Abstract:
:Hypermutable Pseudomonas aeruginosa strains are found with high frequency in the lungs of patients with chronic infections and are associated with high antibiotic resistance rates. The in vivo consequences of hypermutation for treatment in a mouse model of lung infection using strain PAO1 and its hypermutable derivative PAOdeltamutS are investigated. Groups of 30 mice were treated for 3 days with humanized regimens of ciprofloxacin (CIP), tobramycin (TOB), CIP plus TOB, or placebo, and mortality, total lung bacterial load, and 4x- and 16x-MIC mutants were recorded. The rates of mutation and the initial in vivo frequencies of mutants (at the onset of treatment) were also estimated and the in vitro- and in vivo-selected mutants characterized. Since both strains had identical MICs, the same pharmacokinetic/pharmacodynamic (PK/PD) parameters were obtained: area under the 24-h concentration-time curve (fAUC)/MIC = 385 for CIP and maximum concentration of drug in serum (fC(max))/MIC = 19 for TOB. Despite adequate PK/PD parameters, persistence of high bacterial numbers and amplification (50,000-fold) of resistant mutants (MexCD-OprJ hyperexpression) were documented with CIP treatment for PAOdeltamutS, in contrast to complete resistance suppression for PAO1 (P < 0.01), showing that conventional PK/PD parameters may not be applicable to infections by hypermutable strains. On the other hand, the efficacy of TOB monotherapy in terms of mortality reduction and bacterial load was very low regardless of the strain but not due to resistance development, since mutants were not selected for PAO1 and were only modestly amplified for PAOdeltamutS. Finally, the CIP-plus-TOB combination was synergistic, further reducing mortality and bacterial load and completely preventing resistance even for PAOdeltamutS (P < 0.01 compared to monotherapy), showing that it is possible to suppress resistance selection in infections by hypermutable P. aeruginosa using appropriate combined regimens.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Maciá MD,Borrell N,Segura M,Gómez C,Pérez JL,Oliver Adoi
10.1128/AAC.50.3.975-983.2006subject
Has Abstractpub_date
2006-03-01 00:00:00pages
975-83issue
3eissn
0066-4804issn
1098-6596pii
50/3/975journal_volume
50pub_type
杂志文章abstract::The effects of ceftizoxime and gentamicin alone and in combination were determined against 100 Pseudomonas aeruginosa strains. Concentrations of 32 micrograms of ceftizoxime and 8 micrograms of gentamicin per ml inhibited 22 and 43% of the strains, respectively. At concentrations of ceftizoxime and gentamicin that are...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.25.6.770
更新日期:1984-06-01 00:00:00
abstract::Two genes (rpsL and rrs) with mutations associated with streptomycin resistance in Mycobacterium tuberculosis were characterized in 78 streptomycin-resistant and 61 streptomycin-susceptible isolates recovered from patients living in the United States, South America, Europe, Africa, and Asia. Fifty-four percent of the ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.40.4.1024
更新日期:1996-04-01 00:00:00
abstract::Gardimycin, a new antibiotic, at 100 mug/ml, specifically inhibited cell wall synthesis and induced accumulation of uridine 5'-diphosphate-N-acetylmur-amylpentapeptide in whole cells of Bacillus subtilis. The antibiotic was active in a particulate enzyme preparation from Bacillus stearothermophilus: 60 mug/ml caused 5...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.11.3.396
更新日期:1977-03-01 00:00:00
abstract::The distributions of tet(M) and conjugative transposons related to Tn1545 were studied by hybridization in 47 clinical isolates of Streptococcus pneumoniae resistant to tetracycline. Resistance to tetracycline was always associated with resistance to minocycline and was due to the presence of the tet(M) gene. Associat...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.35.8.1657
更新日期:1991-08-01 00:00:00
abstract::The opportunistic Gram-negative pathogen Pseudomonas aeruginosa, known for its intrinsic and acquired antibiotic resistance, has a notorious ability to form biofilms, which often facilitate chronic infections. The evolutionary paths to antibiotic resistance have mainly been investigated in planktonic cultures and are ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00320-18
更新日期:2018-07-27 00:00:00
abstract::Osteoarticular mucormycosis cases are quite rare and challenging infections that are mostly due to direct inoculation during traumatic injury among immunocompetent patients. Classic management includes a combination of aggressive surgical debridement, which may lead to amputation, and long-term systemic liposomal amph...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01006-18
更新日期:2018-12-21 00:00:00
