scholarly journals Pharmacodynamics and bactericidal activity of ceftriaxone therapy in experimental cephalosporin-resistant pneumococcal meningitis.

1997 ◽  
Vol 41 (11) ◽  
pp. 2414-2417 ◽  
Author(s):  
I Lutsar ◽  
A Ahmed ◽  
I R Friedland ◽  
M Trujillo ◽  
L Wubbel ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Pneumococcal Meningitis ◽  
Stepwise Regression ◽  
Drug Resistant ◽  
Beta Lactam ◽  
Time Curve ◽  
Bacterial Killing ◽  
Killing Rate ◽  
Beta Lactam Antibiotics ◽  
Concentration Time

Adequate concentrations of beta-lactam antibiotics in cerebrospinal fluid (CSF) are difficult to achieve for meningitis caused by drug-resistant Streptococcus pneumoniae. Ceftriaxone in dosages of 150 or 400 mg/kg of body weight per day, given in one or two doses, was used for the treatment of experimental highly cephalosporin-resistant (MIC and MBC, 4 microg/ml) pneumococcal meningitis. The bacterial killing rate (delta log10 CFU per milliliter per hour) and pharmacokinetic indices, including percentage of time the antibiotic concentration exceeded the MBC during a 24-h period (T>MBC), CSF peak concentration above the MBC, and area under the concentration-time curve from 0 to 24 h above MBC, were measured and correlated. By multiple stepwise regression, only T>MBC independently predicted the bacterial killing rate. There was a direct linear correlation between T>MBC in CSF and the bacterial killing rate during the first 24 h of therapy (r = 0.87; P = 0.004). Sterilization of CSF was achieved only when the T>MBC was 95 to 100%. In the first 24 h, the 200-mg/kg/12-h regimen, compared with the 400-mg/kg/24-h regimen, was associated with a greater T>MBC (87% +/- 10% versus 60% +/- 22%; P = 0.03) and greater bacterial killing rate (0.2 +/- 0.04 versus 0.13 +/- 0.07; P = 0.003), confirming that ceftriaxone exhibits time-dependent bactericidal activity. After 24 h, the T>MBC and the CSF sterilization rates were similar whether ceftriaxone was given once or twice daily.

Correlation of pharmacodynamic parameters of five beta-lactam antibiotics with therapeutic efficacies in an animal model.

1996 ◽  
Vol 40 (12) ◽  
pp. 2686-2690 ◽  
Author(s):  
F Soriano ◽  
P García-Corbeira ◽  
C Ponte ◽  
R Fernández-Roblas ◽  
I Gadea
Keyword(s):  
Linear Regression Analysis ◽  
Inoculum Size ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Time Curve ◽  
Beta Lactam Antibiotics ◽  
Concentration Time ◽  
Intraperitoneal Infection ◽  
Different Doses

The MIC is the main microbiologic parameter used to predict the efficacies of antibiotics. However, it is well known that MICs may vary according to the inoculum size used (inoculum effect), especially with some beta-lactam antibiotics. In order to correlate the pharmacologic and microbiologic properties of some beta-lactams, an experimental model of intraperitoneal infection caused by Escherichia coli in nonneutropenic and neutro-penic mice was developed. The animals were treated with three different doses of either ampicillin, piperacillin, aztreonam, cefazolin, or cefotaxime. The linear regression analysis obtained in our model shows a better correlation between in vitro activity and efficacy when the MICs considered were those obtained with a large inoculum (ca. 1 x 10(8) CFU/ml) instead of the standard inoculum (5 x 10(5) CFU/ml). The correlations for the MICs obtained with the large inoculum were 0.78 for log2 maximum concentration of drug in serum (Cmax)/ MIC, 0.72 the time that the concentrations exceeded the MIC, and 0.79 for log2 area under the serum concentration-time curve (AUC)/MIC at 24 h in nonneutropenic mice. The corresponding values in neutropenic mice, also for the MICs obtained with the large inoculum, were 0.54, 0.68, and 0.64, respectively, at 24 h. A good correlation was also obtained for the same parameters in nonneutropenic mice at 48 h. The values of Cmax, AUC, and the time that the concentrations exceeded the MIC were parallel among the antibiotics studied, and our study confirms that the time that the levels in serum exceed the MIC is a significant parameter determining the efficacies of beta-lactam antibiotics, but the correlation is much better when the MICs obtained with the large inoculum instead of those obtained with the standard (low) inoculum are considered.

