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June 7-24.pdf

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“In truth, we really can’t prevent antimicrobial resistance. Rather, handle that,” Kollef said. “New technologies are being developed it’s something we need to try to control,” stated Marin H. Kollef, to provide rapid microbiologic evaluation, but until they become MD, from Washington University in St. Louis, Missouri. One key available we still have to treat infections broadly. De-escalation is to controlling resistance is to look at antimicrobial treatment in the one tool we can use to try to minimize resistance.” Examples of ICU as a balancing act. “On one hand, we need to think about de-escalation in the treatment of ventilator-acquired pneumonia appropriately treating patients,” Kollef said. “On the other hand, (VAP) have been reported in the literature (Rello et al. Crit Care Med. we always need to be thinking about avoiding unnecessary antimi- 2004;32:2183; Leone et al. Crit Care Med. 2007;35:379). De-escala- tion, which involves narrowing the therapy once microbiologic Antimicrobial resistance is of great concern because of its asso- results are obtained, also enables the clinician to use the shortest ciated increase in morbidity, mortality, and healthcare costs–and course of therapy that is clinically adequate for the infection. because fewer effective antimicrobial agents are available today. Duration of antimicrobial therapy is of concern in terms of One example of ineffective agents can be seen in the quinolone efficacy and potential for resistance. Investigators have reported class. According to a study reported in 2003, increases in fluoro- that longer (15 days vs. 8 days) antimicrobial therapy for VAP had quinolone use paralleled increases in resistance rates in Pseudomonas no impact on survival (Chastre et al. JAMA. 2003;290:2588). Other aeruginosa and gram-negative bacilli infections from 1990 to 2000 researchers examined the occurrence of unnecessarily prolonged (Neuhauser et al. JAMA. 2003;289:885). “Part of the reason for antibiotic use in the ICU and found that 50% of patients who had this may have been some underdosing of quinolones,” noted Kollef, no evidence of infection were still receiving “particularly for infections in the lung, where you might not get antimicrobial therapy one week later (Aarts et al. Intensive Care Med. 2007;33:1369).
The link between more frequent use of an antimicrobial agent H[i_ijWdY[7ced]>eif_jWb_p[Z7Zkbji
and increased resistance, and hence, increased mortality, is well minimizing antimicrobial resistance. “You known. “We also know that the resistance mechanisms involve Fh[l[dj?d\[Yj_ed
beta-lactamases and multiple efflux pumps,” he said. “Whether we with the right dose,” he said. He cited an like it or not, accumulation of extended-spectrum beta-lactamases investigation of four dosing regimens of Ij[f(0 H[cel[YWj^[j[hiWiieedWifeii_Xb[ (ESBLs), AmpC beta-lactamases, and fluoroquinolone resistance is driving more use of carbapenem.” The consequence of that is dose (2 g every 8 hours over a 3-hour infu- :_W]dei[WdZJh[Wj?d\[Yj_ed;\\[Yj_l[bo
sion) gave the greatest likelihood of appro- The incidence of sepsis in the United States has been rising priately treating P aeruginosa and minimiz- and is expected to continue to climb over the next few decades ing the emergence of resistance (Santos et (Angus et al. Crit Care Med. 2001;29:1303). “Thus, we’ll see the al. Clin Microbiol Infect. 2007;13:579). need for increased antimicrobial use and more problems with resis- Ki[7dj_c_YheX_WbiM_i[bo
tance,” said Kollef. Using the appropriate agent initially is crucial, involve treating the infection, not the con- he noted, citing data that revealed increased mortality when inap- propriate initial antimicrobial therapy was administered (Ibrahim et Ij[f-0 Jh[Wj_d\[Yj_ed"dejYedjWc_dWj_ed bronchoalveolar lavage (BAL). Ibrahim et Ij[f.0 Jh[Wj_d\[Yj_ed"dejYebed_pWj_ed Illustrating the importance of appropriate initial therapy, al described the results of a protocol for Ij[f/0 Ademm^[djeiWodejelWdYecoY_d Kollef described a study involving patients who presented to the emergency department (ED) with septic shock (Micek et al. Crit Care suspected VAP (Ibrahim et al. Crit Care Ij[f'&0 IjefWdj_c_YheX_Wbjh[Wjc[djm^[dYkh[Z Med. 2006;34:2707). Computer-based algorithms indicating appro- Med. 2001;29:1109). All were treated with priate antimicrobial treatment for patients with septic shock were combination antimicrobial therapy, based Fh[l[djJhWdic_ii_ed
developed for ED staff. Most patients received combination therapy on the unit-specific antibiogram. “The consisting of three antibiotic agents. The ED-based sepsis protocol key part was de-escalation,” said Kollef. was associated with reductions in mortality, decreasing from 48.3% to 30% (p=.04), length of stay, and costs. No new antimicrobial based on the culture results, and was lim- 9[dj[hi\eh:_i[Wi[9edjhebWdZFh[l[dj_ed9:9 resistance occurred among these patients, and they were more likely ited to 7 days. Importantly, the protocol to be treated with an appropriate initial regimen compared with reduced the duration of treatment in the patients who were treated before the algorithms were instituted.
