Risk assessment on the impact of environmental usage of triazoles on the development and spread of resistance to medical triazoles in Aspergillus species

In recent years, triazole resistance in human Aspergillus diseases appears to have been increasing in several European countries. However, current data on the prevalence of resistance are based on a small number of studies which are only available from a few European countries. If present, triazole resistance can severely limit treatment options since alternatives, which are only available in intravenous form, have been shown to be associated with more side effects and poorer outcomes. Triazole resistance in Aspergillus spp. can evolve during therapy. Several point mutations, particularly in the cyp51A gene, have been associated with the development of resistance. Increasingly however, resistant isolates are also being detected in azole-naive patients. These isolates tend to have a particular genetic alteration consisting of a 34-base pair tandem repeat in the promoter coupled with a point mutation in the cyp51A target gene. This leads to an amino-acid substitution at codon 98 (TR34/L98H) causing multi-azole resistance. In patients whose Aspergillus isolates have developed resistance during azole therapy wildtype isolates, closely related genetically to the resistant isolates, have regularly been recovered from samples taken before the start of therapy or during an earlier phase. To date however, no isogenic isolate with a wild-type phenotype has been recovered from patients infected with an Aspergillus strain carrying the TR34/L98H genetic alteration. This suggests a possible environmental origin of the resistant fungus. This particular resistance mechanism has been observed most frequently in clinical isolates in the Netherlands where it has also been found in the environment. Moreover, the resistance mechanism has been demonstrated in clinical isolates in eight other European countries. Azole fungicides are widely used for crop protection and material preservation in Europe. They protect crops from disease, ensure yields and prevent fungal contamination of produce. It has been proposed that triazole resistance has evolved in the environment and could be driven by the selective pressure of azole fungicides. Although evidence supporting this hypothesis is growing, the link between the environmental use of azole fungicides and the development of triazole resistance in Aspergillus spp. is not yet proven. Triazole therapy has become the established treatment for invasive aspergillosis and is widely used in the treatment of allergic aspergillosis and chronic pulmonary aspergillosis. Antifungal therapy for invasive pulmonary aspergillosis is usually prescribed for a minimum of 6–12 weeks, but often may need to be continued for months depending on the period of immunosuppression. Treatment of allergic aspergillosis and chronic pulmonary aspergillosis may need to continue for years or even throughout a patient’s lifetime. We estimated the burden of allergic, chronic and invasive aspergillosis using population statistics and published literature. Of the 733 million inhabitants in the European region1 [1], at any one time 2 100 000 patients may be suffering from allergic aspergillosis and 240 000 from chronic aspergillosis, that would be an indication for antifungal therapy. For invasive aspergillosis, we have estimated an annual incidence of 63 250 cases, complicating multiple underlying conditions including leukaemia, transplantation, chronic obstructive pulmonary disease (COPD) and medical intensive care. The inability to treat these patients with triazoles due to multi-azole resistance would have significant impact on patient management and associated health costs. Early and thorough investigation of this emerging public health problem is warranted in order to avoid the development and spread of resistance. This report examines current evidence for the environmental origin of resistance in Aspergillus spp. and makes recommendations for further steps to assess the risks and consequences of the environmental usage of azole derivatives. Improved surveillance of clinical isolates, including antifungal susceptibility testing, is the key to a better understanding of the magnitude of this emerging problem. Furthermore, the diagnosis of Aspergillus diseases needs to be improved and molecular methods allowing detection of resistance in culture-negative specimens must be further developed and implemented in laboratory practice. Finally, further environmental and laboratory studies are needed to confirm the environmental hypothesi

Clostridium-difficile-Ribotyp 027: Epidemiologie und Klinik des erstmaligen endemischen Auftretens in Deutschland