scholarly journals High Cerebrospinal Fluid (CSF) Penetration and Potent Bactericidal Activity in CSF of NZ2114, a Novel Plectasin Variant, during Experimental Pneumococcal Meningitis

2009 ◽  
Vol 53 (4) ◽  
pp. 1581-1585 ◽  
Author(s):  
Christian Østergaard ◽  
Dorthe Sandvang ◽  
Niels Frimodt-Møller ◽  
Hans-Henrik Kristensen
Keyword(s):  
Cerebrospinal Fluid ◽  
Bactericidal Activity ◽  
Pneumococcal Meningitis ◽  
Interquartile Range ◽  
Gram Positive ◽  
Time Curve ◽  
Csf Penetration ◽  
Gram Positive Bacteria ◽  
Concentration Time ◽  
Bacterial Concentrations

ABSTRACT Plectasin is the first defensin-type antimicrobial peptide isolated from a fungus and has potent activity against gram-positive bacteria. By using an experimental meningitis model, the penetration of plectasin into the cerebrospinal fluid (CSF) of infected and uninfected rabbits and the bactericidal activities in CSF of the plectasin variant NZ2114 and ceftriaxone against a penicillin-resistant Streptococcus pneumoniae strain (NZ2114 and ceftriaxone MICs, 0.25 and 0.5 μg/ml, respectively) were studied. Pharmacokinetic analysis showed that there was a significantly higher level of CSF penetration of NZ2114 through inflamed than through noninflamed meninges (area under the concentration-time curve for CSF/area under the concentration-time curve for serum, 33% and 1.1%, respectively; P = 0.03). The peak concentrations of NZ2114 in purulent CSF were observed ∼3 h after the infusion of an intravenous bolus of either 20 or 40 mg/kg of body weight and exceeded the MIC >10-fold for a 6-h study period. Treatment with NZ2114 (40 and 20 mg/kg at 0 and 5 h, respectively; n = 11) caused a significantly higher reduction in CSF bacterial concentrations than therapy with ceftriaxone (125 mg/kg at 0 h; n = 7) at 3 h (median changes, 3.7 log10 CFU/ml [interquartile range, 2.5 to 4.6 log10 CFU/ml] and 2.1 log10 CFU/ml [interquartile range, 1.7 to 2.6 log10 CFU/ml], respectively; P = 0.001), 5 h (median changes, 5.2 log10 CFU/ml [interquartile range, 3.6 to 6.1 log10 CFU/ml] and 3.1 log10 CFU/ml [interquartile range, 2.6 to 3.7 log10 CFU/ml], respectively; P = 0.01), and 10 h (median changes, 5.6 log10 CFU/ml [interquartile range, 5.2 to 5.9 log10 CFU/ml] and 4.2 log10 CFU/ml [interquartile range, 3.6 to 5.0 log10 CFU/ml], respectively; P = 0.03) after the start of therapy as well compared to the CSF bacterial concentrations in untreated rabbits with meningitis (n = 7, P < 0.05). Also, significantly more rabbits had sterile CSF at 5 and 10 h when they were treated with NZ2114 than when they were treated with ceftriaxone (67% [six of nine rabbits] and 0% [zero of seven rabbits], respectively, at 5 h and 75% [six of eight rabbits] and 14% [one of seven rabbits], respectively, at 10 h; P < 0.05). Due to its excellent CSF penetration and potent bactericidal activity in CSF, the plectasin variant NZ2114 could be a promising new option for the treatment of CNS infections caused by gram-positive bacteria, including penicillin-resistant pneumococcal meningitis.

scholarly journals 839. Epidemiology of Extended-Spectrum Beta-lactamase (ESBL) Producing Enterobacteriaceae in the South East Tennessee, October-December 2017

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S460-S461
Author(s):  
Daniel Muleta ◽  
Cullen Adre ◽  
Benji-Byrd Warner
Keyword(s):  
Klebsiella Oxytoca ◽  
Health Department ◽  
Population Based ◽  
Klebsiella Pneumonia ◽  
Drug Resistant ◽  
Beta Lactam ◽  
Extended Spectrum Beta Lactamase ◽  
Catchment Population ◽  
Beta Lactam Antibiotics ◽  
Extended Spectrum

