Kei , Kaneko Hisatoshi , Kira Toshihiko , Hashimoto Koh-ichi , Ogasawara Masahiro , Ohtani Katsuki , Wakamiya Nobutaka , Saijo Masayuki
Published: April 2003

A total of 21 clones of acyclovir (ACV)-resistant (ACVr) herpes simplex virus type 1 (HSV-1) and 23 clones of penciclovir (PCV)-resistant (PCVr) HSV-1, emerging during serial passages in the presence of ACV or PCV, were isolated under conditions excluding contamination of resistant mutants in the starting virus culture, and their mutations in the thymidine kinase (TK) and DNA polymerase (DNA Pol) genes were analyzed comparatively. Mutations in the TK genes from ACVrmutants consisted of 50% single nucleotide substitutions and 50% frameshift mutations, while the corresponding figures for the PCVrmutants were 4 and 96%, respectively (P< 0.001). Eight of the 21 ACVrclones, but none of the 23 PCVrclones, had mutations in DNA Pol. Only nucleotide substitution(s) could be detected in the DNA Pol gene, as the gene is essential for virus replication. Therefore, the results for the DNA Pol mutants are concordant with those for the TK mutants in that a single nucleotide substitution was commonly observed in the ACVr, but not in the PCVr, mutants. These results clearly point to differential mutation patterns between ACVrand PCVrHSV-1 clones.
Efficacy of Daptomycin in Experimental Endocarditis Due to Methicillin-Resistant
Staphylococcus
aureus
Authors: Sakoulas George , Eliopoulos George M. , Alder Jeff , Eliopoulos Claudie Thauvin-
Published: April 2003

Methicillin-resistant
Staphylococcus
aureus
is becoming increasingly prevalent as both a nosocomial and a community-acquired pathogen. Daptomycin, a lipopeptide antibiotic now in phase III clinical trials, is rapidly bactericidal in vitro against a range of gram-positive organisms, including methicillin-resistant
S. aureus
(MRSA). In this study, we compared the efficacy of daptomycin with that of vancomycin, each with or without rifampin, in a model of experimental aortic valve endocarditis due to MRSA. The infecting strain (MRSA strain 32) was susceptible to daptomycin (MIC = 1 μg/ml), vancomycin (MIC = 0.5 μg/ml), and rifampin (MIC = 0.5 μg/ml). Daptomycin was administered at 25 or 40 mg/kg q24h (q24h) by subcutaneous injection in an attempt to simulate human doses of 4 and 6 mg/kg q24h, respectively. Vancomycin was given at 150 mg/kg q24h by continuous intravenous infusion. Rifampin was given at 25 mg/kg by intramuscular injection q24h. Treatment was started 6 h postinoculation and continued for 4.5 days. Outcome was assessed by counting the residual viable bacteria in vegetations. The mean peak daptomycin levels in serum at 2 h after subcutaneous administration of 25 and 40 mg/kg were 64 and 91 μg/ml, respectively. Daptomycin was undetectable in serum at 24 h. The total exposure was comparable to that achieved clinically in humans receiving the drug. Bacterial counts (mean log
10
number of CFU per gram ± the standard deviation) in untreated controls reached 10.6 ± 0.8. In treated rats, bacterial counts were as follows: vancomycin, 7.1 ± 2.5; daptomycin at 25 mg/kg, 5.5 ± 1.7; daptomycin at 40 mg/kg, 4.2 ± 1.5. The difference between daptomycin at 40 mg/kg and vancomycin at 150 mg/kg was statistically significant (
P
= 0.004). In the study of combination therapy, vegetation bacterial counts were as follows: daptomycin at 40 mg/kg, 4.6 ± 1.6; rifampin, 3.6 ± 1.3; vancomycin plus rifampin, 3.3 ± 1.1; daptomycin plus rifampin, 2.9 ± 0.8. The difference between daptomycin and daptomycin plus rifampin was statistically significant (
P
= 0.006). These results support the continued evaluation of daptomycin for serious MRSA infections, including infective endocarditis.
Multiple Resistance Mechanisms among
Aspergillus fumigatus
Mutants with High-Level Resistance to Itraconazole
Authors: Nascimento Adriana M. , Goldman Gustavo H. , Park Steven , Marras Salvatore A. E. , Delmas Guillaume , Oza Uma , Lolans Karen , Dudley Michael N. , Mann Paul A. , Perlin David S.
Published: April 2003

