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7: Antimicrobial Drugs - Biology

7: Antimicrobial Drugs - Biology


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An antimicrobial is an agent that kills microorganisms or stops their growth. For example, antibiotics are used against bacteria and antifungals are used against fungi

Thumbnail: Staphylococcus aureus - Antibiotics Test plate. Image used with permission (Public Domain; CDC / Provider: Don Stalons).​​​​​​


List of 8 Important Antibacterial Drugs | Drugs | Pharmacology

List of eight important antibacterial drugs:- 1. Sulfonamides 2. Trimethoprim 3. Co-Trimoxazole 4. Nitrofurantoin 5. Methenamine 6. Metronidazole 7. Quinolones 8. Fluoroquinolones.

Antibacterial Drug # 1. Sulfonamides:

Sulfonamides are rarely used, because of increasing bacterial resistance. They have been replaced by antibiotics, which are generally more potent and less toxic.

Sulfonamides are bacteriostatic. They, being structural analogues of para-amino benzoic acid (PABA), are taken up by bacteria instead of PABA (competitive inhibition) and prevent bacterial folic acid synthesis, which is necessary for their multiplication. Susceptible bacteria are those, which need PABA, because they are incapable of using folic acid directly. Human cells use exogenous folic acid and thus, a lack of PABA does not affect them.

Sulfonamides, with exceptions, are readily absorbed following oral administration. They are widely distributed into body fluids and cross blood brain barrier to enter cerebrospinal fluid. They are metabolized by acetylation in the liver, which negates the antibacterial activity, but not the adverse effects. The acetylated fraction is very poorly soluble and tends to precipitate in the urine, unless an adequate flow in maintained.

Antibacterial spectrum:

Sulfonamides are effective against a fairly wide range of bacteria, which includes gram-positive bacteria and some gram-negative bacteria such as E. coli (the organism responsible for acute urinary tract infection), Haemophilus influenza and Shigella. Other susceptible organisms include B. anthrax, Nocardia, Toxoplasma.

Sulfonamides are rarely used in urinary tract infections and chronic bronchitis, provided the causative organisms are susceptible and for the prophylaxis of rheumatic fever. Sulfadimidine (1 g every 6 hours) or long acting sulfametopyrazine (2 g once weekly) are the preferred sulfonamides. Silver sulfadiazine is applied locally as a cream to prevent infections in burns. Sulfasalazine is used for ulcerative colitis, Crohn’s disease and rheumatoid arthritis.

Severe side effects of sulfonamides are rashes, Stevens-Johnson syndrome, renal failure, bone marrow depression and agranulocytosis. Sulfonamides are contraindicated in hepatic or renal failure and in porphyria.

Antibacterial Drug # 2. Trimethoprim:

Trimethoprim is chemically related to the antimalarial drug pyrimethamine. It is bacteriostatic in action and acts by interfering with folic acid metabolism at the phase when folic acid is converted to folinic acid to build up the cell nucleus. Trimethoprim selectively inhibits the enzyme dihydrofolate reductase which converts the folic acid to folinic acid resulting in the death of the bacterial cell. The pharmacological aspects of trimethoprim are very similar to sulfonamides. Trimethoprim can be used alone for urinary and respiratory infections, prostatitis, shigellosis and invasive salmonella infection.

Antibacterial Drug # 3. Co-Trimoxazole:

It is a combination of a sulfonamide (sulfamethoxazole) and trimethoprim in the proportion of 5 parts to 1 part and is bactericidal because of their synergistic activity. It has excellent tissue penetration, including bone, prostate and brain. Co-trimoxazole is the drug of choice in Pneumocystis crainii and Nocardia infection. It can also be used in acute exacerbation of chronic bronchitis, urinary tract infections and acute otitis media in children, provided the causative organism is susceptible. It is given in doses of500 mg twice daily. Side effects are essentially that of sulfonamides.