abstract::The opportunistic apicomplexan parasite Toxoplasma gondii damages fetuses in utero and threatens immunocompromised individuals. The toxicity associated with standard antitoxoplasmal therapies, which target the folate pathway, underscores the importance of examining alternative pharmacological strategies. Parasitic pro...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.49.6.2172-2179.2005
更新日期:2005-06-01 00:00:00
abstract::A preliminary study was conducted with netilmicin, a new aminoglycoside antibiotic. Its effectiveness was evaluated in vitro against 546 strains of Enterobacteriaceae and Pseudomonas aeruginosa isolated from clinical material. Its effectiveness against gentamicin-susceptible strains was roughly similar to that of gent...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章
doi:10.1128/aac.12.4.503
更新日期:1977-10-01 00:00:00
abstract::The production of Klebsiella pneumoniae carbapenemases (KPCs) by Enterobacteriaceae has become a significant problem in recent years. To identify factors that could predict isolation of KPC-producing K. pneumoniae (KPCKP) in clinical samples from hospitalized patients, we conducted a retrospective, matched (1:2) case-...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02373-13
更新日期:2014-06-01 00:00:00
abstract::The accumulation of norfloxacin by Bacteroides fragilis NCTC 9343 was determined by the modified fluorescence method. The time required to achieve a steady-state concentration (SSC) after allowing B. fragilis to accumulate norfloxacin in an aerobic or an anaerobic environment was approximately 2 min; the SSC achieved ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.44.9.2361-2366.2000
更新日期:2000-09-01 00:00:00
abstract::In 2002, the first two clinical isolates of vancomycin-resistant Staphylococcus aureus (VRSA) containing vanA were recovered in Michigan and Pennsylvania. Tn1546, a mobile genetic element that encodes high-level vancomycin resistance in enterococci, was present in both isolates. With PCR and DNA sequence analysis, we ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.49.1.470-472.2005
更新日期:2005-01-01 00:00:00
abstract::We report the capacity of copper oxide-containing filters to reduce infectious titers of a panel of viruses spiked into culture media. Enveloped, nonenveloped, RNA, and DNA viruses were affected, suggesting the possibility of using copper oxide-containing devices to deactivate a wide spectrum of infectious viruses fou...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00125-07
更新日期:2007-07-01 00:00:00
abstract::Carbovir is a novel carbocyclic nucleoside which has been shown to have potent in vitro activity against human immunodeficiency virus, the causative agent of acquired immunodeficiency syndrome. Sprague-Dawley male rats were used to investigate the pharmacokinetics and bioavailability of carbovir. Six rats received car...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.33.2.171
更新日期:1989-02-01 00:00:00
abstract::More than 250 Providencia strains isolated from the urine of institutionalized elderly patients were tested against cefaclor, cefuroxime, cefetamet, cefpodoxime, ciprofloxacin, and amoxicillin-clavulanic acid. Our results confirm the strong activities of expanded-spectrum oral cephalosporins against Providencia isolat...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.39.12.2819
更新日期:1995-12-01 00:00:00
abstract::We found earlier that deferoxamine (DFO), a drug used for treatment of iron overload, is active against a rat model of Pneumocystis carinii pneumonia (PCP). We had assumed a mode of action by deprivation of nutritional iron; however, data here show that DFO penetrates P. carinii, causing irreversible damage, thus indi...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.45.12.3560-3565.2001
更新日期:2001-12-01 00:00:00
abstract::The new oral 200-mg rifamycin SV MMX modified-release tablets, designed to deliver rifamycin SV directly into the colonic lumen, offer considerable advantages over the existing immediate-release antidiarrheic formulations. In two pharmacokinetics studies of healthy volunteers, the absorption, urinary excretion, and fe...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章,随机对照试验
doi:10.1128/AAC.01504-10
更新日期:2011-05-01 00:00:00
abstract::Rifampin was shown in vitro to decrease the amphotericin B minimal inhibitory concentrations of all of 10 strains of Coccidioides immitis tested. These decreases ranged from two- to fourfold and occurred with rifampin concentrations of 10 to 40 mug/ml. Rifampin alone was without effect. ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.6.6.783
更新日期:1974-12-01 00:00:00
abstract::Exposure to isoniazid induced the expression of several secreted proteins in Mycobacterium tuberculosis H37Rv. Two-dimensional gel electrophoresis and immunoblot analyses indicated that two of the prominent isonicotinic acid hydrazide-inducible polypeptides were members of the antigen 85 complex, recently demonstrated...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.40.7.1754