Abstract Background The increasing spread of drug resistant gram-negative organisms is one of the major public health challenges. ESBL-producing Enterobacteriaceae has become the most common multi drug resistant pathogen in the last three decades. These organisms confer resistance to most beta-lactam antibiotics, including penicillins, third generation cephalosporins, monobactams and tazobactam. Methods The Tennessee Health Department (TDH) collaborated with CDC to pilot population based surveillance of ESBL producing organisms in Maury, Wayne, Lewis and Marshall Counties during October to December 2017. A case was defined as isolation of Escherichia coli, Klebsiella pneumoniae, or Klebsiella oxytoca resistant to at least one extended-spectrum cephalosporin (ceftazidime, cefotaxime or ceftriaxone) and non-resistant to all carbapenem antibiotics from urine or normally sterile body sites from a resident of the surveillance catchment area. A line list of ESBL-producing organisms was received from the labs that serve the catchment population. Case report forms were completed for the first ESBL culture collected from a single patient in a 30 day-period. Results A total of 154 cases were identified during the study period. E.coli constitutes 92.2% of the ESBL producing organisms followed by Klebsiella pneumonia (5.2%) and K. oxytoca (2.6%). The estimated annual incidence rate was 400.7 per 100,000 population which is more than twice of the average rates of other sites that conducted similar studies. The most common isolate source was urine (97%), and 81.2% of all cases were female. Patient ages ranged from 3-99 years, with average of 67 years. Thirty-two isolates underwent additional sequence typing and 76.7% (23) of the isolates were ST 131. 21 (91.3%) of ST-131 isolates were resistant to ciprofloxacin. Conclusion The study revealed that the incidence of ESBL producing organisms is very high in the Tennessee study area compared to other sites. The most common ESBL-producing pathogen was found to be ST 131 and most of these were resistant to ciprofloxacin suggesting that resistance to fluoroquinolone may be co-transmitted in ESBL producing pathogens through plasmids. Continued surveillance of molecular epidemiology is important to guide the prevention of the spread of drug resistant pathogens. Disclosures All Authors: No reported disclosures

scholarly journals Meropenem Combined with Ciprofloxacin Combats Hypermutable Pseudomonas aeruginosa from Respiratory Infections of Cystic Fibrosis Patients

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Vanessa E. Rees ◽  
Rajbharan Yadav ◽  
Kate E. Rogers ◽  
Jürgen B. Bulitta ◽  
Veronika Wirth ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Time Course ◽  
Respiratory Infections ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Time Curve ◽  
Bacterial Killing ◽  
Content Type ◽  
Concentration Time

ABSTRACT Hypermutable Pseudomonas aeruginosa organisms are prevalent in chronic respiratory infections and have been associated with reduced lung function in cystic fibrosis (CF); these isolates can become resistant to all antibiotics in monotherapy. This study aimed to evaluate the time course of bacterial killing and resistance of meropenem and ciprofloxacin in combination against hypermutable and nonhypermutable P. aeruginosa. Static concentration time-kill experiments over 72 h assessed meropenem and ciprofloxacin in mono- and combination therapies against PAO1 (nonhypermutable), PAOΔmutS (hypermutable), and hypermutable isolates CW8, CW35, and CW44 obtained from CF patients with chronic respiratory infections. Meropenem (1 or 2 g every 8 h [q8h] as 3-h infusions and 3 g/day as a continuous infusion) and ciprofloxacin (400 mg q8h as 1-h infusions) in monotherapies and combinations were further evaluated in an 8-day hollow-fiber infection model study (HFIM) against CW44. Concentration-time profiles in lung epithelial lining fluid reflecting the pharmacokinetics in CF patients were simulated and counts of total and resistant bacteria determined. All data were analyzed by mechanism-based modeling (MBM). In the HFIM, all monotherapies resulted in rapid regrowth with resistance at 48 h. The maximum daily doses of 6 g meropenem (T>MIC of 80% to 88%) and 1.2 g ciprofloxacin (area under the concentration-time curve over 24 h in the steady state divided by the MIC [AUC/MIC], 176), both given intermittently, in monotherapy failed to suppress regrowth and resulted in substantial emergence of resistance (≥7.6 log10 CFU/ml resistant populations). The combination of these regimens achieved synergistic killing and suppressed resistance. MBM with subpopulation and mechanistic synergy yielded unbiased and precise curve fits. Thus, the combination of 6 g/day meropenem plus ciprofloxacin holds promise for future clinical evaluation against infections by susceptible hypermutable P. aeruginosa.