Antibacterial Drug # 4. Nitrofurantoin:

Nitrofurantoin has a fairly wide antibacterial spectrum against gram-negative bacteria responsible for urinary tract infections. It is well absorbed and is considerably concentrated in the urine. It is bactericidal and is used in uncomplicated lower urinary tract infections (especially in vancomycin-resistant Enterococcus faeciumi) except those caused by Proteus and P. aeruginosa. Prolonged therapy with nitro-furantoin should be avoided, as it is associated with chronic pulmonary syndromes that can be fatal. Nausea is the most common adverse effect and others include rashes, fever and blood disorders. It should not be used in impaired renal function, as accumulation will occur.

Antibacterial Drug # 5. Methenamine:

Methenamine is a urine/bladder antiseptic that is converted to formaldehyde in the urine when the pH is less than 6.0. It is rarely used because of the large number of antibiotics that are available. However, it has a limited role in uncomplicated UTI caused by multiple drug-resistant bacteria or yeast. Side effects include bladder irritation, dysuria, and hematuria with prolonged use. It is contraindicated in glaucoma, renal insufficiency, and acidosis and should not be used concomitantly with sulfonamides.

Antibacterial Drug # 6. Metronidazole:

Metronidazole (500 mg orally or by IV infusion every 8 hours) is one of the most important antimicrobial drug and is extensively used in diverse clinical conditions. It kills anaerobic bacteria and some protozoa.

Metronidazole is well absorbed orally (bioavailability 90%) and is widely distributed in the body tissues, attaining therapeutic concentrations in vaginal secretions, semen, saliva, breast milk and CNS. It penetrates into bone and abscess cavities. More than 50% of the drug is metabolized in the liver.

Antimicrobial spectrum:

Metronidazole is highly effective against anaerobic bacteria and protozoa. It has greater activity against gram-negative than gram- positive anaerobes but is active against Clostridium perfringens (causative organism for gas gangrene, colitis and food poisoning) and C. difficile (causes pseudomembranous colitis). Protozoa that respond to metronidazole include Giardia lamblia, Entamoeba histolytica, and Trichomonas vaginalis. It has no direct effect on helminth Dracunculus medinensis, but helps in the elimination of guineaworm.

Metronidazole is one of the most widely used drugs in diverse clinical disorders, which includes

Acute invasive intestinal amoebic dysentery and extra­-intestinal amoebiasis including amoebic liver and brain abscess (800 mg 6 hourly/ 5-10 days). Urogenital trichomoniasis (2 g as a single dose or 200 mg 8 hourly/ 7 days). Giardiasis (2 g daily/ 3 days).

Metronidazole is highly effective against anaerobic infections in:

a. Leg ulcers and pressure sores

c. Acute ulcerative gingivitis

d. Acute dental infections

e. Antibiotic associated colitis (pseuomembranous colitis)

Intra-abdominal infections and brain abscess (usually in combination with a cephalosporin). Surgical and gynecological sepsis in which its activity against colonic anaerobes, especially B. fragilis is important. Intravenous (500 mg every 8 hours) metronidazole together with human tetanus immunoglobulin in established cases of tetanus.

H. pylori eradication along with omeprazole (proton pump inhibitor) and clarithromycin.Topical metronidazole gel 0.75% in the management of acne rosacea and for reduction of the odour produced by anaerobic bacteria in fungating tumours.

Metronidazole may cause GIT disturbances. Rarely, it may cause neurological and blood disorders and anaphylaxis. With alcohol, it produces disulfiram like reactions.

Antibacterial Drug # 7. Quinolones:

Nalidixic acid was the first quinolone to be introduced in 1960 for the treatment of GIT and urinary infections, but bacterial resistance and side effects limited its use. The development of fluorinated derivatives called fluoro­quinolones resulted in antibacterial activity with extended spectrum, higher potency, better tissue penetration and lesser bacterial resistance.

Antibacterial Drug # 8. Fluoroquinolones:

Fluoroquinolones are rapidly bactericidal. They interfere with an enzyme (DNA gyrase) which is necessary for the cell division (DNA replication) of bacteria.

