ArticleLiterature Review

Pharmacokinetics of carbapenems

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Abstract

Carbapenems, beta-lactam antibiotics, are ideal candidates for the treatment of serious nosocomial infections including sepsis for their exceptionally broad antibacterial spectrum and high efficiency. They are administered parenterally by intravenous infusion. Carbapenems penetrate well and rapidly into many different tissue compartments and the interstitial fluid. They are metabolized by renal dihydropeptidase-1. Therefore, imipenem must be co-administered with an inhibitor of dihydropeptidase-1. Other carbapenems registered in the Czech Republic (meropenem, ertapenem and doripenem) are more stable to this enzyme. Carbapenems are mainly eliminated via the kidneys and dose adjustment in patients with renal impairment is necessary. The elimination half-life of most carbapenems is around 1 hour with the exception of ertapenem, with 3.8-hour half-life, which allows its once-daily use. Carbapenems are a group of antibiotics with time-dependent effect. Their typical pharmaceutical property is a limited stability in solution after dilution. Administration in the prolonged infusion appears to be a convenient strategy to achieve higher efficiency. Pharmacokinetic parameters of carbapenems may vary individually, especially in critically ill patients and those treated by renal replacement therapy. Therefore, individualization of dosing regimens based on knowledge of pharmacokinetic parameters of individual patients may be useful.

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... [26] Most intestinal indigenous bacteria, that is, E. coli, along with conditional pathogens that are susceptible to ceftriaxone are killed under the high concentration of ceftriaxone in the intestinal tract, leading to decreased BT. However, almost all imipenem is rapidly excreted via the kidneys [27] and unable to reach a high concentration in the gut, which weakens its bactericidal activity to intestinal bacteria and leads to more BT than occurs with ceftriaxone. ...
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Background: Antibiotics are frequently used to treat critically ill patients, and its use is often accompanied by intestinal dysbiosis that might further lead to bacterial translocation (BT). Nevertheless, studies on the relationship between antibiotic therapy and BT are rare. In the present study, we investigated the effect of broad-spectrum antibiotics on BT in an experimental rat model of burn or sepsis injury. Methods: The septic rat model was simulated by a second insult with lipopolysaccharides after burn injury. Ninety-two male Sprague-Dawley rats were randomly divided into control, burn, and sepsis groups (n = 8 or 9, each group), and the latter two groups were then treated with imipenem or ceftriaxone for 3 or 9 days. The mesenteric lymph nodes, liver, lungs, and blood were collected at each time point under sterile conditions for quantitative bacterial culture and strain identification. The differences between the groups were compared by Fisher exact test or Mann-Whitney U test. Results: Only minimal Escherichia coli translocation to the mesenteric lymph nodes was observed in the normal control group, in which the BT rate was 12.5%. Burn injury did not affect the BT rate (Burn group vs. Control group, 12.5% vs. 12.5%, P = 1.000), whereas the BT rate showed an increased trend after the second insult with lipopolysaccharide (Sepsis group vs. Control group, 44.4% vs. 12.5%, P = 0.294), and many strains of Enterobacteria spp. were detected in distant organs (liver, lung, and blood) [Sepsis group vs. Control group, 0 (0,3) vs. 0 (0,0), U = 20, P = 0.045]. After the antibiotic treatment, BT to the distant organs