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

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.11.2414 ◽

1997 ◽

Vol 41 (11) ◽

pp. 2414-2417 ◽

Cited By ~ 51

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.

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In vitro selection of one-step mutants of Streptococcus pneumoniae resistant to different oral beta-lactam antibiotics is associated with alterations of PBP2x.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.1.152 ◽

1996 ◽

Vol 40 (1) ◽

pp. 152-156 ◽

Cited By ~ 49

Author(s):

F Sifaoui ◽

M D Kitzis ◽

L Gutmann

Keyword(s):

Streptococcus Pneumoniae ◽

In Vitro Selection ◽

Point Mutations ◽

Fold Increase ◽

Beta Lactam ◽

Beta Lactams ◽

Beta Lactam Antibiotics ◽

One Step ◽

Resistant Mutants

Many oral penicillins and cephalosporins are used to treat clinical infections caused by Streptococcus pneumoniae. Therefore, using different beta-lactams as selectors, we estimated the frequencies of one-step mutations leading to resistance. Resistant mutants were obtained from penicillin-susceptible, intermediately resistant, and penicillin resistant strains. For cefixime, cefuroxime, cefpodoxime, cefotaxime, and ceftriaxone, the frequencies of mutation ranged from 10(-6) to 10(-8) when resistant mutants were selected at 2- to 8-fold the MIC, and the MICs increased 2- to 16-fold. For ampicillin, ampicillin-sulbactam, amoxicillin, amoxicillin-clavulanic acid, cefaclor, and loracarbef, the frequencies of mutation were about 10(-7) to 10(-8), and the MICs increased twofold at most. One to three resistance profiles of the resulting mutants were selected for each of the selecting antibiotics. Among those, some showed resistance to the cephalosporins associated with a 2- to 32-fold increase in susceptibility to the penicillins. Competition experiments showed a decreased affinity of PBP2x for cefpodoxime in all mutants. In some mutants that were more susceptible to amoxicillin, a decreased affinity of PBP2x for cefpodoxime was associated with an increased affinity for amoxicillin and a particular substitution of alanine for threonine at position 550 just after the KSG triad. From these results we infer (i) that among the beta-lactams tested the penicillins, cefaclor, and loracarbef selected one-step resistant mutants less frequently and that they achieved a lower level of resistance, and (ii) that mutants with different profiles may have acquired different point mutations in PBP2x.

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Continuing Education: Alternative Approaches to Optimizing Antimicrobial Pharmacodynamics in Critically Ill Patients

Journal of Pharmacy Practice ◽

10.1177/0897190009356550 ◽

2010 ◽

Vol 23 (1) ◽

pp. 6-18 ◽

Cited By ~ 4

Author(s):

Tammy M. Winterboer ◽

Kassandra A. Lecci ◽

Keith M. Olsen

Keyword(s):

Treatment Outcomes ◽

Successful Treatment ◽

Beta Lactam ◽

Beta Lactams ◽

Time Curve ◽

Icu Patients ◽

Beta Lactam Antibiotics ◽

Dosing Strategies ◽

Hospital Stays ◽

Alternative Approaches

Critical illness results in a constellation of physiologic changes that subsequently impact antibiotic pharmacokinetic and pharmacodynamic parameters. These changes can result in poorly treated infections that in turn lead to longer intensive care unit (ICU) and hospital stays, prolonged use of mechanical ventilation, and higher mortality rates. Research has expanded our understanding of antibiotic pharmacodynamics among ICU patients, and some investigators and clinicians have questioned traditional antibiotic dosing schemes among this population. Alternative dosing strategies to optimize antibiotic pharmacodynamics of aminoglycosides, beta-lactams, fluoroquinolones, and vancomycin have been explored. Appropriate duration of exposure to beta-lactam antibiotics has been recognized as an important parameter associated with successful treatment outcomes. To maximize this exposure, continuous infusions over a 24-hour period have resulted in higher clinical response rates and improved surrogate markers of infection. Equally as promising is the alternative of extending the infusion time to increase exposure while maintaining the same daily beta-lactam dose and frequency. Data from clinical trials have suggested that the area under the concentration–time curve to minimum inhibitory concentration ratio for aminoglycosides, fluoroquinolones, and vancomycin is a better correlate for successful treatment outcomes. Optimizing antibiotic pharmacodynamics by changing dosage methods should be considered in ICU patients to improve treatment response and success.

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Involvement of a 43-kilodalton outer membrane protein in beta-lactam resistance of Shigella dysenteriae.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.10.2302 ◽

1997 ◽

Vol 41 (10) ◽

pp. 2302-2304 ◽

Cited By ~ 8

Author(s):

A K Kar ◽

A S Ghosh ◽

K Chauhan ◽

J Ahamed ◽

J Basu ◽

...

Keyword(s):

Membrane Protein ◽

Outer Membrane ◽

Outer Membrane Protein ◽

Outer Membrane Proteins ◽

Shigella Dysenteriae ◽

Beta Lactam ◽

Beta Lactams ◽

Beta Lactam Antibiotics ◽

Resistant Strains

A beta-lactam-sensitive strain (C152) of Shigella dysenteriae showed two major outer membrane proteins (OMPs) with M(r)s of 43,000 and 38,000, while the clinical isolate M2 lacked the 43,000-Mr OMP, which acted as a channel for beta-lactam antibiotics. Permeability of beta-lactams across the outer membrane (OM) of M2 was lower than that across the OM of C152. Mutants deficient in the 43-kDa OMP could be selected in vitro from strain C152 in the presence of cefoxitin. All beta-lactam-resistant strains were sensitive to imipenem.