The Centers for Disease Control and Prevention (CDC) pro- In closing, Kollef contrasted the old and new paradigm of anti- vides a 12-step approach to preventing antimicrobial resistance microbial treatment. The old paradigm advocated starting therapy among hospitalized adults (see Table 1). One step involves cath- with narrow-spectrum agents, such as penicillin, and using the effi- eters. “Removing catheters as soon as possible is critical because cient low dose, which also may be associated with fewer adverse that's where biofilm forms and where resistance can emerge,” effects. Duration of therapy under the old paradigm was long: at Kollef said. Prevention programs are effective in educating ICU least 2 weeks. “With the new paradigm, you want to get it right the nurses and physicians on maintenance of catheters, hand-washing, first time and follow an aggressive de-escalation approach,” Kollef proper attire during catheter placement, sterilization technique, explained. “That means hitting the organism hard up front. You also proper barrier precautions, and other procedures that will mini- want to avoid low doses, which promote resistance. It’s important to mize the rate of catheter-related infections.
optimize the dosing; our pharmacy colleagues can guide us. In terms The CDC also recommends targeting pathogens and using of duration, seldom do we need to push therapy beyond 7 days.” local data. "De-escalation and local surveillance are the ways to CE credit at JUNE 2008
New antimicrobial agents are on the horizon that target mul- escens, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, and tiple-drug resistant infections, which include methicillin-resistance N meningitidis. Colistin and polymyxin B show no activity against the Staphylococcus aureus (MRSA), P aeruginosa, Acinetobacter species, and other gram-negative organisms. In addition, one compound that Colistin and polymyxin often are used with other drugs in has been around for a while shows promise in combating multiple- combination therapy. Limited data suggest a synergistic bacteri- drug resistant infections, according to Steven J. Martin, PharmD, cidal effect in vitro is achieved when colistin is used with rifampin FCCM, from the University of Toledo College of Pharmacy.
or ceftazidime, particularly against P aeruginosa (Sarkar. Am J Newer agents showing efficacy against MRSA include dalba- Health Syst Pharm. 2007;64:2462; Zavascki. J Antimicrob Chemother. vancin, oritavancin, telavancin, daptomycin, linezolid, tigecycline, and ceftobiprole. In the treatment of gram-negative organisms, Clinical data focus on case reports on the use of colistin in the effective newer agents include doripenem, ceftobiprole, and tige- treatment of P aeruginosa, Acinetobacter baumannii, E coli, and K pneu- cycline, and colistin, which is the oldest of these drugs. Martin moniae (Sarkar. Am J Health Syst Pharm. 2007;64:2462). “Although there are limited data in the literature on the microbiologic response observed with this drug in multidrug-resistant infections, empirically Doripenem. Doripenem, a new carbapenem, has a similar bacteri- colistin therapy appears to be a sound idea,” Martin noted. cidal spectrum to that of imipenem and meropenem. It has broad Use of colistin fell out of favor in the 1960s due to its neph- activity against most gram-negative rods, most gram-positive cocci, rotoxic properties. In case reports of 199 critically ill patients who and most anaerobes. Binding to bacterial membranes, doripenem were treated with colistin for multidrug-resistant infections, nephro- demonstrates similar or somewhat better potency against P aerugino- toxicity was observed in 52 (26%) patients (Sarkar. Am J Health Syst sa compared with imipenem or meropenem. Doripenem also exerts Pharm. 2007;64:2462). Colistin also has neurotoxic properties as a strong activity against Acinetobacter species, Enterobacter aerogenes, neuromuscular blocking agent, but a neurotoxic effect may be dif- ESBL-producing organisms (Escherichia coli, Klebsiella pneumoniae), ficult to detect in sedated or critically ill patients.