A collection of
Aspergillus fumigatus
mutants highly resistant to itraconazole (RIT) at 100 μg ml
−1
were selected in vitro (following UV irradiation as a preliminary step) to investigate mechanisms of drug resistance in this clinically important pathogen. Eight of the RIT mutants were found to have a mutation at Gly54 (G54E, -K, or -R) in the azole target gene
CYP51A
. Primers designed for highly conserved regions of multidrug resistance (MDR) pumps were used in reverse transcriptase PCR amplification reactions to identify novel genes encoding potential MDR efflux pumps in
A. fumigatus
. Two genes,
AfuMDR3
and
AfuMDR4
, showed prominent changes in expression levels in many RIT mutants and were characterized in more detail. Analysis of the deduced amino acid sequence encoded by
AfuMDR3
revealed high similarity to major facilitator superfamily transporters, while
AfuMDR4
was a typical member of the ATP-binding cassette superfamily. Real-time quantitative PCR with molecular beacon probes was used to assess expression levels of
AfuMDR3
and
AfuMDR4
. Most RIT mutants showed either constitutive high-level expression of both genes or induction of expression upon exposure to itraconazole. Our results suggest that overexpression of one or both of these newly identified drug efflux pump genes of
A. fumigatus
and/or selection of drug target site mutations are linked to high-level itraconazole resistance and are mechanistic considerations for the emergence of clinical resistance to itraconazole.
Persistence of Salmonellae in Blood and Bone Marrow: Randomized Controlled Trial Comparing Ciprofloxacin and Chloramphenicol Treatments against Enteric Fever
Authors: Gasem M. Hussein , Keuter Monique , Dolmans Wil M. V. , van der Ven-Jongekrijg Johanna , Djokomoeljanto Robert , van der Meer Jos W. M.
Published: April 2003

We performed a randomized controlled trial involving 55 adult patients with enteric fever to compare ciprofloxacin and chloramphenicol. Blood and bone marrow cultures and cytokine profiles during therapy were done to compare the clinical and bacteriological efficacies of these drugs. All patients were randomly assigned to receive chloramphenicol (500 mg four times a day orally) for 14 days or ciprofloxacin (500 mg twice a day orally) for 7 days. In each treatment group, patients were subsequently randomized to have blood and bone marrow cultured after either 3 or 5 days of treatment. Twenty-seven patients received chloramphenicol, and 28 received ciprofloxacin. The two groups were similar in terms of baseline characteristics. No significant differences in clinical cure and time to defervescence were found. All strains isolated were susceptible to both antibiotics. Although ciprofloxacin was more effective in the elimination of
Salmonella
enterica
serovars Typhi and Paratyphi A from bone marrow than chloramphenicol, there was still an impressive persistence of
Salmonella
in the bone marrow culture (67%). In the ciprofloxacin-treated patients the suppressed cytokine production capacity showed a trend to normalize earlier than in patients treated with chloramphenicol.
Pharmacokinetics of Intramuscularly Administered Ertapenem
Authors: Musson Donald G. , Majumdar Anup , Birk Kimberly , Holland Sherry , Wickersham Peter , Li Susan X. , Mistry Goutam , Fisher Alison , Waldman Scott , Greenberg Howard , Deutsch Paul , Rogers J. Douglas
Published: April 2003

Ertapenem (INVANZ) is a new once-a-day parental β-lactam antimicrobial agent that has been shown to be highly effective as a single agent for treatment of various community-acquired and mixed infections. The plasma pharmacokinetics of a 1-g intramuscular (i.m.) dose was compared with those of a 1-g intravenous (i.v.) dose infused over 30 min, the recommended rate of i.v. infusion for comparison, and over 120 min, which more closely mimicked the time course for absorption of the i.m. form. In a three-period crossover study (Part A), 26 healthy subjects received single doses of ertapenem administered i.m., i.v. infused over 30 min, and i.v. infused over 120 min. Blood for ertapenem analysis was collected over 24 h postdose for each treatment. In Part B, these fasted subjects received a 1-g i.m. dose of ertapenem once daily for 7 days. Following a 1-g i.m. dose and a 1-g i.v. dose infused over 120 min, the geometric mean area under the concentration curve from hour 0 to infinity (AUC
0-∞
) was 541.8 μg · hr/ml following i.m. administration and 591.4 μg · hr/ml following a 120-min infusion; the geometric mean ratio was 0.92 with a 90% confidence interval of 0.88 to 0.95. The geometric mean AUC
0-∞
was nearly identical when 1-g doses were infused over 30 or 120 min. Although the maximum concentration of drug in serum was somewhat lower following i.m. administration than following i.v. administration, the shape of the plasma concentration profiles was roughly comparable at later time points. Ertapenem did not accumulate after multiple 1-g i.m. daily doses over 7 days. The geometric mean ratio for AUC
0-24
(day 7/day 1) was 0.98 with a 90% confidence interval of 0.94 to 1.02. Thus, the relative bioavailability of the 1-g i.m. dose was 92%. Ertapenem does not accumulate following multiple daily 1-g i.m. doses over 7 days.
In Vitro Activity of Linezolid against Slowly Growing Nontuberculous Mycobacteria
Authors: Brown-Elliott Barbara A. , Crist Christopher J. , Mann Linda B. , Wilson Rebecca W. , Wallace Richard J.
Published: April 2003