Hintergrund: Im September 2007 trat eine Häufung von ungewöhnlich schwer verlaufenden Clostridium-difficile-assoziierten Infektionen (CDI) in einem Trierer Krankenhaus auf. Es wurde vermutet, dass ein neuer Stamm (PCR-Ribotyp 027) mit diesen Ereignissen im Zusammenhang stehen könnte. Zur Untersuchung der Erkrankungsfälle wurde das Gesundheitsamt Trier auf Einladung des Landes Rheinland-Pfalz von einem Feldteam des Robert Koch-Instituts unterstützt. Ziel der Untersuchung war die Aufklärung und Unterbrechung der vermuteten Infektkette. Methoden: Neben einer retrospektiven Fallsuche von schwer verlaufenden CDI durch Analyse von Patientenakten und Totenscheinen erfolgte eine intensivierte Surveillance von schweren CDI in den Krankenhäusern der betroffenen Region. Dazu wurden bei allen neu auftretenden Verdachtsfällen parallel ein Toxin-A/B-Nachweis und eine selektive Anzucht auf C. difficile durchgeführt. Die Isolate wurden mittels PCR ribotypisiert. Daten zum Krankheitsverlauf und zur Letalität wurden mit einem standardisierten Erhebungsbogen erfasst und statistisch in einer multivariaten Analyse ausgewertet. In dem Index-Krankenhaus wurden Personaluntersuchungen durchgeführt. Ergebnisse: Bis zum 31.1.2008 wurden insgesamt 27 schwere CDI ohne Ribotypisierung und 21 bestätigte Fälle von C.-difficile-Ribotyp-027-Infektionen der Region Trier identifiziert. Im Rahmen der intensivierten Surveillance wurden 399 Patienten untersucht, von denen 76 (19 %) C.-difficile-Isolate angezüchtet werden konnten. Bei 20 Patienten wurde der PCR-Ribotyp 027 nachgewiesen. Insgesamt kam es zu 9 Todesfällen (19 %). Eine bestehende immunsupressive Therapie (Odds Ratio 35,8; 95 %-Konfidenzintervall 2,8 - 464,5) war unabhängiger Risikofaktor für einen letalen Krankheitsverlauf. Schwer verlaufende Infektionen wurden auch bei anderen, Nicht-027-Ribotypen beobachtet. Im Screening vom Krankenhauspersonal des Indexkrankenhauses (n = 161) waren 6 % der Mitarbeiter C.-difficile-Toxin positiv. Diskussion: In dieser Untersuchung konnte erstmalig die endemische Verbreitung von C.-difficile-PCR-Ribotyps 027 in einer Region Deutschlands nachgewiesen werden. Als direkte Konsequenz des Ausbruchs wurde Ende 2007 die Ärztliche Meldepflicht für schwer verlaufende CDI eingeführt. Neben krankenhaushygienischen Maßnahmen ist die kritische Verwendung von Antibiotika eine wichtige Maßnahme zur Verhinderung einer weiteren Zunahme von CDI

Update of Clostridium difficile infection due to PCR ribotype 027 in Europe, 2008.

Outbreaks of Clostridium difficile infections (CDI) with increased severity, high relapse rate and significant mortality have been related to the emergence of a new, hypervirulent C. difficile strain in North America and Europe. This emerging strain is referred to as PCR ribotype 027 (Type 027). Since 2005, individual countries have developed surveillance studies about the spread of type 027.C. difficile Type 027 has been reported in 16 European countries. It has been responsible for outbreaks in Belgium, Germany, Finland, France, Ireland, Luxembourg, The Netherlands, Switzerland and the United Kingdom (England, Wales, Northern Ireland and Scotland). It has also been detected in Austria, Denmark, Sweden, Norway, Hungary, Poland and Spain. Three countries experienced imported patients with CDI due to Type 027 who acquired the infection abroad.The antimicrobial resistance pattern is changing, and outbreaks due to clindamycin-resistant ermB positive Type 027 strains have occurred in three European countries. Ongoing epidemiological surveillance of cases of CDI, with periodic characterisation of the strains involved, is required to detect clustering of cases in time and space and to monitor the emergence of new, highly virulent clones