Antibacterial spectrum:

Fluoroquinolones have a wide range of antibacterial activity. They are active against both gram- positive and gram-negative bacteria. They are particularly active against gram-negative bacteria, including Salmonella, Shigella, Campylobacter, Neisseria and Pseudomonas. They are moderately active against gram-positive bacteria such as Strep, pneumonia and Enterococcus fecalis, Chlamydia, Mycoplasma and some Mycobacteria. Most anaerobic organisms are not susceptible.

Pharmacokinetics:

Fluoroquinolones are well absorbed orally. The maximum serum levels are similar irrespective of the route (oral or IV) of administration. They are widely-distributed throughout the body. Concentrations in lung, sputum, muscle, bone, prostate and phagocytes exceed that in plasma. They are excreted in urine. Antacids, sucralfate, bismuth, iron, calcium and zinc preparations markedly impair oral absorption.

Norfloxacin (400 mg 12 hourly) and lomefloxacin (400 mg daily) orally are useful in urinary tract infections caused by gram-negative organisms, but are not the fluoroquinolones of choice. They are not used for systemic infections. They should not be used in children and pregnancy, in cases of porphyria and renal impairment.

Ciprofloxacin (500 mg orally once a day or 200-400 mg IV 12 hourly) and ofloxacin (200-400 mg orally or IV 12 hourly) are active against gram-negative aerobes including many ampicillin beta-lactamase-producing organisms. These drugs are commonly used for anthrax, urinary tract infections, pyelonephritis, infectious diarrhea, typhoid fever, prostatitis, gonorrhea (single-dose therapy) and intra-abdominal infections (with metronidazole). They are the preferred drugs in adults as a prophylactic for close contact with meningococcal meningitis.

Ciprofloxacin is the most active quinolone against P. aeruginosa and is the quinolone of choice for serious infections with this organism. It has relatively poor activity against gram-positive cocci and anaerobes, and should not be used as empiric mono-therapy for community-acquired pneumonia, skin and soft-tissue infections or intra-abdominal infections.

Levofloxacin (250-750 mg), gatifloxcin (400 mg), sparfloxacin (200-400 mg) and moxifloxacin (400 mg) are newer fluoroquinolones with improved coverage of aerobic gram-positive organisms (streptococci, staphylococci) and atypical respiratory pathogens (Chlamydia pneumonia, Mycoplasma, Legionella) but have less gram-negative activity (especially against P. aeruginosa) than ciprofloxacin. They can be used orally or IV, given every 12 hourly. Moxifloxacin and gatifloxacin have reasonable anaerobic activity, making them useful in mixed aerobic/anaerobic infections.

The important therapeutic uses of newer fluoroquinolones are:

a. Sinusitis, bronchitis and community acquired pneumonia

b. Urinary tract infections (except moxifloxacin, since it is minimally excreted in the urine)

c. Soft-tissue infections as an alternative to β lactum antibiotics

d. Postoperative surgical, obstetrical/gynaecological infections

e. Multidrug resistant TB and atypical mycobacterial infections

The principal adverse reactions with fluoroquinolones are gastrointestinal upsets (nausea) and skin rashes. They should be avoided, if possible, in patients with epilepsy as they have the potential to cause seizures, and in children they may cause damage to developing weight-bearing joints. They can also cause pain and inflammation of tendons, especially in older people.

Fluoroquinolones should be discontinued if psychiatric, neurological or hypersensitivity symptoms occur. NSAIDs and theophylline increase the risk of convulsions and anticoagulant action of warfarin is enhanced, if used with fluoroquinolones.


Life&rsquos operating system

But when asked to define exactly what synthetic biology is, Farah and Hubby hesitate. &ldquoThat&rsquos a good question,&rdquo says Farah, chuckling. After some thought, he adds: &ldquoWe think of it as the modular design of genomes, and therefore cells, for a particular function.&rdquo Synthetic biologists sometimes liken it to computer programming. &ldquoOften we use an operating-system analogy &mdash DNA and cells are the operating system for life,&rdquo says Farah.