and many other gram-negative rod organisms. In terms of activity The dosing, pharmacokinetics, and pharmacodynamics of against gram-positive cocci, doripenem is not effective in treating colistin have not been studied well. More work has been reported on MRSA, but it does demonstrate efficacy against pneumococci, par- the use of colistin in patients with cystic fibrosis than in the critically ticularly penicillin-resistant pneumococcus. Current indications for ill population, leaving the door open to future research in this area.
doripenem include intra-abdominal infection, urinary tract infec-tion, and pyelonephritis. Dalbavancin. Dalbavancin is a second-generation glycopeptide that Doripenem has a relatively short (1 h) half-life, as do other car- received recent Food and Drug Administration (FDA) approval. bapenems, and is administered every 8 hours. “Infusion time and the Like vancomycin, it has broad gram-positive activity, which includes pharmacodynamic properties of this drug can be put to advanta- MRSA, penicillin-resistant Streptococcus pneumoniae and vancomy- geous use,” said Martin. Doripenem undergoes renal elimination. cin-resistant enterococci (VRE). Unlike vancomycin, dalbavancin Recent data from two international multicenter trials show the has a very long half-life (170-210 h). “Thus, dalbavancin allows efficacy of doripenem in the treatment of nosocomial pneumonia once-weekly dosing, which is an interesting concept,” Martin (Ortho-McNeil, Inc. Data on file; 2007.) In one study, patients with stated. “Dalbavancin provides a long period of time in which early onset VAP were randomized to receive doripenem 500 mg the concentration is above the MIC for most MRSA organisms.” every 8 hours or piperacillin/tazobactam 4.5 g every 6 hours. The Approximately 40% of the intact drug is eliminated renally, and up infusion time for the doripenem dose was short (30 min). When to 50% is excreted into the feces. Dalbavancin does not appear to Pseudomonas or MRSA infections were suspected, adjuvant therapy produce any significant adverse effects.
consisting of amikacin (80%)/vancomycin (15%) was instituted. Microbiologic data indicate that dalbavancin possesses slightly “Although the overall clinical cure rates were similar in patients who more potent MICs against methicillin-sensitive S aureus (MSSA) did not have P aeruginosa infection, differences in clinical cure rates than vancomycin and greater potency against MRSA infections were observed for the two therapies among patients with P aerugi- than vancomycin, linezolid, or daptomycin (Chen. Int J Clin Pract. nosa–83% for doripenem versus 71% for piperacillin,” he said. 2007;61:853). When studied in complicated skin and skin struc- The second study compared doripenem 500 mg every 8 hours ture infections, dalbavancin and linezolid had similar cure rates over a prolonged (4-hour) infusion with imipenem 500 mg every (Jauregui. Clin Infect Dis. 2005;41:1407). In an open-label multi- 6 hours in patients with early/late VAP. “Once again, dramatic center trial comparing dalbavancin and vancomycin in the treat- differences favoring doripenem were seen in patients who had P ment of catheter-related bacteremia, the success rates were 87% aeruginosa infection. Clinical cure rates were 65% with doripenem and 50% for dalbavancin and vancomycin, respectively.
