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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDICAL FRONTIERS - 19th European Congress of Clinical Microbiology and Infectious Diseases

Helsinki, Finland / May 16-19, 2009

Impact of Candidemia

The Multicentre European Study carried out in 198 intensive care units (ICUs) across 24 countries showed how strongly yeasts are implicated in severe sepsis and septic shock. The study revealed that in 2006, some 15.2% of all episodes were caused by yeasts, 70% being Candida albicans and 22% by non-albicans species. Importantly, C. glabrata is now the second most common Candida isolate in Europe, accounting for approximately 14% of invasive fungal infections, noted Prof. Olivier Lortholary, Hôpital Necker-Enfants Malades, Université Paris Descartes, France.

The impact of candidemia is far from trivial, as he also noted. Based on French data, investigators reported mortality rates of 38.5% among patients who developed candidemia, 59% of patients dying less than eight days from infection onset. “Recent exposure to fluconazole significantly influenced the development of fluconazole-resistant fungemia,” Prof. Lortholary added—not an uncommon resistance, since 17% of one survey of Candida isolates in France were found to be resistant to fluconazole. Approximately 50% of C. glabrata isolates were resistant to fluconazole in the same survey.

In contrast, the echinocandins have demonstrated excellent in vitro activity against Candida species, including fluconazole-resistant isolates. Regardless of whether European Committee on Antibiotic Susceptibility Testing (EUCAST) or Clinical Laboratory Standards Institute (CLSI) break-points were used, investigators found that caspofungin was consistently active against all species of Candida, including C. glabrata, Prof. Lortholary observed. Regarding management strategies, Prof. Lortholary reminded delegates that their therapeutic strategy must be based on an accurate diagnosis using conventional mycology accompanied by histology when necessary.

Physicians also need to consider the local epidemiology of the Candida species and weigh the risk that they are dealing with a non-albicans vs. a C. albicans infection. Potential non-albicans infections need to be further divided into either C. glabrata or C. krusei vs. others. “We also have to consider patient characteristics,” Prof. Lortholary continued. These factors include the presence or absence of renal or liver failure or neutropenia, whether the infection is occurring in a child or in an elderly person, whether the patient has recently received another antifungal, especially fluconazole, and whether the organism colonizing the patient is known. The nature of the infection must also be considered (candidemia, central nervous system, eye, bone) along with individual antifungal properties. Based on IDSA 2009 guidelines for the management of invasive candidiasis, the primary treatment for candidemia in non-neutropenic patients should now be either fluconazole or an echinocandin, a recommendation that carries the highest level of evidence to support it, Prof. Lortholary noted.

The echinocandins are also favoured for moderately severe to severe illness, for patients with recent fluconazole exposure and for patients with or suspected to have C. glabrata infections. Liposomal amphotericin B, conventional amphotericin B or voriconazole may be considered as alternative treatments for non-neutropenic patients with candidemia. The same recommendation was made for the empiric treatment of suspected candidiasis in the same patient group.

For neutropenic patients, primary therapy should be either an echinocandin or liposomal amphotericin B, while either caspofungin-not echinocandins in general-liposomal amphotericin B or voriconazole are recommended for the empiric treatment of suspected candidiasis in this patient group.

Figure 1. IDSA 2009 Guidelines for Invasive Candidiasis

EORTC 65041 Study

Based on an early comparative trial of voriconazole vs. both conventional and liposomal formulations of amphotericin B, voriconazole is indicated as first-line treatment for invasive aspergillosis (IA), with liposomal amphotericin B being reserved as an alternative in patients who cannot tolerate voriconazole.

In an effort to assess the efficacy and safety of the echinocandins in the primary treatment of IA, investigators launched the EORTC 65041 phase II study, in which patients with either haematological malignancies or autologous or allogenic stem cell transplant recipients received caspofungin 70 mg on day 1 followed by a 50-mg maintenance dose. If patients weighed >80 kg, they received a maintenance dose of 70 mg/day. “We also wanted to look at the activity of the drug in the disease so only patients with proven or probable IA remained in the study,” noted Prof. Johan Maertens, Associate Professor of Hematology, University of Leuven, Belgium. Proven or probable IA was defined as 100% positive mycology; patients were not recruited into the study on the basis of a Halo sign alone.

The primary outcome was the proportion of patients with a complete or partial response at the end of therapy. Among patients with a hematological malignancy (n=61), 75% had uncontrolled underlying cancer at baseline, Prof. Maertens indicated, and the vast majority had some sort of leukemia. After a median of 15 days of therapy, 33% of this particular cohort had achieved a complete or partial response at the end of therapy (EOT) while disease stabilized in another 15%. “None of the baseline characteristics affected EOT response,” Dr. Maertens indicated.

In contrast, survival at day 84 was affected by baseline remission status, with only 40% of patients being alive at day 84 who were not in remission at study entry vs. 93% of patients who were in remission. “The higher the Karnofsky score, the better the outcome,” Prof. Maertens added, with both success at the EOT and survival at week 12 being significantly better for those with a Karnofsky score >60 than those with a score of <50.

In the allogenic stem cell transplant cohort, the median duration of therapy was longer at 24 days, and significantly fewer patients were not in remission (22%) at study entry than in the first cohort. All responses were partial responses which were achieved in 42% of the group. The favourable response rate at day 84 was 33%. “None of the baseline characteristics was predictive of success,” Prof. Maertens noted. Survival at week 6 among the allogenic stem cell transplant group was 79%.

There were no discontinuations due to treatment-related adverse events and no drug-related serious AEs. “Caspofungin exhibited an excellent safety profile and response rates were comparable to those obtained with first-line therapies in similar settings,” Prof. Maertens concluded.