Synthetic biology is in some ways a sophisticated version of genetic engineering, which in its basic form has been around for decades. But there are differences. Old-fashioned genetic engineering adds or removes individual genes, which is like downloading or deleting a new piece of software on your computer. In contrast, synthetic biology rewrites your whole operating system and adds some novel code at the same time. &ldquoIt is a matter of scale,&rdquo says Farah. In synthetic biology, whole new metabolic pathways, genes or even organisms are designed by using the principles of modern engineering. DNA sequences are written like code, synthesised in the lab and inserted into the cell. Traditional genetic-engineering techniques cannot deal with large gene constructs or whole genomes, says Farah.

One of the pioneers of synthetic biology was J. Craig Venter, who founded Synthetic Genomics. In 1995, Venter led the team that sequenced the first cellular genome, that of the bacteria Haemophilus influenzae
[1]
. And in 2001, he led a private project to sequence the human genome [2]
that ran alongside the Human Genome Project. He established the J. Craig Venter Institute in 2006, and in 2010 announced that he had succeeded in creating a synthetic cell, built from a chemically synthesised genome and capable of self-replication [3]
. As Farah puts it: &ldquoWhat Craig has been able to do is go from reading the genome to writing the genome.&rdquo

What Craig has been able to do is go from reading the genome to writing the genome

As the science has progressed, so has the technology underpinning it. A 60-kilobase viral genome can now be synthesised in a day this was simply not possible a few years ago. &ldquoMegabase genomes in bacteria would have taken years to synthesise &mdash now we can do this in weeks or months,&rdquo says Farah. This speed is accelerating the cycle of design, build and test that is so essential to synthetic biology. &ldquoIt&rsquos going to have a big impact on discovery and development,&rdquo he adds.

Synthetic Genomics says that it can now create vaccine seeds for virtually any strain of flu within a couple of days.


Other approaches to solving the problem of antimicrobial drug resistance

Other strategies for combating antimicrobial drug resistance fall into three main types. First, simply develop new drugs. The post-genomic era has led to the discovery of a whole host of essential genes in bacteria whose products might represent targets for novel antimicrobial drugs. But the exploitation of these targets is proving very difficult. More useful has been the adaptation of known drug scaffolds so that they overcome existing resistance mechanisms [11, 12]. It is, however, unlikely that permeability-mediated resistance mechanisms of Gram-negative bacteria will be overcome by these new drug variants, as these resistance mechanisms affect a broad spectrum of antibiotics [5]. The second approach is to stop using a particular drug and reintroduce it when resistance levels have fallen. This idea derives from the assumption that resistance mechanisms come with a fitness cost and that in the absence of selection, resistant strains will be out-competed by sensitive strains. Recent work has revealed, however, that most resistance mechanisms impose no significant fitness cost indeed some may provide a fitness advantage [13, 14], and this may explain why sulfonamide-resistance levels in E. coli did not fall in the UK even 10 years after the use of sulfonamides had been discontinued [15]. The third strategy is to learn more about the resistance mechanisms themselves. This area of research is focused on degradative enzymes and efflux pumps. The β-lactamase inhibitors already used clinically have been most successful but do not inhibit a large swathe of these enzymes, so more are required [16] efflux-pump inhibitors exist but are not currently in a clinically useful form [17].

In conclusion, the problem of antimicrobial drug resistance is very real, and is set to get worse before it gets better. The more we learn about the responses of bacteria to antimicrobial challenge, and about the fundamental mechanisms of drug resistance in bacteria, the more likely we are to be able to develop strategies for reducing the burden of resistance. The availability of large amounts of complete bacterial genome sequence data, coupled with the development of post-genomic technologies aimed at comparing gene complements and gene-expression patterns in resistant and non-resistant bacteria (for example [18, 19]), gives us an excellent platform to study resistance mechanisms. So, the dawn of the post-genomic era may help to delay a return to the pre-antibiotic era. Only time will tell.