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The renal mitochondrial toxicity of beta-lactam antibiotics: in vitro effects of cephaloglycin and imipenem.

Journal of the American Society of Nephrology ◽

10.1681/asn.v15815 ◽

1990 ◽

Vol 1 (5) ◽

pp. 815-821

Author(s):

B M Tune ◽

C Y Hsu

Keyword(s):

Protective Action ◽

Substrate Uptake ◽

Dependent Manner ◽

Mitochondrial Toxicity ◽

Beta Lactam ◽

Beta Lactams ◽

Beta Lactam Antibiotics ◽

In Vitro Exposure

The nephrotoxic beta-lactam antibiotics cephaloridine, cephaloglycin, and imipenem produce irreversible injury to renal mitochondrial anionic substrate uptake and respiration after 1 to 2 h of in vivo exposure. Toxicity during in vitro exposure is nearly identical but is immediate in onset and is reversed by the mitochondria being washed or the substrate concentrations being increased. A model of injury that accounts for these findings proposes that the beta-lactams fit carriers for mitochondrial substrate uptake, causing inhibition that is initially reversible and becomes irreversible as the antibiotics acylate the transporters. These studies were designed to create an environment of prolonged in vitro exposure, first, to determine whether toxicity becomes irreversible with time and, second, to study the molecular properties of toxicity. Respiration with and the uptake of succinate and ADP were measured in rabbit renal cortical mitochondria exposed for 2 to 6 h to 300 to 3,000 micrograms of cephalexin (nontoxic) or cephaloglycin or imipenem (nephrotoxic) per mL and then washed to remove the antibiotic. In vitro cephalexin reduced respiration only slightly and was therefore not studied further. Cephaloglycin and imipenem irreversibly reduced both respiration and succinate uptake. ADP uptake was unaffected by cephaloglycin and was slightly reduced by imipenem. Finally, cilastatin, which prevents the tubular necrosis produced by imipenem in vivo, reduced its mitochondrial toxicity in vitro. It is concluded that the pattern of in vitro injury of the nephrotoxic beta-lactams to mitochondrial substrate uptake and respiration evolves in a time-dependent and concentration-dependent manner, consistent with the proposed model of acylation and inactivation of substrate transporters, and that the protective action of cilastatin against imipenem occurs at least partly at a subcellular level.

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Lack of correlation between in vitro and in vivo studies of combinations of rifampin plus vancomycin or beta-lactam antibiotics against Streptococcus pneumoniae.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.6.1573 ◽

1996 ◽

Vol 40 (6) ◽

pp. 1573-1574 ◽

Cited By ~ 4

Author(s):

F Tuban ◽

C Cabellos ◽

J Liñares

Keyword(s):

Streptococcus Pneumoniae ◽

In Vivo Studies ◽

Beta Lactam ◽

Beta Lactam Antibiotics

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In-vitro activities of cefepime and other beta-lactam antibiotics against clinical isolates from a Colombian teaching hospital

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/42.4.550 ◽

1998 ◽

Vol 42 (4) ◽

pp. 550-552 ◽

Cited By ~ 10

Author(s):

S. Mattar ◽

L. Sanchez ◽

D. Perez ◽

A. Arango ◽

R. Parodi ◽

...

Keyword(s):

Teaching Hospital ◽

Clinical Isolates ◽

Beta Lactam ◽

Beta Lactam Antibiotics

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Pharmacological Basis of CD101 Efficacy: Exposure Shape Matters

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00758-17 ◽

2017 ◽

Vol 61 (11) ◽

Cited By ~ 12

Author(s):

Elizabeth A. Lakota ◽

Justin C. Bader ◽

Voon Ong ◽

Ken Bartizal ◽

Lynn Miesel ◽

...

Keyword(s):

Time Course ◽

Fungicidal Activity ◽

Control Group ◽

Time Curve ◽

Content Type ◽

Treatment Groups ◽

Concentration Time ◽

Treatment Control Group ◽

Pharmacological Basis

ABSTRACT CD101 is a novel echinocandin with concentration-dependent fungicidal activity in vitro and a long half-life (∼133 h in humans, ∼70 to 80 h in mice). Given these characteristics, it is likely that the shape of the CD101 exposure (i.e., the time course of CD101 concentrations) influences efficacy. To test this hypothesis, doses which produce the same total area under the concentration-time curve (AUC) were administered to groups of neutropenic ICR mice infected with Candida albicans R303 using three different schedules. A total CD101 dose of 2 mg/kg was administered as a single intravenous (i.v.) dose or in equal divided doses of either 1 mg/kg twice weekly or 0.29 mg/kg/day over 7 days. The studies were performed using a murine disseminated candidiasis model. Animals were euthanized at 168 h following the start of treatment. Fungi grew well in the no-treatment control group and showed variable changes in fungal density in the treatment groups. When the CD101 AUC from 0 to 168 h (AUC0–168) was administered as a single dose, a >2 log10 CFU reduction from the baseline at 168 h was observed. When twice-weekly and daily regimens with similar AUC values were administered, net fungal stasis and a >1 log10 CFU increase from the baseline were observed, respectively. These data support the hypothesis that the shape of the CD101 AUC influences efficacy. Thus, CD101 administered once per week demonstrated a greater degree of fungal killing than the same dose divided into twice-weekly or daily regimens.

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