MICs of linezolid in broth microdilutions were tested against 341 slowly growing nontuberculous mycobacteria (NTM) belonging to 15 species. The proposed linezolid susceptibility MICs for all
Mycobacterium marinum
,
Mycobacterium szulgai
,
Mycobacterium kansasii
,
Mycobacterium malmoense
, and
Mycobacterium xenopi
isolates and for 90% of
Mycobacterium gordonae
and
Mycobacterium triplex
isolates were ≤8 μg/ml. Linezolid has excellent therapeutic potential against most species of NTM.
Burkholderia
Is Highly Resistant to Human Beta-Defensin 3
Authors: Sahly Hany , Schubert Sabine , Harder Jürgen , Rautenberg Peter , Ullmann Uwe , Schröder Jens , Podschun Rainer
Published: April 2003

The bactericidal activity of the novel beta-defensin hBD-3 against 28 species and 55 strains of gram-positive cocci and gram-negative fermentative and nonfermentative rods was tested. All strains proved to be highly or intermediately susceptible to hBD-3 (minimal bactericidal concentration [MBC], ≤50 μg/ml), except for
Burkholderia cepacia
, for all 23 tested strains of which MBCs were >100 μg/ml.
In Vitro Susceptibilities ofRhodococcus equiand Other Common Equine Pathogens to Azithromycin, Clarithromycin, and 20 Other Antimicrobials
Authors: Jacks Stephanie S. , Giguère Steeve , Nguyen An
Published: April 2003

The objective of this study was to determine in vitro activities of azithromycin (AZM), clarithromycin (CLR), and 20 other antimicrobial agents againstRhodococcus equiand other common equine bacterial pathogens. A total of 201 bacterial isolates from various equine clinical samples were examined. CLR was more active than AZM againstR. equi, with MICs at which 90% of the isolates were inhibited of 0.12 and 1.0 μg/ml, respectively. Other antimicrobial agents highly active against at least 90% ofR. equiisolates in vitro included rifampin, gentamicin, and imipenem. Both AZM and CLR showed good activity against beta-hemolytic streptococci andStaphylococcusspp. AZM was more active than other macrolides againstPasteurellaspp. andSalmonella enterica.
Novel 3-
N
-Aminoglycoside Acetyltransferase Gene,
aac
(
3
)-
Ic
, from a
Pseudomonas aeruginosa
Integron
Authors: Riccio Maria Letizia , Docquier Jean-Denis , Dell'Amico Emanuela , Luzzaro Francesco , Amicosante Gianfranco , Rossolini Gian Maria
Published: April 2003

A novel gene,
aac
(
3
)-
Ic
, encoding an AAC(3)-I aminoglycoside 3-
N
-acetyltransferase, was identified on a gene cassette inserted into a
Pseudomonas aeruginosa
integron that also carries a
bla
VIM-2
and a
cmlA7
gene cassette. The
aac
(
3
)-
Ic
gene product is 59 and 57% identical to AAC(3)-Ia and AAC(3)-Ib, respectively, and confers resistance to gentamicin and sisomicin.
High Prevalence of PER-1 Extended-Spectrum β-Lactamase-Producing
Acinetobacter
spp. in Korea
Authors: Yong Dongeun , Shin Jong Hee , Kim Sinyoung , Lim Youngsik , Yum Jong Hwa , Lee Kyungwon , Chong Yunsop , Bauernfeind Adolf
Published: April 2003

PER-1, an extended-spectrum β-lactamase, has been reported only in Europe. We detected PER-1 in 53 of 97 acinetobacters in Korea, mainly in the sputum of intensive care unit patients. Pulsed-field gel electrophoresis analysis suggested that clonal spread had occurred. Only PCR reliably detected PER-1 producers. PER-1 producers may also exist in other Asian countries.
Influences of Linezolid, Penicillin, and Clindamycin, Alone and in Combination, on Streptococcal Pyrogenic Exotoxin A Release
Authors: Coyle Elizabeth A. , Cha Raymond , Rybak Michael J.
Published: April 2003

An in vitro model was used to compare the effects of linezolid, clindamycin, and penicillin, alone and in combination, on streptococcal pyrogenic exotoxin A (SPE A) release against virulent group A streptococci (GAS). All regimens exhibited lower (P< 0.05) SPE A release at 1 h than those with penicillin alone. Linezolid and clindamycin, alone or in combination with penicillin, may optimize the treatment of GAS infections by reducing bacterial burden and exotoxin release.
Susceptibilities of Simian Immunodeficiency Virus to Protease Inhibitors
Authors: Giuffre Angelica C. , Higgins Joanne , Buckheit Robert W. , North Thomas W.
Published: April 2003

We used a focal infectivity assay with HeLa H1-JC.37 cells to directly compare susceptibilities of simian immunodeficiency virus (SIV) and human immunodeficiency virus type 1 (HIV-1) to protease inhibitors. SIVmac239 was inhibited by indinavir, saquinavir, and ritonavir, with 50% effective concentrations (means ± standard deviations) of 39 ± 8, 55 ± 3, and 13 ± 5 nM, respectively. The corresponding values for inhibition of HIV-1 were 66 ± 4, 47 ± 10, and 25 ± 14 nM, respectively.