scholarly journals 1379. Determination of the Arbekacin Exposure Required to Prevent Amplification of Resistant Subpopulations Using Patient Pharmacokinetics Simulated in a Hollow-Fiber Infection Model (HFIM)

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S422-S423 ◽  
Author(s):  
Brian D VanScoy ◽  
Elizabeth A Lakota ◽  
Sujata M Bhavnani ◽  
Greg Giesel ◽  
Ana I Carranco ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Antimicrobial Agents ◽  
Therapy Resistance ◽  
Step Function ◽  
Infection Model ◽  
Drug Resistant ◽  
Total Drug ◽  
Research Support ◽  
Time Curve ◽  
Concentration Time

Abstract Background ME1100 (arbekacin inhalational solution) is an aminoglycoside in clinical development for the treatment of patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). Due to the increase in resistance of Staphylococcus aureus and Pseudomonas aeruginosa to many antimicrobial agents, it is important to understand the relationships between amplification of drug resistance and each of drug exposure and therapy duration. The objective of the studies described herein was to utilize the HFIM to determine the arbekacin exposure after ME1100 administration required to prevent the emergence of drug-resistant subpopulations. Methods Duplicate 10-day HFIM assays were completed in which arbekacin total-drug epithelial lining fluid (ELF) concentration–time profiles following inhalational administration of ME1100 every 12 hours were simulated. Four isolates, two methicillin-resistant S. aureus (Arbekacin MIC = 1 mg/L), and two P. aeruginosa (Arbekacin MIC = 4 mg/L), were exposed to total-drug ELF area under the concentration–time curve (AUC) values ranging from 217 to 25,053 mg hour/L, which were simulated using two different half-lives, 1 hour (α) and 6.93 hours (β). The initial bacterial burden was 1.0 × 108 CFU/mL. Samples were collected for enumeration of both the total and drug-resistant bacterial burdens and evaluation of pharmacokinetic samples using LC/MS–MS. Results Total-drug ELF AUC:MIC ratios required to prevent amplification of MRSA and P. aeruginosa resistance in the HFIM over 10 days were 1,512 and 2,942, respectively. The higher AUC:MIC ratio required to prevent resistance for P. aeruginosa was most likely due to the presence of a small colony variant population. The relationship between total-drug ELF AUC:MIC ratio and change in log10 CFU from baseline of the drug-resistant sub-populations found on agar plates on Day 10 took the form of an inverted-U for three pathogens and a step-function for one (Figure 1). Conclusion These data, which address the goal of considering arbekacin exposures that prevent the development of on-therapy resistance in a clinical setting, will help to provide guidance for future ME1100 dose selection for the treatment of patients with HABP/VABP. Disclosures B. D. VanScoy, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. E. A. Lakota, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. S. M. Bhavnani, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. G. Giesel, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. A. I. Carranco, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. Y. Nagira, Meiji Seika Pharma Co. Ltd.: Employee, Salary. S. Ouchi, Meiji Seika Pharma Co. Ltd.: Employee, Salary. K. Kondo, Meiji Seika Pharma Co. Ltd.: Employee, Salary. P. G. Ambrose, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support.

scholarly journals Pharmacokinetics and pharmacodynamics of two multiple-dose piperacillin-tazobactam regimens.

1997 ◽  
Vol 41 (11) ◽  
pp. 2511-2517 ◽  
Author(s):  
D J Occhipinti ◽  
S L Pendland ◽  
L L Schoonover ◽  
E B Rypins ◽  
L H Danziger ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Dosage Regimen ◽  
Multiple Dose ◽  
Antimicrobial Agents ◽  
Plasma Concentrations ◽  
Culture Collection ◽  
Beta Lactam ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Time Curve ◽  
Bacteriological Response

