Antimicrobials 5

What are the two outcomes of therapy? (1)

Outcome 1 - bacteria present, antibiotic used, kills all bacterial organisms - preferred outcome of therapy

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What are the two outcomes of therapy? (2)

Outcome 2 - In the second case, resistance can emerge, suboptimal therapy, patient non-compliance

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Describe features of the bacterial plasmid and chromosome (1)

The bacterial chromosome is the DNA that contains typically all the genes required for cellular maintenance and growth (spreads vertically).

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Describe features of the bacterial plasmid and chromosome (2)

A bacterial plasmid is a DNA molecule that replicates independently of the chromosome and regulates its own replication (can spread horizontally or vertically)

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Describe features of the bacterial plasmid and chromosome (3)

Horizontal spread between cells of the same species or – a key point – between cells of different species.

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Describe features of the structure of one multi-drug resistance plasmid (1)

Complex scenario – costly to the cell to carry but can resist certain antibiotics. This affects a cells’ fitness (where fitness here is the ability of a cell to survive and reproduce in its environment)

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Describe features of the structure of one multi-drug resistance plasmid (2)

Multiresistant plasmids are advantage in places where many antibiotics are used heavily e.g. hospitals, but a disadvantage if no antibiotics are being used. In terms of outcome it’s a trade off - cost of carriage vs benefit?

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What are the implications?

The acquisition of one of these plasmids by a strain previously sensitive is a major concern. One of the first detected was in Japan in 1959 (a strain of E.coli became resistant to multiple antibiotics through acquiring a plasmid from a Salmonella)

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What are the human consequences?

In the European Union, 25 000 people die each year as a result of infection by multidrug-resistant bacteria. In the United States, medical costs attributable to drug-resistant infections are estimated at over US$ 20 billion each year

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Describe features of antibiotic stewardship (1)

Controlling antibiotic resistance and its spread then means having proper antibiotic stewardship in place. The aim is to maintain the effectiveness of currently available agents

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Describe features of antibiotic stewardship (2)

“this involves selecting [the right] drug and optimizing its dose/ duration to cure an infection while minimizing toxicity and conditions for selection of resistant bacterial strains.”

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Describe features of antibiotic stewardship (3)

Inappropriate antibiotic use is common. Countries differ – inappropriate use is 3 x higher in France than Holland. Many other countries likely to be worse. Online sales

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Describe features of antibiotic stewardship (4)

Antibiotic stewardship is a global problem. Here in the UK, antibiotics are tightly controlled. Concern over resistance emerging primarily linked to other countries. Resistance that emerges becomes a problem for all countries though

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Describe features of antibiotic stewardship (5)

Methods - make antibiotics generally less available – easy choices e.g. stopping agricultural use, antibiotic rotation, resistance surveillance, look for new antibiotics (but few new antibiotics coming to market - cost)

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What are the problems other an antibiotic resistance when using antibiotics?

Adverse reactions, drug interactions, cost, impact on host microbes

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Give examples of adverse reactions caused by antibiotics (1)

Aminoglycosides – ototoxicity, nephrotoxicity. Cephalosporins – anaphylaxis. Erythromycin – gastrointestinal intolerance. Nalidixic acid – rashes. Penicillins – rashes, anaphylaxis. Rifampicin – hepatotoxicity. Sulfonamides – rashes

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Give examples of adverse reactions caused by antibiotics (2)

Tetracyclines – gastrointestinal intolerance. Vancomycin – nephrotoxicity

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Describe features of drug interactions (1)

More than one antibiotic at a time can provide a degree of synergy i.e. improved effectiveness that is more than would be achieved by either antibiotic alone

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Describe features of drug interactions (2)

However, for some cases this is inappropriate e.g. increased risk of nephrotoxicity and ototoxicity when aminoglycosides are given with vancomycin

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State feature for the cost of treatment with antibiotics for a day

Ampicillin (£7). Gentamicin (£8). Cefuroxime (£46). Cefotaxime (£56). Imipenem (£67)

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Describe the impact on normal microbiota (1)

Happens to a greater or lesser extent for every antibiotic. Even narrow spectrum antibiotics like penicillin G impact on the microbiota of the mouth. More of a problem for broad spectrum antibiotics

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Describe the impact on normal microbiota (2)

Consequences e.g. Clostridium difficile, other infections can arise e.g. candidiasis (known as thrush). Impact on the genus Bacteroides in the gut microbiota of taking a course of clindamycin

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Describe features of antifungal drugs

Fungi are generally opportunistic pathogens (except dermatophytes). Most common infections - thlete’s foot or vaginal thrush. Systemic mycoses have increased in frequency

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What are the reasons for the rise in systemic mycoses?

E.g. broad spectrum antibiotic use. Immunosuppressant drugs. More immunocompromised patients. More foreign travel. (No clear answers)

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Why are antifungals more difficult to find? (1)

Fungi are eukaryotic organisms (selective toxicity). Antifungal agents more difficult to find that are not too toxic for use in or on humans. Normally, topically applied antifungals are tolerated and so infections can be treated well

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Why are antifungals more difficult to find? (2)

Systemic mycoses (fungal infections) cause many problems however

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What are the targets for selective toxicity in fungi?