and 35% with imipenem,” he reported. “These findings suggest that perhaps a change in the infusion length could have an impact Ceftobiprole. Ceftobiprole is an extended spectrum cephalosporin that has activity against MRSA and penicillin-resistant S pneumoniae and Research indicates that for concentration-independent anti- limited activity against P aeruginosa and Acinetobacter species. It has a microbial drugs such as the carbapenems, bactericidal activity is 3- to 4-hour half-life, and is administered as a pro-drug. Ceftobiprole obtained when the time above the minimal inhibitory concentra- tion (MIC) for the dosing interval reaches at least 40%. “Thus, a Ceftobiprole studies indicate that the agent is effective in inhib- 4-hour infusion instead of a 30-minute infusion of doripenem may iting the growth of 92% of 372 Enterobacteriaceae isolates. This make a great deal of sense,” said Martin. includes ESBL- and AmpC-producing strains (Jones. Clin Microbiol Infect. 2007;13[suppl 2]:17). “Ceftobiprole is the only cephalosporin Colistin and Polymyxin B. Although colistin and polymyxin B have that has effective MRSA activity, as well as other staph infections,” been around for decades, their use in the treatment of infections Martin said. “It has a similar potency to linezolid or vancomycin caused by gram-negative organisms is new. Both of these agents are bactericidal and exert their action by binding to the phosphate In summing up his presentation, Martin noted that more data groups in the lipids of the cytoplasmic membrane of the organism. are needed to learn about these new compounds. He also stressed that They are active against nearly all gram-negative bacteria, except the number of new antimicrobials is limited. “With that in mind, good Proteus species, Burkholderia cepacia, Providencia species, Serratia marc- stewardship of antimicrobial use is key to drug preservation,” he said.
“Fungal infections are an important problem in the ICU,” said cant–and certainly interesting–finding was that the blood did not Pamela A. Lipsett, MD, FCCM, from Johns Hopkins University clear as well with high-dose fluconazole therapy. At present, there is School of Medicine and Nursing in Baltimore, Maryland. “In fact, no recommendation to use high-dose fluconazole on a routine basis 10% of bloodstream infections in the ICU are caused by Candida spe- or to use a combination of amphotericin and fluconazole,” Lipsett cies, and these infections–the third most common seen in critical care –have crude mortality rates ranging from 40% to 80%.” In the echinocandin class, half-life differences are seen among Approximately 72% of all fungal pathogens in the ICU are the three agents. Anidulafungin, the most recently released of these C albicans. The second most common ICU fungal pathogen is C drugs, has the longest half-life (26.5 h) and the largest volume of glabrata. Others include C tropicalis, C parapsilosis, and C krusei. In distribution. It also is the only echinocandin that is metabolized patients who have undergone solid organ transplantation or who chemically, with no hepatic involvement. have neutropenia, Aspergillus species and other molds are emerg- ing as pathogens of concern. About 50% of respiratory and rectal cultures and a smaller percentage of urinary and wound cultures reveal the presence of fungi, but this does not necessarily signify JWXb[($H_ia<WYjehie\<kd]Wb?d\[Yj_ediI[[d_dj^[?9K
infection. Rather, it is colonization that usually indicates infection. H_ia<WYjeh
(Laverdiere et al. J Crit Care. 2007;22:245; Pfaller et al. Clin Microbiol “It is important to identify the fungal species, because some are either resistant or partially susceptible to azole agents,” Lipsett 9WdZ_ZW"Jh_Y^eifehed"7if[h]_bbki stated. For example, amphotericin may not be effective against C glabrata. Fluconazole should not be used against C krusei, which is resistant to the agent. It is also ineffective in Aspergillus infections.
Clinicians also must be aware that fungi can have dose-depen- dent sensitivity to antifungals: the larger the dose, the greater the likelihood of eradication. “Some C glabrata infections, for instance, require a higher than normal dose of fluconazole,” said Lipsett. “Instead of administering a standard dose of 400 mg, you can give an 800-mg dose and it will be effective. This is called dose-dependent =[[hji[jWb$9^[ij$(&&-1''/0')(+ In discussing antifungal use, Lipsett defined some terms. Treatment refers to therapy for proven or probable infections. Empiric treatment refers to therapy given for suspected infection. In the triazole class, voriconazole was found to be as effective Preemptive treatment refers to therapy given when the patient has as a regimen of amphotericin followed by fluconazole in the treat- fungal colonization and risk factors for infection. When a patient ment of candidemia in patients without neutropenia (Kullberg et al. has risk factors but no known colonization, antifungal therapy is Lancet. 2005;366:1435). “This would not be true for Aspergillus infec- referred to as either general or targeted prophylaxis.
tions, however,” remarked Lipsett. “Voriconazole is actually more “The problem is there are no consensus definitions about what a effective than fluconazole in treating Asperigillus infections.” fungal infection is and is not in patients who do not have neutropenia,” Identifying patients at risk for candidemia is important, as they stated Lipsett. According to the published microbiologic definition, can develop this infection within the first 2 days of entering the fungal infection consists of the following: detection of fungal ele- ICU. “Many fungal pathogens grow slowly, so if you don’t suspect a ments by cytology or direct microscopy from sterile fluids, detection of fungal infection and you do not begin therapy empirically, there's a Candida casts in the urine without a catheter, or detection of Candida in high risk of mortality,” Lipsett said.
the blood (de Paw et al. Clin Infect Dis. 2005;41[suppl 6]:S377).