was increased in burned rats [Burn IT3 group vs. Burn group, 0 (0,2) vs. 0 (0,0); Burn IT9 group vs. Burn group, 0 (0,1) vs. 0 (0,0); Burn CT9 group vs. Burn group, 0 (0,2) vs. 0 (0,0); all U = 20 and P = 0.076] but decreased in septic rats [Sepsis CT3 group vs. Sepsis group, 0 (0,0) vs. 0 (0,3), U = 20, P = 0.045]. The total amount of translocated bacteria, regardless of which antibiotic was used, was increased in burned rats [Burn IT9 group vs. Burn group, 2.389 (0,2.845) vs. 0 (0,2.301) Log10 colony-forming units (CFU)/g, U = 14, P = 0.034; Burn CT3 group vs. Burn group, 2.602 (0,3.633) vs. 0 (0,2.301) Log10 CFU/g, U = 10.5, P = 0.009], but there was a slightly decreased trend in septic rats [Sepsis IT9 group vs. Sepsis group, 2.301 (2,3.146) vs. 0 (0,4.185) Log10 CFU/g, U = 36, P = 0.721; Sepsis CT9 group vs. Sepsis group, 2 (0,3.279) vs. 0 (0,4.185) Log10 CFU/g, U = 32.5, P = 0.760]. Remarkably, the quantity of Enterococci spp. dramatically increased after broad-spectrum antibiotic treatment in both the burned and septic groups [Burn IT3 group vs. Burn group, 1 (0,5.164) vs. 0 (0,0) Log10 CFU/g, U = 16; Burn IT9 group vs. Burn group, 1 (0,2.845) vs. 0 (0,0) Log10 CFU/g, U = 16; Burn CT3 group vs. Burn group, 2.602 (0,3.633) vs. 0 (0,0) Log10 CFU/g, U = 8; Burn CT9 group vs. Burn group, 1 (0,4.326) vs. 0 (0,0) Log10 CFU/g, U = 16; Sepsis IT3 group vs. Sepsis group, 2.477 (0,2.903) vs. 0 (0,0) Log10 CFU/g, U = 4.5; Sepsis IT9 group vs. Sepsis group, 2 (0,3.146) vs. 0 (0,0) Log10 CFU/g, U = 9; Sepsis CT3 group vs. Sepsis group, 1.151 (0,2.477) vs. 0 (0,0) Log10 CFU/g, U = 18; Sepsis CT9 group vs. Sepsis group, 2 (0,3) vs. 0 (0,0) Log10 CFU/g, U = 13.5; all P < 0.05]. Conclusions: Broad-spectrum antibiotics promote BT in burned rats but prevent BT in septic rats, especially preventing BT to distant organs, such as the liver and lung. Moreover, Enterococci spp. with high drug resistance and high pathogenicity translocated most after antibiotic treatment.
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The rates of degradation, catalysed by Zn(2+), of four classical penicillins-amoxicillin, ampicillin and penicillins G and V-were followed at 20 degrees C in methanol by spectrophotometric assays. Kinetic schemes of the reactions of degradation catalysed by Zn(2+) ions were analogous to those given previously for the reaction catalysed by Cd(2+) ions. The methanolysis of penicillin V occurs with the formation of a single intermediate substrate-metal complex (SM), whereas the degradations of amoxicillin, ampicillin and penicillin G occur with the initial formation of two complexes with different stoichiometry, SM and S(2)M, both in equilibrium. In all cases, the degradation reaction is of the first order with respect to SM, with velocity constants at 20 degrees C of 0.0093, 0.0288, 0.0304 and 0.0349 min(-1), for amoxicillin, ampicillin, penicillin V and penicillin G, respectively. The compound S(2)M degraded at a much lower rate than SM and constitutes a zero-order process. The catalytic effect of the ion Zn(2+) in the degradation of the penicillins was much weaker than that of the ion Cd(2+), owing to the lesser ionic radius of the former and the fact that in the case of the reaction catalysed by Zn(2+), the compound S(2)M occurred in a much greater amount than the SM. At the end of the degradation reaction, the corresponding penamaldic derivative of the antibiotic was produced, established by the coordination of the Zn(2+) ion, forming a single complex 2:1 (derivative penamaldic-metal) in the case of amoxicillin and ampicillin; and two complexes, 1:1 and 2:1, for the other antibiotics. Finally, the molar absorption coefficients of the products of reaction at the wavelength of maximum absorption at 20 degrees C were calculated.
