Dosages Increase with Infections
The meningitis outbreak and resulting advice to use AmB in combination with voriconazole is likely to aggravate concerns, most recently voiced in a study published last month in Nature Scientific Reports about the rise seen over the past 20 years in the frequency of invasive fungal infections. Those infections have been followed by corresponding increases in illnesses and deaths —and more worrisome, to increased dosages in the use of AmB, following by increased resistance to the antifungal and complications such as kidney failure.
At such doses, about half of patients suffer from some form of kidney poisoning; 15% of patients on AmB in a 1999 study (Wingard, et. al., Clinical Infectious Diseases) were forced into kidney dialysis. Less commonly but more frighteningly, AmB use can result in complete failure of the kidneys, liver, or heart. Kidney toxicity explains why two decades ago the lipid forms of AmB were developed, but they only reduce nephrotoxicity.
“The blood vessels in the kidney and the cell membranes of the kidney tubules seem to be particularly susceptible to amphotericin; the drug damages the membranes of these cells and causes changes to the body’s sodium levels. Both directly and indirectly, therefore, the drug causes a constriction of the renal blood vessels and thereby makes the kidney less efficient in removing unwanted waste from the blood,” the study’s corresponding author, David Barlow, Ph.D., of King’s College London’s (KCL) Institute of Pharmaceutical Science, remarked.
Dr. Barlow, who is head of KCL’s pharmaceutical chemistry teaching section and also a reader in computational & molecular biophysics, joined two research colleagues from his institute and from France’s Institut de Laue Langevin in the study, which featured results from neutron diffraction studies of AmB’s incorporation within lipid-sterol membranes.
They noted that combating the problems associated with AmB through development of new antifungal drugs or antimycotics will require detailed knowledge of the fungus’ molecular mechanism, which remains to be understood.