Turnabout is fair play: use of the bacterial Multivalent Adhesion Molecule 7 as an antimicrobial agent

Pathogen attachment to host tissues is one of the initial and most crucial events during the establishment of bacterial infections and thus interference with this step could be an efficient strategy to fight bacterial colonization. Our recent work has identified one of the factors involved in initial binding of host cells by a wide range of Gram-negative pathogens, Multivalent Adhesion Molecule (MAM) 7. Interference with MAM7-mediated attachment, for example by pre-incubation of host cells with recombinant MAM7, significantly delays the onset of hallmarks of infection, such as pathogen-mediated cytotoxicity or the development of other adhesive structures such as actin pedestals. Thus, we are trying to develop tools based on MAM7 that can be used to prevent or diminish certain Gram-negative bacterial infections. Herein, we describe the use of bead-coupled MAM7 as an inhibitor of infection with the clinically relevant pathogen Pseudomonas aeruginosa.


Abstract

The emergence of resistance to antibacterial agents is a pressing concern for human health. New drugs to combat this problem are therefore in great demand, but as past experience indicates, the time for resistance to new drugs to develop is often short. Conventionally, antibacterial drugs have been developed on the basis of their ability to inhibit bacterial multiplication, and this remains at the core of most approaches to discover new antibacterial drugs. Here, we focus primarily on an alternative novel strategy for antibacterial drug development that could potentially alleviate the current situation of drug resistance — targeting non-multiplying latent bacteria, which prolong the duration of antimicrobial chemotherapy and so might increase the rate of development of resistance.


7 Antimicrobial Activity and Action of Silver

This chapter discusses antimicrobial activity and action of silver. Silver and its compounds have long been used, in one form or another, as antimicrobial agents. The silver compound of major therapeutic interest at the present time is silver sulphadiazine. Many in healthcare know that other silver compounds are still in use. It is worth stating that the treatment of ophthalmia neonatorum was revolutionized by the instillation of silver derivatives into the eyes of new-born sufferers. Several factors influence the antimicrobial activity of silver salts. Silver has a marked tendency to adsorb to surfaces and bactericidal activity is reduced in the presence of phosphates, chlorides, sulphides and hard water. Activity is increased as the temperature is raised and is pH-dependent, increasing with increasing pH. Sodium thioglycollate has been recommended as a suitable neutralizing agent for use in bactericidal testing although other SH compounds also fulfil this role. Silver, one of the native metals and second only to gold in its stability amongst the metals of antiquity, has provided several therapeutic agents which have been employed since the beginning of recorded history. These agents range from the metal itself, its salts and complexes with proteins and other macromolecules to the latest, silver sulphadiazine (AgSD).


Pharmacokinetics/Pharmacodynamics of Antiviral Agents Used to Treat SARS-CoV-2 and Their Potential Interaction with Drugs and Other Supportive Measures: A Comprehensive Review by the PK/PD of Anti-Infectives Study Group of the European Society of Antimicrobial Agents

There is an urgent need to identify optimal antiviral therapies for COVID-19 caused by SARS-CoV-2. We have conducted a rapid and comprehensive review of relevant pharmacological evidence, focusing on (1) the pharmacokinetics (PK) of potential antiviral therapies (2) coronavirus-specific pharmacodynamics (PD) (3) PK and PD interactions between proposed combination therapies (4) pharmacology of major supportive therapies and (5) anticipated drug-drug interactions (DDIs). We found promising in vitro evidence for remdesivir, (hydroxy)chloroquine and favipiravir against SARS-CoV-2 potential clinical benefit in SARS-CoV-2 with remdesivir, the combination of lopinavir/ritonavir (LPV/r) plus ribavirin and strong evidence for LPV/r plus ribavirin against Middle East Respiratory Syndrome (MERS) for post-exposure prophylaxis in healthcare workers. Despite these emerging data, robust controlled clinical trials assessing patient-centred outcomes remain imperative and clinical data have already reduced expectations with regard to some drugs. Any therapy should be used with caution in the light of potential drug interactions and the uncertainty of optimal doses for treating mild versus serious infections.


7: Antimicrobial Drugs - Biology

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Watch the video: Antibiotic Classes in 7 minutes!! (October 2022).