New guidelines from the Infectious Diseases Society of America Intensivists need to be knowledgeable in the major risk factors are expected to be released soon. These guidelines will include the for various ICU fungal infections (see Table 2). Several risk factors new agents that have established their non-inferiority in clinical trials also have been identified for disseminated fungal disease: antibi- and that might be better in some situations of resistance or toxicity. otic therapy for longer than 6 days, treatment with three or more Lipsett concluded her discussion of ICU fungal infections by antimicrobial agents, acute renal failure, central venous catheter, emphasizing the need to consider the possibility of fungal infection age older than 40 years, gastrointestinal surgery, diabetes mellitus, in high-risk patients. “Initial therapy needs to be timely and correct. cancer, parenteral nutrition, trauma (multiple), steroids, burns and Because of low rates of resistance to azole drugs, I believe fluconazole is the drug of choice. However, if you are in a situation where there “There is much excitement in antifungal drug development are high rates of either azole resistance or C glabrata or C krusei organ- today,” she said. “We now have a wide variety of treatment options isms, echinocandins should be considered as first-line therapy.” for candidemia.” These include amphotericin B deoxycholate, fluconazole (intravenous and oral), amphotericin B lipid complex Supported by an educational grant from Pfizer, Inc. (ABLC), amphotericin B colloidal dispersion (ABCD), liposomal amphotericin B, the three echinocandins that became available in 2007 (caspofungin, micafungin, and anidulafungin), and the new 9edj_dk_d];ZkYWj_edI[b\#7ii[iic[dj
tertiary azole agents (voriconazole and posaconazole).
In making a selection among these antifungals, the availability <?=>J?D=J>;D;L;H#;D:?D=87JJB;7=7?DIJ7DJ?C?9HE8?7BH;I?IJ7D9;
of the agent must be determined. “Then you need to have some idea about the likely pathogen and be familiar with your local pathogens )$ 7ced]fWj_[djim_j^l[dj_bWjeh#WYgk_h[Zfd[kced_W"Wdj_c_YheX_Wbj^[hWfo\eh'+ZWoi and the sensitivity these pathogens,” stated Lipsett. “You also need to mWiWiieY_Wj[Zm_j^bem[hcehjWb_johWj[iYecfWh[Zm_j^.ZWoie\Wdj_c_YheX_Wbj^[hWfo$ know if the patient has been exposed to any azole agents, which may suggest development of a more resistant pathogen profile.” According to a meta-analysis of studies comparing the use of *$ M^_Y^e\j^[\ebbem_d]W][dji^Wi[\\_YWYoW]W_dijc[j^_Y_bb_d#h[i_ijWdjIjWf^obeYeYYki flucanazole versus amphotericin in candidemia, no differences in clinical or microbiologic response rates were found, but a greater amount of toxicity was associated with amphotericin (Kontoyiannis et al. Mycoses. 2001;44:125). Other data show generally no differ- ences in efficacy outcomes between high-dose (800 mg) fluconazole compared with placebo and with fluconazole plus amphotericin 9ecfb[j[j^[feij#j[ijWjmmm$iYYc$eh]%9ed]h[iiH[l_[m&.$ (Rex et al. Clin Infect Dis. 2003;36:1221). “Perhaps the only signifi- CE credit at JUNE 2008


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Europäisches Patentamt European Patent Office Office européen des brevets EP 0 989 848 B1 EUROPEAN PATENT SPECIFICATION (51) Int Cl.7: A61K 9/28 of the grant of the patent: 29.09.2004 Bulletin 2004/40 PCT/IB1998/000883 (21) Application number: 98921690.8 (22) Date of filing: 08.06.1998 WO 1998/056360 (17.12.1998 Gazette 1998/50) (54) FILM-COATED TABLET FOR IMP

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