The pharmacokinetics and pharmacodynamics of two multiple-dose regimens of piperacillin-tazobactam (3.375 g every 6 h and 4.5 g every 8 h) were evaluated at steady state for 12 healthy adult volunteers. Inhibitory and bactericidal activities for the two regimens were determined with five American Type Culture Collection (ATCC) organisms (Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Bacteroides fragilis). The percentage of time that plasma concentrations remained above the MIC (T > MIC) for each organism and dosage regimen was calculated. Areas under the inhibitory (AUIC0-24) and bactericidal activity (AUBC0-24) curves were calculated with the trapezoidal rule by using the reciprocal of the inhibitory and bactericidal titers determined for each dosage regimen. In order to assess the validity of predicted measures of bactericidal (AUC0-24/MBC) and inhibitory (AUC0-24/MIC) activity to determine bacteriological response to beta-lactam antimicrobial agents, AUC0-24/MBC and AUC0-24/MIC values were compared with measured AUBC0-24 and AUIC0-24 values. Total body clearance values were equivalent for piperacillin (183.96 +/- 22.66 versus 181.72 +/- 19.54 ml/min/1.73 m2, P > 0.05) and tazobactam (184.71 +/- 19.89 versus 184.87 +/- 18.35 ml/min/1.73 m2, P > 0.05) following the administration of the 3.375-g-every-6-h and 4.5-g-every-8-h dosages, respectively. Comparison of area under the plasma concentration-time curve (AUC0-24) for piperacillin (967.74 +/- 135.56 microg x h/ml versus 978.88 +/- 140.96 microg x h/ml) and tazobactam (120.14 +/- 15.78 microg x h/ml versus 120.01 +/- 16.22 microg x h/ml) revealed no significant differences (P > 0.05) between the 3.375-g-every-6-h and 4.5-g-every-8-h regimens, respectively. Both regimens provided T > MIC values of > 60% for all organisms tested. Measured values of bactericidal (AUBC) and inhibitory (AUIC) activity were significantly different (P < 0.05) from predicted values (AUC0-24/MBC and AUC0-24/MIC) for all organisms studied with the exception of the bactericidal activity for P. aeruginosa and S. aureus. Additionally, ATCC organisms possessing the same MICs and MBCs exhibited great differences in measured AUBC0-24 and AUIC0-24 values. Reasons for this difference may be inherent differences in organism specific susceptibility.

scholarly journals In Vivo Activity of QPX7728, an Ultrabroad-Spectrum Beta-Lactamase Inhibitor, in Combination with Beta-Lactams against Carbapenem-Resistant Klebsiella pneumoniae

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Mojgan Sabet ◽  
Ziad Tarazi ◽  
David C. Griffith
Keyword(s):  
Klebsiella Pneumoniae ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Bacterial Killing ◽  
Clinical Issue ◽  
Content Type ◽  
Beta Lactam Antibiotics ◽  
Carbapenem Resistant ◽  
Lactamase Inhibitor

ABSTRACT Resistance to beta-lactams has created a major clinical issue. QPX7728 is a novel ultrabroad-spectrum cyclic boronic acid beta-lactamase inhibitor with activity against both serine and metallo-beta-lactamases developed to address this resistance for use in combination with beta-lactam antibiotics. The objective of these studies was to evaluate the activity of QPX7728 in combination with multiple beta-lactams against carbapenem-resistant Klebsiella pneumoniae isolates in a neutropenic mouse thigh infection model. Neutropenic mice were infected with strains with potentiated beta-lactam MICs of ≤2 mg/liter in the presence of 8 mg/liter QPX7728. Two strains of carbapenem-resistant K. pneumoniae were tested with aztreonam, biapenem, cefepime, ceftazidime, ceftolozane, and meropenem alone or in combination with 12.5, 25, or 50 mg/kg of body weight of QPX7728 every 2 hours for 24 hours. Treatment with all beta-lactams alone either was bacteriostatic or allowed for bacterial growth. The combination of QPX7728 plus each of these beta-lactams produced bacterial killing at all QPX7728 doses tested. Overall, these data suggest that QPX7728 administered in combination with different partner beta-lactam antibiotics may have utility in the treatment of bacterial infections due to carbapenem-resistant K. pneumoniae.

scholarly journals Preclinical Development of Inhalable D-Cycloserine and Ethionamide To Overcome Pharmacokinetic Interaction and Enhance Efficacy against Mycobacterium tuberculosis

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Rajeev Ranjan ◽  
Ashish Srivastava ◽  
Reena Bharti ◽  
Trisha Roy ◽  
Sonia Verma ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bactericidal Activity ◽  
Half Life ◽  
Pharmacokinetic Interaction ◽  
Preclinical Development ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Oral Doses ◽  
Plasma Half Life

