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Antibiotics and antibiotic resistance (21/01/22 19:39:30) Reply
    Our present pandemic - bad as it is, with millions of victims - is a benign one compared to the horror called the Black Death
    "causing the death of 75–200 million people in Eurasia and North Africa, peaking in Europe from 1347 to 1351"
    https://en.wikipedia.org/wiki/Black_Death
    aused by the bacterium Yersinia Pestis
    https://en.wikipedia.org/wiki/Yersinia_pestis

    It is still around
    (https://www.cdc.gov/plague/healthcare/clinicians.html)
    " DO NOT WAIT FOR DIAGNOSTIC TEST RESULTS IF YOU SUSPECT PLAGUE

    The decision to initiate antibiotic therapy for plague should be made based on clinical signs and symptoms and a careful patient history. A recent flea bite, exposure to areas with rodents, or contact with a sick or dead animal are risk factors for plague in endemic areas.

    A confirmatory diagnosis can be established later using specialized laboratory tests. Never delay or withhold treatment pending the receipt of laboratory test results.
    .....
    If patients with pneumonic or septicemic plague are not given specific antibiotic therapy, the disease can progress rapidly to death."

    This was just a preamble to the real thing: the matter idicated in the headline. Antibiotics - those wonder drugs - are threatened by Darwinian mechanisms: The ability to withstand antibiotics, learning to cope with antibiotics: it's in the genes of the bacteria, and it can be transferred p2p between bacteria, related or nonrelated.

    I don't think Yersinia pestis is a problem right now, but there are plenty of others.

    So: What to do? Every few years there is at least a press release from some university trumpeting the discovery of a new antibiotic from some bacterium or mold. But then there is silende. I suspect some of these substances are just rediscoveries or substances that have been found to be useless. Going to nature for more candidates might not be useful any more.

    A taste of the complexity might be seen here
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4888801/

    But don't let that discourage you.

    The by far most valuable class of antibiotics is the beta lactam class. They work by inactivating one or more key enzymes that are essential for building cell walls of bacteria. Resistance mechanisms are plentiful, but if you have an inventor asking for money to develop a set of candidates for a class C betalactamase inhibitor based on a proof-of-concept molecule, then perhaps. If you read the article, you may see why.

    So: How to cope?
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Moralism and antibiotic resistance (22/01/22 13:43:51) Reply
    When antibiotics are used, some selection of resistant variants is inevitable. Some are harmless. Others are worrying. Rifampicin (as part of combination regimes) for tuberculosis is one.

    "The drug rifampicin (Rif) was initially developed in the 1960s, through modification of the natural isolate rifamycin B1. This novel, orally available, semi-synthetic agent, was shown to block the DNA-dependent RNA polymerase transcription initiation complex1, which confers its bactericidal activity. Since its discovery, Rif has become part of the backbone treatment for mycobacterial tuberculosis (TB) and leprosy infections and remains their most effective therapeutic available today2,3. The introduction of Rif to the TB multi-drug regimen reduced treatment time from 18 to 9 months4, which was further shortened to 6 months through introduction of pyrazinamide5. Inclusion of Rif as part of the multi-drug therapy regimen for leprosy in the mid-80 s reduced initial disease incidence from over 5 million to less than 200,000 cases in the two following decades6. Clinically, Rif is also reserved as a last line drug in multi-drug resistant (MDR) infections from Staphylococcus aureus (methicillin-resistant S. aureus; MRSA)7 and Pseudomonas aeruginosa8, among other infections7.

    Following its introduction, resistance in the mycobacteria M. tuberculosis and M. leprae has developed as a direct result of evolutionary purging upon extended Rif exposure, primarily through missense mutations in drug targets or activating enzymes9. This phenomenon affected over half a million tuberculosis cases in 2018, of which, 78% were also classified as MDR-TB2."

    https://www.nature.com/articles/s41598-020-74648-y
e

Ah yeah, the moralism (23/01/22 21:49:16) Reply
    There is a lot of pressure here. The public wants quick fixes, and antibiotics, on good indications, do deliver quick fixes - except for mycobacterial infections. So there is overuse when people are heard and doctors do not want to lose business by refusing. The moralists say: Use less. Most infections are self-limited even without antibiotics. It's hard to resist.

    In countries and systems with little resistance, that attitude might be useful in preserving the simpler antibiotics, like phenoxymethylpenicillin. In countries with much resistance, simple antibiotics are useless, and overuse of more advanced ones will accelerate their demise.

    Southern Europe are much worse off than northern Europe.

    So it is a question of attitude, no doubt. But - there is also an urgent need for a lot of new antibiotics and for radical and new strategies for diagnosing serious infections, and radical new and restrictive policies that are actively enforced. For that we need responsible politicians. In Europe we will have to rely on the EU commission. Elsewhere - dream on.

    Maybe - I hate to say it - China.
e

Hah (30/01/22 20:10:20) Reply
    (note to self - you're welcome to peep)
    I haven't updated myself on this topic for at least five years. So here's some help

    https://pubmed.ncbi.nlm.nih.gov/33806604/

    Cefiderocol! Nice.
    Relebactam
    Vaborbactam

    "Meropenem-vaborbactam has recently demonstrated higher clinical cure rates versus best available therapy for the treatment of carbapenem-resistant Enterobacteriaceae (CRE), as well as for HABP and VABP. The safety and tolerability of imipenem-relebactam and meropenem-vaborbactam has been reported in various phase I pharmacokinetic studies and phase II and III clinical trials. Both combinations appear to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date. In conclusion, relebactam and vaborbactam serve to broaden the spectrum of imipenem and meropenem, respectively, against β-lactamase-producing Gram-negative bacilli. The exact roles for imipenem-relebactam and meropenem-vaborbactam will be defined by efficacy and safety data from further clinical trials."
e

Re: Hah (04/02/22 19:21:03) Reply
    So there is work on it. New beta lactamase inhibitors breathe new life into old heroes.

    I'm eagerly waiting for new beta lactam antibiotics to be orally effective against tuberculosis. Meropenem-clavulanic acid have shown effect experimentally (years ago), but meropenem must be given intravenously and is really only suitable for intensive care.

    I wish someone would give me decisive power on the choice between hypersonic missiles + nuclear subs and improved beta lactams.
e

But (05/02/22 14:00:55) Reply
    Beta lactam antibiotics active against Mycobacterium tuberculosis: AFAIK there is at least one special requirement to be met: They must penetrate the thick lipid-rich bacterial wall - so simple penicillins will not do.
    The downside to this is that they are likely to be broad-spectrum antibiotics, so the ecological footprint of a treatment course is likely to be heavy - heavier than the standard anti-TB therapy. Today's and yeaterday's standard therapy: Rifampicin, isoniazid, ethambutol and pyrazinamide - well, the latter three of the four of them are specific against M. tuberculosis. So they do not induce resistance in the normal bacterial flora. Rifampicin is by far the most effective, but just one single mutation, and the drug is inactive.

    So I withdraw my wish for an anti-TB beta lactam. I don't believe it is practical or useful. Sorry.
e


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