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Hello. I am Dr Tom Chiller, deputy chief of the Mycotic Diseases Branch at the Centers for Disease Control and Prevention (CDC). I am pleased to talk to you about antifungal resistance, a topic that needs more attention.
Although antibiotic-resistant bacterial infections are a widely recognized public health threat, much less is known about the burden and consequences of drug-resistant fungal infections. Since the discovery and widespread use of antibacterial medicines in the 1960s and with increasing numbers of high-risk patients, we have seen the emergence and increased rates of serious invasive fungal infections.
Over the past decade, we have made some progress in combating healthcare-associated bacterial infections. Improving care of central venous catheters and a focus on antibiotic stewardship programs have led to decreases in bloodstream infections caused by resistant bacteria, although we still have a ways to go. However, those decreases have resulted in the fungus Candida becoming the most common cause of healthcare-associated bloodstream infections in many hospitals across the United States.[1] The development of a few classes of antifungal agents has given us the ability to treat these invasive infections, but just like bacteria, some fungi have developed resistance and no longer respond to the antifungals that are used to treat them.
Some types of Candida are becoming increasingly resistant to first-line and second-line antifungals—namely, echinocandins and fluconazole. Approximately 7% of all Candida bloodstream isolates tested at CDC are resistant to fluconazole. Most of these isolates are Candida glabrata, 14% of which are resistant.[2,3] The good news is that CDC’s surveillance data indicate that fluconazole resistance has remained fairly constant over the past 20 years.[3,4,5]
In contrast, echinocandin resistance appears to be on the rise, with 3%-5% of C glabrata isolates being resistant to echinocandin.[2] Isolates tested by CDC before 2004 showed no resistance, so this resistance has emerged after the echinocandins became widely used. Today, the prevalence of echinocandin resistance is more than 10% at some hospitals and is continuing to increase.[6,7]
Finally, a growing concern is the presence of multidrug-resistant Candida infections (those that are resistant to both fluconazole and echinocandins), because few treatment options remain, other than amphotericin B. Not surprisingly, there is growing evidence to suggest that patients who have drug-resistant candidemia have worse outcomes than patients who have susceptible infections.[8,9]
Some studies have indicated that antibacterials may also contribute to antifungal resistance; this could occur for a variety of reasons, one of which is that antibacterials reduce bacteria in the gut and create favorable conditions for Candida growth.[10] It’s not yet known whether decreasing the use of all or certain antimicrobial agents can reduce Candida infections, but appropriate use of antibacterials and antifungals is one of the most important factors in fighting drug resistance.
Although most of the resistance that we are concerned about is in Candida species, resistance in other fungi also occurs. I want to highlight the emergence of azole resistance in Aspergillus fumigatus. Since its approval in 2002, the antifungal agent voriconazole has been the primary treatment for invasive aspergillosis. However, more than a decade ago, several countries in Europe began seeing an increasing amount of azole-resistant Aspergillus fumigatus.
Studies in Europe suggest that resistance in Aspergillus may be partially driven by the use of agricultural azoles, which protect crops from fungal diseases.[11,12] Prevalence as high as 30% has been seen in some hospitals in Europe.[13] Patients with these resistant isolates had a much higher mortality—closer to 90%, compared with approximately 40% for patients with susceptible strains.[14] Resistant isolates have been now also identified in the Middle East, Asia, Africa, South America, and most recently in the United States.
The Mycotic Diseases Branch at the CDC is collecting isolates of A fumigatus for US surveillance of resistance. We encourage clinical labs to send samples to CDC. Please refer to the Web resources below for instructions on submitting isolates.
In summary, we encourage hospital executives and infection control staff to:
- Assess antifungal use as part of their antibiotic stewardship programs; and
- Ensure adherence to guidelines for hand hygiene, prevention of catheter-associated infections, and environmental infection control efforts.
We encourage physicians and other hospital staff to:
- Prescribe antifungal medications appropriately;
- Ask their laboratories to routinely determine the species of every Candida sterile body site isolate if it is not reported, and if C glabrata is found, consider ordering antifungal susceptibility testing;
- Document the dose, duration, and indication for every antifungal prescription;
- Be aware of local antifungal resistance patterns; and
- Be active in efforts within your hospital to improve antifungal prescribing.