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The pharmacokinetics of imipenem were studied in adult intensive care unit (ICU) patients during continuous venovenous hemofiltration (CVVH; n=6 patients) or hemodiafiltration (CVVHDF; n=6 patients). Patients (mean+/-standard deviation age, 50.9+/-15.9 years; weight, 98.5+/-15.9 kg) received imipenem at 0.5 g every 8 to 12 h (total daily doses of 1 to 1.5 g/day) by intravenous infusion over 30 min. Pre- and postmembrane blood (plasma) and corresponding ultrafiltrate or dialysate samples were collected 1, 2, 4, and 8 or 12 h (depending on dosing interval) after completion of the drug infusion. Drug concentrations were measured using validated high-performance liquid chromatography methods. Mean systemic clearance (CL(S)) and elimination half-life (t1/2) of imipenem were 145+/-18 ml/min and 2.7+/-1.3 h during CVVH versus 178+/-18 ml/min and 2.6+/-1.6 h during CVVHDF, respectively. Imipenem clearance was substantially increased during both CVVH and CVVHDF, with membrane clearance representing 25% and 32% of CL(S), respectively. The results of this study indicate that CVVH and CVVHDF contribute to imipenem clearance to a greater degree than previously reported. Imipenem doses of 1.0 g/day appear to achieve concentrations adequate to treat most common gram-negative pathogens (MIC up to 2 microg/ml) during CVVH or CVVHDF, but doses of 2.0 g/day or more may be required to adequately treat and prevent resistance in pathogens with higher MICs (MIC=4 to 8 microg/ml). Higher doses should only be used after consideration of potential central nervous system toxicities or other risks of therapy in these severely ill patients.
Article
The antimicrobial class of penems has the potential to address most of the relevant resistance issues associated with beta-lactam antibiotics because of their exceptionally broad spectrum of antibacterial activity and their intrinsic stability against hydrolytic attack by many beta-lactamases including ESBL and AmpC enzymes. The subclass of carbapenems covers the spectrum of hospital pathogens whereas the subclass of penems covers community pathogens. The only currently available penem, faropenem, has a low propensity for resistance development, beta-lactamase induction and selection of carbapenem-resistant Pseudomonas aeruginosa. This makes it attractive for the treatment of community-acquired infections and for step-down or sequential therapy following carbapenem treatment without jeopardizing the activity of carbapenems or the entire beta-lactam class in the hospital environment.
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The stability of broad-spectrum antibiotic meropenem was studied in order to investigate the kinetics of degradation of this drug in powder for injection and reconstituted sample. Carbapenem was submitted to conditions of accelerated thermal decomposition. Degradation of meropenem was adequately modeled by specific equations for order rate kinetics. The analyses of the degraded samples were performed by high-performance liquid chromatographic (HPLC) method and microbiological assay. At higher temperatures, the decomposition reactions of meropenem in powder for injection could be described by first-order kinetics. The higher rate of degradation was observed in meropenem reconstituted in 0.9% sodium chloride, and the thermal decomposition obeyed also first-order kinetics. The results obtained confirm the reliability of chromatographic method for determining the kinetics run of meropenem in the presence of its degradation products. The present study reveals the thermal lability of the drug, especially as reconstituted sample. Thus, appropriate thermal protection is recommended during the storage and handling.
