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At present, the development of antibiotic resistance appears to be an inevitable process, which is associated with greater patient morbidity, higher mortality rates, and increased costs to the healthcare system. Strategies to reduce antibiotic resistance include de-escalation therapy, 1 alteration in availability of empirical antibiotic choices in response to outbreaks of infection with antibiotic-resistant organisms, 2 antibiotic cycling 2 and mixing, 3 and computer-assisted management programs. 4 References: 1. Kollef M. Appropriate empirical antibacterial therapy for nosomial infections: getting it right the first time. Drugs. 2003;63:2157–2168. 2. Paterson D, Rice LB. Empirical antibiotic choice for the seriously ill patient: are minimization of selection of resistant organisms and maximization of individual outcome mutually exclusive? Clin Infect Dis. 2003;36:1006–1012. 3. Levin B, Bonten M. Cycling antibiotics may not be good for your health. Proc Natl Acad Sci USA. 2004;101:13101–13102. 4. Evans RS, Pestotnik S, Classen D, et al. A computer-assisted management program for antibiotics and other antiinfective agents. N Engl J Med. 1998;338:232–238.
Penetration of Vancomycin Into Human Lung Tissue 1 Thirty patients (23 males; aged 62 ± 11.2 years; weight 77.7 ± 14.3 kg) were enrolled. Twenty-eight patients underwent thoracotomy for lung cancer, 1 patient for relapsing pneumothorax, and 1 patient because of a tubercular abscess. All patients had normal kidney and liver function. Vancomycin was administered at 1 g IV over 1 hour; the timing was planned in order to collect blood and tissue levels at discrete times in the 1- to 12-hour interval after the end of infusion. At the time of lung resection, healthy tissue and venous blood samples were collected. Reference 1. Cruciani M, Gatti G, Lazzarini L, et al. Penetration of vancomycin into human lung tissue. J Antimicrob Chemother . 1996;38:865-869.
Linezolid Pharmacokinetics in Ventilator-Associated Pneumonia (VAP) 1 The linezolid pharmacokinetic profiles for 16 critically ill adult patients with late-onset VAP (5 or more days on the ventilator) were evaluated 2 days after they started therapy (600 mg q12h IV). Samples for linezolid determination from epithelial lining fluid (ELF) were collected with a mini–bronchoalveolar lavage (BAL) brush. Mean peak and trough concentrations were 17.7±4 and 2.4±1.2, respectively, in plasma, and 14.4±5.6 and 2.6±1.7, respectively, in ELF. This shows a mean linezolid penetration in ELF of approximately 100% at steady state. All MRSA VAP patients improved after 10 days of linezolid therapy. Baseline characteristics for the study population: Age, 59±15 years Gender (m/f), 10/6 Weight, 73±15 kg Simplified acute physiology score (SAPS II), 40±13 Creatinine clearance, 81±45 mL/min PaO 2 /FIO 2 ratio, 231±117 mm Hg Main diagnosis: Pneumonia, 7 Abdominal surgery, 5 Pancreatitis, 2 Encephalitis, 2 Reference 1. Boselli E, Breilh D, Rimmelé T, et al. Pharmacokinetics and intrapulmonary concentrations of linezolid administered to critically ill patients with ventilator-associated pneumonia. Crit Care Med . 2005;33:1529-1533.