Medical and Patient education videos
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Title
Description
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Video interview with patient with an aspergilloma and chronic pulmonary aspergillosis, diagnosed after coughing up blood who later developed azole resistance on voriconazole. Patient History This patient had severe kyphoscoliosis as a child with insertion of spinal rods in early adulthood. She is a life-long non-smoker. She first presented in 2001 with an irritating cough and several treatments with antibiotics failed to alleviate it. After 2 years the cough worsened and she developed a fever. She was investigated but results were inconclusive. She then coughed up large amounts of blood (haemoptysis) and had a very severe bleed which was treated with embolisation and oral tranexamic acid. She continued to cough and produce green sputum and lose weight. Aspergillus precipitin titre was high and she was initially diagnosed with chronic pulmonary aspergillosis with one cavity containing an aspergilloma. Treatment with itraconazole did not alleviate her symptoms (despite adequate blood levels) and she started voriconazole and considerable improvement was seen initially and she gained some weight. She continued voriconazole for 2 years. However her Aspergillus titre remained high and her cough continued. Further tests showed her trough plasma levels of voriconazole to be more than 0.5mg/L, however isolates revealed that her Aspergillus fumigatus was drug resistant to itraconazole, voriconazole and posaconazole. The patient has now commenced amphotericin B therapy. We thank the patient for kindly providing this interview.
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Video Interview with long-term ABPA patient who coughed up large sputum plugs. This patient had several episodes of pneumonia and developed bronchiectasis after diagnosis for a collapsed left lung. She was treated with inhaled corticosteroids and bronchodilators and progressed well. She was later diagnosed with possible ABPA (aspergillus precipitins were negative), after producing a large sputum plug which was positive for aspergillus hyphae. Her main symptoms were severe coughing with production of clear sputum. In December 04 her coughing became very severe and she coughed badly for 7 months. Her treatment was modified to include itraconazole (400mg/day solution- she required a higher dose than normal as she was taking other medication which reduced it’s absorption). 8 weeks later she started very severe bouts of coughing over 3 days – which produced a large number of small mucous plugs, finally a very large plug (resembling a piece of grey chewing gum) was coughed up. After this, the coughing subsided and the patient felt well and a chest X-ray at this time showed a significant improvement with clearing of shadows from the right lower lobe. Itraconazole levels have been reduced to 300mg per day and steroid intake reduced. The patient remained well in July 2007. We thank the patient for kindly providing this interview.
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Video interview with patient with childhood asthma and ABPA, who showed a marked improvement in her ABPA and asthma when she commenced nebulised Amphotericin B. Her medication was changed from itraconazole at this time to allow for her to try for pregnancy. Two types of nebuliser – VentStream and the Pari LC system are discussed in the interview. Her condition is still stable using inhaled amphotericin B. We thank the patient for kindly providing this interview
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Video interview with this patient with childhood asthma and ABPA. After persistent chest infections and continuous steroids and a bad productive cough, Aspergillus was cultured from sputum in 2002. After successfully taking itraconazole, the patient developed peripheral neuropathy (tingling and loss of sensation) in the hands. After stopping itraconazole – persistent chest infections requiring antibiotics and prednisolone were common. The patient at this point had a high IgE level and positive RAST tests. Voriconazole was then prescribed – which has successfully treated the aspergillus infection – no steroids are required and the cough is greatly reduced with the patient feeling well. However an unfortunate side effect of voriconazole has been a photosensitive rash on any exposed skin. Despite using complete sunscreen – the rash continues. The patient is continuing to take voriconazole.
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Video interview with patient JW with childhood asthma and subsequent ABPA, describes his experience with 3 different azole types of antifungal drugs and who showed a marked improvement when taking posaconazole.
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Video interview with Catherine, who developed severe invasive aspergillosis following a kidney transplant. Fortunately, she was successfully treated with antifungal drugs. We thank the patient for kindly providing this interview and Pfizer for supporting the production of this video.
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