Article
The carbapenems are β-lactam antimicrobial agents with an exceptionally broad spectrum of activity. Older carbapenems, such as imipenem, were often susceptible to degradation by the enzyme dehydropeptidase-1 (DHP-1) located in renal tubules and required co-administration with a DHP-1 inhibitor such as cilastatin. Later additions to the class such as meropenem, ertapenem and doripenem demonstrated increased stability to DHP-1 and are administered without a DHP-1 inhibitor. Like all β-lactam antimicrobial agents, carbapenems act by inhibiting bacterial cell wall synthesis by binding to and inactivating penicillin-binding proteins (PBPs). Carbapenems are stable to most β-lactamases including AmpC β-lactamases and extended-spectrum β-lactamases. Resistance to carbapenems develops when bacteria acquire or develop structural changes within their PBPs, when they acquire metallo-β-lactamases that are capable of rapidly degrading carbapenems, or when changes in membrane permeability arise as a result of loss of specific outer membrane porins. Carbapenems (imipenem, meropenem, doripenem) possess broad-spectrum in vitro activity, which includes activity against many Gram-positive, Gram-negative and anaerobic bacteria; carbapenems lack activity against Enterococcus faecium, methicillin-resistant Staphylococcus aureus and Stenotrophomonas maltophilia. Compared with imipenem, meropenem and doripenem, the spectrum of activity of ertapenem is more limited primarily because it lacks activity against Pseudomonas aeruginosa and Enterococcus spp. Imipenem, meropenem and doripenem have in vivo half lives of approximately 1 hour, while ertapenem has a half-life of approximately 4 hours making it suitable for once-daily administration. As with other β-lactam antimicrobial agents, the most important pharmacodynamic parameter predicting in vivo efficacy is the time that the plasma drug concentration is maintained above the minimum inhibitory concentration (T>MIC). Imipenem/cilastatin and meropenem have been studied in comparative clinical trials establishing their efficacy in the treatment of a variety of infections including complicated intra-abdominal infections, skin and skin structure infections, community-acquired pneumonia, nosocomial pneumonia, complicated urinary tract infections, meningitis (meropenem only) and febrile neutropenia. The current role for imipenem/cilastatin and meropenem in therapy remains for use in moderate to severe nosocomial and polymicrobial infections. The unique antimicrobial spectrum and pharmacokinetic properties of ertapenem make it more suited to treatment of community-acquired infections and outpatient intravenous antimicrobial therapy than for the treatment of nosocomial infections. Doripenem is a promising new carbapenem with similar properties to those of meropenem, although it appears to have more potent in vitro activity against P. aeruginosa than meropenem. Clinical trials are required to establish the efficacy and safety of doripenem in moderate to severe infections, including nosocomial infections.
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Among the many different structurally distinct classes of beta-lactams, the carbapenem class is regarded as that which is most potent and which has the widest spectrum of antimicrobial activity. Rapidly bactericidal, and demonstrating time-dependent killing, carbapenemes have a spectrum of antimicrobial activity that includes Gram-positive and Gram-negative aerobic and anaerobic pathogens. Their in-vitro activity includes extended-spectrum beta-lactamase (ESBL)-producing pathogens and carbapenems are currently considered to be the treatment of choice for serious infections due to ESBL-producing organisms. However, isolates acquiring resistance under treatment have been reported. Imipenem, meropenem and ertapenem are licensed in the European Community and panipenem and biapenem are also available in Japan and South Korea. Other carbapenemes are under development.
Article
The compatibility of doripenem diluted for infusion with 82 other drugs during simulated Y-site administration was studied. Five-milliliter samples of doripenem 5 mg/mL in 5% dextrose injection and separately in 0.9% sodium chloride injection were combined with 5 mL of 82 other drugs, undiluted or diluted in 5% dextrose injection or 0.9% sodium chloride injection. Visual examinations were performed with the unaided eye in fluorescent light and using a Tyndall beam to enhance visualization of small particles and low-level turbidity. The turbidity of each sample was measured, and particulate content was evaluated. Samples were inspected initially and one and four hours after preparation. Of the drugs tested, doripenem 5 mg/mL in 5% dextrose injection and in 0.9% sodium chloride injection was incompatible with diazepam, potassium phosphates, and undiluted propofol. Doripenem 5 mg/mL in 0.9% sodium chloride injection but not in 5% dextrose injection was incompatible with amphotericin B-containing drugs due to the diluent. Doripenem was found to be compatible when combined with the other 75 drugs for at least four hours. Doripenem 5 mg/mL in 5% dextrose injection or in 0.9% sodium chloride injection was physically compatible for four hours at room temperature with 75 drugs during simulated Y-site administration. Three drugs combined with doripenem in 5% dextrose injection or 0.9% sodium chloride injection and 7 drugs combined with doripenem in 0.9% sodium chloride injection resulted in unacceptable precipitation or an increase in measured haze and should not be simultaneously administered with doripenem admixtures.
Ertapenem a jeho postavení mezi ostatními karbapenemy
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