ABSTRACT We compared the pharmacokinetics and efficacy of a combination of d-cycloserine (DCS) and ethionamide (ETO) via oral and inhalation routes in mice. The plasma half-life (t1/2) of oral ETO at a human-equivalent dose decreased from 4.63 ± 0.61 h to 1.64 ± 0.40 h when DCS was coadministered. The area under the concentration-time curve from 0 h to time t (AUC0–t) was reduced to one-third. Inhalation overcame the interaction. Inhalation, but not oral doses, reduced the lung CFU/g of Mycobacterium tuberculosis H37Rv from 6 to 3 log10 in 4 weeks, indicating bactericidal activity.

scholarly journals Pharmacodynamics and Bactericidal Activity of Moxifloxacin in Experimental Escherichia coliMeningitis

2001 ◽  
Vol 45 (11) ◽  
pp. 3092-3097 ◽  
Author(s):  
Violeta Rodriguez-Cerrato ◽  
Cynthia C. McCoig ◽  
Ian C. Michelow ◽  
Faryal Ghaffar ◽  
Hasan S. Jafri ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Rabbit Model ◽  
Time Curve ◽  
Bacterial Killing ◽  
E Coli ◽  
Pharmacodynamic Profile ◽  
Spectrum Activity ◽  
Csf Concentration ◽  
Broad Spectrum Activity

ABSTRACT Moxifloxacin, an 8-methoxyquinolone with broad-spectrum activity in vitro, was studied in the rabbit model of Escherichia colimeningitis. The purposes of this study were to evaluate the bactericidal effectiveness and the pharmacodynamic profile of moxifloxacin in cerebrospinal fluid (CSF) and to compare the bactericidal activity with that of ceftriaxone and meropenem therapy. After induction of meningitis, animals were given single doses of 10, 20, and 40 mg/kg or divided-dose regimens of 5, 10, and 20 mg/kg twice, separated by 6 h. After single doses, the penetration of moxifloxacin into purulent CSF, measured as percentage of the area under the concentration-time curve (AUC) in CSF relative to the AUC in plasma, was approximately 50%. After single doses of 10, 20, and 40 mg/kg, the maximum CSF concentration (C max) values were 1.8, 4.2, and 4.9 μg/ml, respectively; the AUC values (total drug) were 13.4, 25.4, and 27.1 μg/ml · h, respectively, and the half-life values (t ½) were 6.7, 6.6, and 4.7 h, respectively. The bacterial killing in CSF for moxifloxacin, calculated as the Δlog10 CFU per milliliter per hour, at 3, 6, and 12 h after single doses of 10, 20, and 40 mg/kg were −5.70, −6.62, and −7.02; −7.37, −7.37, and −6.87; and −6.62, −6.62, and −6.62, respectively, whereas those of ceftriaxone and meropenem were −4.18, −5.24, and −4.43, and −3.64, −3.59, and −4.12, respectively. The CSF pharmacodynamic indices of AUC/MBC and C max/MBC were interrelated (r = 0.81); there was less correlation withT > MBC (r = 0.74). In this model, therapy with moxifloxacin appears to be at least as effective as ceftriaxone and more effective than meropenem therapy in eradicatingE. coli from CSF.

scholarly journals Intra- and Extracellular Activities of Trimethoprim-Sulfamethoxazole against Susceptible and Multidrug-Resistant Mycobacterium tuberculosis

2014 ◽  
Vol 58 (12) ◽  
pp. 7557-7559 ◽  
Author(s):  
L. Davies Forsman ◽  
T. Schön ◽  
U. S. H. Simonsson ◽  
J. Bruchfeld ◽  
M. Larsson ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Treatment Option ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Potential Treatment ◽  
Time Curve ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Concentration Time ◽  
Strain H37rv

ABSTRACTWe investigated the activity of trimethoprim-sulfamethoxazole (SXT) againstMycobacterium tuberculosis, the pathogen that causes tuberculosis (TB). The MIC distribution of SXT was 0.125/2.4 to 2/38 mg/liter for the 100 isolates tested, including multi- and extensively drug-resistant isolates (MDR/XDR-TB), whereas the intracellular MIC90of sulfamethoxazole (SMX) for the pansusceptible strain H37Rv was 76 mg/liter. In an exploratory analysis using a ratio of the unbound area under the concentration-time curve from 0 to 24 h over MIC (fAUC0–24/MIC) using ≥25 as a potential target, the cumulative fraction response was ≥90% at doses of ≥2,400 mg of SMX. SXT is a potential treatment option for MDR/XDR-TB.

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