更新日期:1996-07-01 00:00:00
abstract::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, an...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.27.3.363
更新日期:1985-03-01 00:00:00
abstract::Multidrug-resistant tuberculosis (MDR-TB) threatens global TB control. The lengthy treatment includes one of the injectable drugs kanamycin, amikacin, and capreomycin, usually for the first 6 months. These drugs have potentially serious toxicities, and when given as intramuscular injections, dosing can be painful. Adv...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02346-12
更新日期:2013-06-01 00:00:00
abstract::Pseudomonas aeruginosa is inherently resistant to most conventional antibiotics. The mechanism of resistance of this bacterium is mainly associated with the low permeability of its outer membrane to these agents. We sought to assess the bactericidal efficacy of liposome-entrapped aminoglycosides against resistant clin...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01547-05
更新日期:2006-06-01 00:00:00
abstract::Epidemiological data on carbapenemase-producing Gram-negative bacteria on the African continent are limited. Here, we report the identification of VIM-2-producing Pseudomonas aeruginosa isolates in Tanzania. Eight out of 90 clinical isolates of P. aeruginosa from a tertiary care hospital in Dar es Salaam were shown to...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01436-13
更新日期:2015-01-01 00:00:00
abstract::7-[alpha-(1-Methyl-4-pyridiniothio)-acetamido] cephalosporanic acid, referred to herein as BL-S 217, is a new broad-spectrum semisynthetic cephalosporin that offers several advantages over cephalothin. A comparison of the activity in vitro of these antibiotics indicates that BL-S 217 is about eightfold more effective ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.1.1.67
更新日期:1972-01-01 00:00:00
abstract::Eight unrelated clinical Acinetobacter baumannii isolates resistant to all commonly used antibiotics were subjected to three-dimensional checkerboard microtiter plate dilution and time-kill studies at one-fourth of their MICs of polymyxin B, imipenem, and rifampin. Synergy was demonstrated with combinations of polymyx...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.48.3.753-757.2004
更新日期:2004-03-01 00:00:00
abstract::Using a rabbit model of methicillin-resistant Staphylococcus aureus knee-prosthesis infection, we studied the efficacy of teicoplanin cement alone or in combination with systemic intramuscular (i.m.) injections of teicoplanin. Seven days after infection, surgical debridement and removal of the infected prostheses were...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.47.10.3365-3367.2003
更新日期:2003-10-01 00:00:00
abstract::The outer membrane of mycobacteria presents an effective permeability barrier for many antibiotics. Transport pathways across this membrane are unknown for most drugs. Here, we examined which antibiotics utilize the porin pathway across the outer membrane of the model organism Mycobacterium smegmatis. Deletion of the ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00239-08
更新日期:2008-09-01 00:00:00
abstract::The clinical use of the neuraminidase inhibitor (NAI) oseltamivir is associated with the emergence of drug resistance resulting from subtype-specific neuraminidase (NA) mutations. The influenza A/Texas/12/2007 (H3N2) virus isolated from an oseltamivir-treated immunocompromised patient exhibited reduced susceptibility ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01608-09
更新日期:2010-05-01 00:00:00
abstract::Selected cephalosporins, including cefamandole, cephaloridine, cephaloglycin, and cefoxitin, were examined for their ability to inhibit the enzymatic activity of and act as substrates for beta-lactamases produced by Enterobacter cloacae and Staphylococcus aureus. Enzyme inhibition was determined by Michaelis-Menten ki...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.10.3.470
更新日期:1976-09-01 00:00:00
abstract::Extensive biochemical testing and 16S rRNA and rpoB sequence analysis revealed that clinical strain CF01Ent1, initially identified as Buttiauxella agrestis by the use of Api 32 biochemical strips, is a new organism in the Enterobacteriaceae family. It produced an inducible AmpC-type beta-lactamase whose sequence share...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.46.10.3316-3319.2002
更新日期:2002-10-01 00:00:00
abstract::The pharmacokinetics and distribution in tissue of several novel triazole antifungal agents were studied in different animal species in order to select an appropriate lead compound. The purpose of the study was also to determine species differences in pharmacokinetics for SYN azoles to select the most appropriate spec...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.44.4.910-915.2000
更新日期:2000-04-01 00:00:00