SMART Study: Surveillance of Resistance

Based on surveillance data from both the global SMART study and the Europe-specific EARSS database, “There has been a striking increase in extended-spectrum beta-lactamase [ESBL]-producing Escherichia coli in recent years,” noted Dr. David Paterson, Professor of Infectious Diseases, University of Pittsburgh Medical Centre, Pennsylvania.

For some time, Turkey and some of the eastern European countries had very high resistance rates to the third-generation cephalosporins. Now those patterns are being seen in Italy as well as some of the Baltic countries. Moreover, over half of E. coli bloodstream isolates are now resistant to the fluoroquinolones in some European countries.

In China, SMART data show that there has been a “dramatic reduction” in E. coli susceptibility to the third-generation cephalosporins to the point where now only 44% of E. coli isolates remain susceptible. “With the fluoroquinolones, the situation is even worse with only 30% of [E. coli] isolates being susceptible,” added Dr. Paterson. Similarly, in India, only 21% of E. coli isolates tested in 2007 remained susceptible to the third-generation cephalosporins and only 17% to the fluoroquinolones.

Conversely, there has been “relative stability” in the in vitro activity against E. coli for both the aminoglycosides and the carbapenems. For Klebsiella pneumoniae, trends are similar to what is being seen with E. coli resistance to both drug classes. Investigators are also concerned about the emergence of carbapenem resistance among the Acinetobacter spp and Pseudomonas aeruginosa, especially in Asia where the susceptibility of the carbapenems has significantly deteriorated.

However, at least in most of Europe, carbapenem-resistant K. pneumoniae is still largely absent. Surveillance shows that between 10% and 25% of pseudomonal isolates are now resistant to piperacillin/tazobactam in most European countries—“the implication being that we are losing our anti-pseudomonal drugs to Pseudomonas,” Dr. Paterson remarked. At the same time, there is a considerable degree of fluoroquinolone resistance to Pseudomonas as well, he added.

Optimal Treatment of Community-acquired Infections

The emergence of gram-negative-resistant organisms is the most compelling reason for physicians to approach the treatment of community-acquired infections with an eye to both the local epidemiology of prevalent organisms and an appreciation of how individual risk factors influence the likelihood that patients will harbour a resistant organism. In general, for high-risk patients for whom empirical therapy is critical, a broad-spectrum antimicrobial is usually prescribed and then treatment can be de-escalated to a narrow-spectrum antimicrobial once the etiology of the infection is known.

Figure 2. Risk of ESBL Among Patients with Comm
: Extrapolated Data

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Based on his own study, Prof. Jesus Rodriguez-Baño, University of Seville, Spain, demonstrated that the risk of acquiring a community-acquired ESBL-producing E. coli infection was highest among patients with recurrent urinary tract infections, previous antimicrobial use and diabetes.

Within specific types of healthcare contacts, the risk of acquiring the same infection was highest for those who had undergone an invasive urinary tract procedure, while for antimicrobial use only, the risk was highest for cephalosporin use. Extrapolating their data, Spanish investigators then determined that the risk of an ESBL organism being present among patients with community-acquired bacteremia was virtually nil when patients had no risk factors, still low at <5% when they had only one risk factor, but that the risk rose to approximately 10% when patients had two risk factors and to >20% when they had more than two.

Therefore, Prof. Rodriguez-Baño reasoned, when a patient presents with a mild to moderate, community-acquired intra-abdominal infection and they have no discernable risk factors for an ESBL-producing E. coli infection, they may be treated with a traditional protocol using either amoxicillin-clavulanate or a second- or third-generation cephalosporin/metronidazole.

If, however, they present with severe sepsis and are at high risk for early mortality, of if they have more than one risk factor for an ESBL-producing E. coli infection, they should be considered for ertapenem. Prof. Rodriguez-Baño also noted that fear of ESBL-producing organisms is one of the leading drivers of carbapenem use in their own hospitals. Consequently, he felt that physicians should try to preserve antimicrobials that will remain active against nosocomial infections, including piperacillin/tazobactam, imipenem and meropenem as a last resort.

Questions and Answers

The following section is based on interviews with Prof. Olivier Lortholary, Hôpital Necker-Enfants Malades, Université Paris Descartes, France and Dr. David Paterson, Professor of Infectious Diseases, University of Pittsburgh Medical Centre, Pennsylvania.

Q: Given the shift towards non-albicans fungal infections, would you now switch to up-front therapy with an echinocandin and then perhaps de-escalate if the organism proves to be susceptible to recommended front-line agents?

Prof. Lortholary: In our ICUs in France, the situation is changing so first-line prescription of an echinocandin either in the ICU or in hematology is increasing. My personal opinion is that I would favour the use of an echinocandin for first-line therapy and then switch if we knew the organism was an albicans provided the patient had not previously received an azole.

Q: Was there a reason why the guidelines recommended caspofungin and not the echinocandins in general for neutropenic patients with suspected candidiasis?

Prof. Lortholary: The recommendation was based on experience with caspofungin as empiric therapy in neutropenic patients. This use in particular was emphasized as the other echinocandins have not been studied in this setting.

Q: Is Canada also seeing an increase in ESBL-producing E. coli?

Dr. Paterson: Pitout et al. have shown that there certainly has been an increase in ESBL-producing E. coli in Canada.

Q: Does resistance always translate into clinical failure?

Dr. Paterson: I think it depends on the type of infection. If a patient has a bloodstream infection and they are really sick, there is no doubt that resistance does affect mortality. But if the infection is just in the urine, where you can get quite high concentrations of antibiotics anyway, resistance might not make a difference to mortality although it is likely to prolong morbidity.