In vitro pharmacodynamic model Daptomycin also had promising activity against MRSA in simulated endocardial vegetations, with bactericidal activity within 24 hours. 1 At a high inoculum, daptomycin achieved bactericidal activity by 24 hours and maintained it throughout the experiment. Vancomycin demonstrated bactericidal activity by 72 hours, but gentamicin did not. Reference 1. LaPlante KL & Rybak MJ. Antimicrob Agents Chemother 2004;48:4665–4672
Clinical Consequences of Rising Vancomycin MICs Key Point: Vancomycin MICs of 2 µg/mL, which is considered within the susceptible range, were associated with decreased eradication rates, increased time to eradication, and increased duration of treatment in MRSA bacteremia Supplemental Information: Moise-Broder et al performed in vitro susceptibility assays on isolates prospectively collected from patients receiving vancomycin therapy for MRSA bacteremia (n = 34). Vancomycin doses were adjusted to achieve peak and trough concentrations of 28-32 µg/mL and 8-12 µg/mL, respectively Median time to clearance was significantly longer at vancomycin MICs of 2.0 µ g/ml vs MICs of ≤ 1.0 µ g/ml Bacteremia caused by MRSA isolates with absent or severely reduced delta-hemolysin expression was of longer duration (10 days vs 6.5 days) and had a decreased probability of eradication (44% vs 78%) Reference : Moise-Broder PA, et al. Antimicrob Agents Chemother. 2007; in press. Median time to clearance was significantly longer at vancomycin MICs of 2.0 µg/ml vs. MICs of ≤ 1.0 µg/ml Bacteremia caused by MRSA isolates with absent or severely reduced delta-hemolysin expression was of longer duration (10 days vs. 6.5 days) and had a decreased probability of eradication (44% vs. 78%)
A study by Moise-Broder in 2004 demonstrates the relationship between minimum inhibitory concentration (MIC) and treatment success Increases in MIC from 0.5 to 1 to 2 were significantly associated with increasing treatment failure Moise-Broder et al. Clin Infect Dis . 2004;38:1700-1705.
This slide illustrates p lasmid -mediated antibiotic resistance, which includes genes for ESBL production/regulation and aminoglycoside modification (multiresistance) [Livermore/ pg S13/ A; pg S14/ A]. 2 Resistance factors other than those for ESBLs may reside on the transferable plasmids observed in enterobacteriaceae . The plasmids tend to be large ( 80 kb) and carry variable resistance to different antimicrobial agents [Jacoby/ pg 1700/ A]. Plasmids encoding ESBLs may carry numerous antibiotic-resistance genes [Jacoby/ 1700/ A]. 1 Transposons are genetic elements that may encode ESBL production or other resistance and can replicate and reinsert into other plasmids or a host chromosome, thus spreading resistance [Livermore/ pg S13/ A]. 2 References: 1. Jacoby GA, Medeiros AA. More extended-spectrum -lactamases . Antimicrob Agents Chemother. 1991 ;35:1697–1704 . 2. Livermore DM. Bacterial resistance: Origins, epidemiology, and impact. Clin Infect Dis. 2003;36:S11–S23. Figure developed from: Livermore/ pg S13/ A; pg s14/ A; Jacoby; pg 1700/ A
Chow et al studied the effects of multidrug resistance emerging in 129 consecutive patients with Enterobacter bacteremia in a prospective, observational trial. Analysis of isolates from initial blood cultures showed that patients who had received any antibiotic therapy before the diagnosis of bacteremia were significantly more likely to harbor multiresistant Enterobacter than those who had not received antibiotic therapy (35% vs 4%; P =.002). In addition, initial blood isolates from patients who had received third-generation cephalosporins were significantly more likely to have resistant organisms than those from patients who had received other antimicrobials (69% vs 20%; P =.001) 1
Ertapenem has similar activity to existing carbapenems, but is much less active against non-fermenters of the genera Pseudomonas aeruginosa and Acinetobacter .
Ertapenem’s most unique feature among carbapenems is its long half life, due to protein binding by the benzoic acid group, mentioned earlier. The total drug level exceeds 4 mg/L (the NCCLS breakpoint for Enterobacteriaceae) throughout the dosage interval. More critically, the free drug level exceeds the breakpoint for 33% of the dosage interval – as required for efficacy with a carbapenem; these margins are evidently greater for lower breakpoints, such as the 2 mg/L value adopted by the British Society for Antimicrobial Chemotherapy.
Ertapenem shares the stability of imipenem and meropenem to beta-lactamases including extended-spectrum types and AmpC enzymes. Resistance can, however, arise when extended-spectrum beta-lactamases (ESBLs) and AmpC enzymes are accompanied by other factors. Enterobacteriaceae with these combined defences may also be resistant to imipenem and meropenem, or remain susceptible. Carbapenems, such as the IMP and VIM enzymes can also cause resistance to carbapenems, including ertapenem, and are explored later in this slide set.