and have excellent activity against Candida, but they all suffer from the same pharmacokinetic setback: lack of an oral formulation. They have considerably fewer drug interactions than azoles, are safer than polyenes, and have great activity against fluconazole-resistant yeasts. Mechanism of Action Echinocandins inhibit beta-1,3-D-glucan synthase, the enzyme responsible for the production of beta-1,3-D-glucan, a vital component of the cell wall of many fungi. They are only active against fungi that are dependent this type of glucan. Spectrum Good: Candida albicans, Candida glabrata, Candida lusitaniae, Candida parapsilosis, Candida tropicalis, Candida krusei, Aspergillus species Moderate: Candida parapsilosis, some dimorphic fungi, Mucorales (in combination with amphotericin B) Poor: most non-Aspergillus molds, Cryptococcus neoformans Adverse Effects Echinocandins have an excellent safety profile. They can cause mild histamine-mediated infusion-related reactions, but these are not common and can be ameliorated by slowing the infusion rate. Hepatotoxicity is also possible with any of these agents, but this is not common. www.allmedicalbooks.com Important Facts Differences among the echinocandins are minor and mostly pharmacokinetic. Caspofungin and micafungin are eliminated hepatically by noncytochrome P450 metabolism, while anidulafungin degrades in the plasma and avoids hepatic metabolism. Despite this unique method of elimination, it is not completely devoid of hepatotoxicity. Echinocandins have excellent fungicidal activity against Candida, but against Aspergillus species they exhibit activity that is neither classically cidal nor static. Instead, they cause aberrant, nonfunctional hyphae to be formed by the actively growing mold. The echinocandins are only modestly active against molds, but do appear to substantially enhance the effects of other antifungals against these pathogens. A randomized controlled trial of voriconazole with or without anidulafungin in invasive aspergillosis showed a trend toward reduced mortality among patients receiving combination therapy (the difference was not statistically significant\u2014p = 0.07\u2014but given the low toxicity of echinocandins many clinicians refuse to submit to the tyranny of the p- value and advocate for the use of this combination therapy). The echinocandins may also enhance the efficacy of liposomal amphotericin B against Mucorales infections, based on in vitro and limited clinical data. Though drug interactions with the echinocandins are minor, you should be aware of some of them, particularly with caspofungin and micafungin. Be careful when you use them with the immunosuppressants cyclosporine (caspofungin) and sirolimus (micafungin). What They\u2019re Good For Echinocandins are drugs of choice for invasive candidiasis, particularly in patients who are clinically unstable or if there is a risk the infection is caused by an azole-resistant species. They are also useful in the treatment of invasive aspergillosis but do not have the level of supporting data that voriconazole and the polyenes do for this indication. All of them are used for esophageal candidiasis, and some are used in prophylaxis or empiric therapy of fungal infections in neutropenic patients. Some clinicians will add an echinocandin to voriconazole (for Aspergillus infections) or an amphotericin B formulation (versus Mucorales) in an attempt to increase likelihood of cure for these infections. www.allmedicalbooks.com Don\u2019t Forget! Echinocandins are great drugs for invasive candidiasis, but they are not cheap and IV therapy can be inconvenient. After beginning empiric therapy with an echinocandin, consider transitioning your patient to fluconazole if he or she has a susceptible strain of Candida and no contraindication to fluconazole. www.allmedicalbooks.com PART 5: Antiviral Drugs www.allmedicalbooks.com 33: Antiviral Drugs Introduction to Antiviral Drugs The term virus has interesting meanings in popular culture: it is commonly used to describe something that has or can spread quickly from person to person, such as a computer virus or a \u201cviral\u201d video, a video that gains quick popularity through Internet or e-mail sharing. This usage represents a basic understanding of the high transmissibility of many respiratory viruses, such as influenza and the rhinoviruses that cause the common cold. However, many less-understood viruses, particularly those that cause chronic disease, can be confusing. The world of viruses is very different from that of prokaryotes and eukaryotes. Viruses are dependent on cells to replicate and cannot perpetuate without them. They are considerably smaller than eukaryotes and even much smaller than most prokaryotes, though they vary widely in size (see Figure 1\u20132). They are relatively simple organisms compared with prokaryotes or eukaryotes, but they outnumber all other life forms on earth. Scientists have debated for many years about whether viruses are life forms or not, and no clear consensus yet exists. The understanding of how they interact with and shape the existence of living cells, however, has increased greatly since they were described by Louis Pasteur in the late nineteenth century. An in-depth discussion of the structure of viruses is beyond the scope of this text, but a basic understanding of viruses will help you understand the actions of antiviral drugs. Viruses are highly diverse, though nearly all of them share a few common characteristics. Many are covered by a viral envelope as their outmost layer, composed of elements of the host cell membrane, endoplasmic reticulum, or nuclear envelope. This layer covers the capsid, a shell composed of identical building blocks of capsomeres. The capsid protects the viral nucleic acid, which is either DNA or RNA but not both (as in www.allmedicalbooks.com cells). The DNA or RNA can be either single- or double-stranded. Finally, many viruses contain enzymes that catalyze reactions that lead to their replication or cell entry. Viruses cannot synthesize their own components to replicate\u2014they are dependent on host cellular processes for all synthetic functions. Individual complete particles of virus are termed virions. The specific steps of the viral life cycle differ from virus to virus, but they follow the same basic pathway. Viruses spread from host to host through various means, some through direct inhalation, some through direct fluid exchange, some through vectors such as mosquitoes. Once a virus reaches its target cell, it has to penetrate the cell membrane. Specific receptors on the cell and viral surfaces often facilitate this process. The virus then uncoats and releases its genetic information from the capsule into the host cell. The host cell reads the genetic material and begins to translate it into viral proteins. How exactly this proceeds depends on the form in which the genetic material exists in the virus. In some cases, the genetic material is encoded as RNA. For some RNA viruses, host cell ribosomes translate the RNA into proteins. In the group of viruses known as retroviruses, the RNA genetic material is first translated into DNA (via an enzyme known as reverse transcriptase) before integrating into the host genome. For these viruses or those viruses whose genome is already encoded as DNA, transcription into messenger RNA occurs, followed by translation into protein. Once the pieces of the puzzle are built, the viral enzymes assemble them into complete virions and they are finally released from the cell. The available antiviral drugs are aimed at various steps in this cycle. Some are aimed at specific receptors against specific viruses (such as influenza), and some are aimed at more general steps to attack multiple viruses. The pharmacotherapy of viral infections is different from that of bacterial infections.