Fungal cell membrane/cell wall. Ergosterol (and the synthesis pathway). Fungal wall differs from bacterial cell wall. Ergosterol - functional equivalent of cholesterol in humans. Look for fungal-specific features

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Give examples of antifungals used to treat systemic infections

Amphotericin B, fluconazole and itraconazole

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Give an example of an antifungal used to treat topical infections

Terbinafine

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Describe features of amphotericin B (1)

From the polyene family. Binds to ergosterol in the fungal cell wall membrane. Causes pores in the fungal membrane. This leads to the leakage of fungal metabolites & in turn this is fungicidal (and more complex roles)

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Describe features of amphotericin B (2)

Selective toxicity comes from the preferred binding of amphotericin B to fungal ergosterol over human cholesterol. Broad spectrum fungicidal activity used for systemic infection e.g. with Candida albicans

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Describe features of amphotericin B (3)

Toxicity in humans though is common, with fatalities possible. Specialist advice is needed

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Describe features of fluconazole and itraconazole (1)

Azole drugs. Inhibit a fungal enzyme important in sterol synthesis. Lanosterol 14-α-demethylase. Blocks ergosterol synthesis

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Describe features of fluconazole and itraconazole (2)

The lack of ergosterol and an accumulation of defective sterol precursors inhibits fungal growth and typically leads to fungal death

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Describe features of fluconazole and itraconazole (3)

Azoles are broad spectrum and are used to treat systemic infection. Both azoles are commonly used in systemic Candida infection treatments currently

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Describe features of terbinafine (1)

Interferes with ergosterol synthesis – this time at the stage before lanosterol formation. Terbinafine has broad spectrum antifungal efficacy with variably fungistatic or fungicidal action. Accumulates in human keratin proteins over time

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Describe features of terbinafine (2)

Best choice to treat nail infections at present

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Describe features of malaria (1)

Mosquitoes act as a vector for infection by a range of Plasmodium species of which P. falciparum is the most serious form. Two drugs - quinine to treat falciparum malaria (or mixed or if not known)

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Describe features of malaria (2)

And chloroquine to treat the normally less serious forms (Plasmodium vivax and less commonly still by P. ovale and P. malariae)

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How do chloroquine and quinine work? (1)

The mechanism is not well understood. As part of their growth cycle in humans though, malarial parasites infect red blood cells. Haemoglobin is used by these parasites as a source of amino acids, but the red haeme pigment remains intact

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How do chloroquine and quinine work? (2)

This haem pigment is toxic to these microbes and has to be converted to other compounds if the parasite is to be able to grow

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How do chloroquine and quinine work? (3)

Both quinine and chloroquine are thought to act to prevent this detoxification of haeme in the parasite. This means the haeme remains and as such is toxic ultimately through cell lysis

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Describe features of antimalarials and resistance (1)

Though this has been effective, just like for antibiotics, resistance is emerging and new/ alternative drugs are needed here too. The balance is shifting now towards artemisinin-based combination therapy (ACT) - try to restrict resistance problems

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Describe features of antimalarials and resistance (2)

One common ACT is artemether/ lumefantrine. Mode of action again is not clear. Artemether – may cause free radical damage of parasitic membranes though. Lumefantrine – may inhibit nucleic acid and protein synthesis

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Describe features of viruses (1)

Obligate intracellular parasites. Use the human host’s eukaryotic cell mechanism for replication. This also makes these agents harder to treat

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Describe features of viruses (2)

Their genomes are smaller and more variable. This makes general antiviral targets harder to find. Also means that antivirals tend to be specific for a particular small group of viruses

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Describe features of viruses (3)

Getting functional antiviral agents means a lot of work for a small span of viral diseases

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Describe features of viruses (4)

Antivirals tend also to be targeted at the viruses considered most important

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Describe features of anti-HIV agents

No cure for HIV but a number of drugs slow or halt disease progression. BNF has 22 antivirals (divided into 5 classes)

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Give examples of anti-HIV agents (1)

Nucleoside reverse transcriptase inhibitors - Zidovudine was the first anti-HIV drug introduced, examples include abacavir, didanosine, emtricitabine, lamivudine, stavudine, and tenofovir

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Give examples of anti-HIV agents (2)

Viral protease inhibitors - examples include atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, ritonavir, saquinavir, and tipranavir

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Give examples of anti-HIV agents (3)

Non-nucleoside reverse transcriptase inhibitors - examples include efavirenz, etravirine, nevirapine, and rilpivirine

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Give examples of anti-HIV agents (4)

Inhibitors of HIV fusion to human cells e.g. Enfuvirtide

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Give examples of anti-HIV agents (5)

HIV integrase inhibitors e.g. Raltegravir and elvitegravir

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Describe features of HIV treatment

Treatment of HIV infection is initiated with 2 nucleoside reverse transcriptase inhibitors, either a non-nucleoside reverse transcriptase inhibitor, or a protease inhibitor, or an integrase inhibitor - highly active antiretroviral therapy (improved)

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Describe features of emerging pathogens and change (1)

Importance of diagnostics in understanding what and how to treat. Alternatives to culture. Quantitative PCR today, but increasingly diagnostics via high throughput sequencing

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Describe features of emerging pathogens and change (2)

Importance of responding to changes in infection patterns - environmental change. New pathogens emerging or old ones with new traits - microbiome

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Antimicrobials 5

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