Prof Saghir Akhtar Department of Pharmacology and Toxicology Room 134 ext Recommended Textbooks: Integrated Pharmacology (Page et al., 2 nd ed.): Pages Pharmacology (Rang et al 5 th ed.) Pages: Introduction to Antimicrobials

Human Infections Bacterial Viral Fungal Protozoal Helminthic

Streptococcal Sore ThroatGingivitis and Chronic Periodontitis Methicillin-Resistant Staphylococcus Aureus (MRSA) Erythema Multiforme

Acne vulgarisLeprosy Tuberculosis Meningitis

Why do you need to study antibacterials? To effectively treat patients with : - Non-contagious infections - Contagious infections - Nosocomial (hospital –acquired) infections (e.g. MRSA superbugs and intervention-related infections)

Antibiotics: A BIG Market for presciptions

Objectives 1.To define selective toxicity, bacteriostatic and bactericidal antibiotics. 2.To understand the mechanism of resistance to antibiotics. 3.To understand the major factors to be considered in drug selection for individual patients. 4.To understand the importance of host status factors such as allergy history, age factors, renal factors, hepatic factors, pregnancy, genetic and metabolic factors, anatomical site of infection.

Selective Toxicity The ideal antibiotic interferes with a vital function of bacteria without affecting host cells Functions that are specific to the bacterium are potential targets, e.g. drugs interfering specifically with the synthesis of the bacterial cell wall are toxic to the bacteria but harmless to the host.

Bacteriostatic anti-infective agents reversibly inhibit the growth and reproduction of bacteria. Bactericidal anti-infective agents irreversibly destroy (kill) the pathogenic bacteria However, categorizing antibiotics as predominantly bacteriostatic or bactericidal is imperfect: Dependent on organism, the dose and duration of therapy e. g. penicillin is a bactericidal antibiotic against streptococci, but is a bacteriostatic against enterococci. Bacteriostatic and Bactericidal Antibiotics

Bacteriostatic vs Bacteriocidal action

When an antibiotic is ineffective against a bacterium, that bacterium is said to be resistant. Antibiotic resistance is classified as either innate or acquired. Innate resistance refers to an intrinsic resistance based in the mechanism of the drug.e.g. anaerobic bacteria lack the oxygen-dependent transport mechanism required for aminoglycosides to enter the bacterial cell. Acquired resistance refers to the acquisition of a resistance gene in a bacteria that is not innately resistant to a particular antibiotic. Antibiotic Resistance: Innate and Acquired

1. Production of an enzyme that inactivates the drug e.g. Inactivation of  –lactam antibiotics The enzymes are  –lactamases, which cleave the  –lactam ring of penicillins and cephalosporins. 2. Alteration of drug-binding sites e.g. aminoglycosides, erythromycin. The protein on the 30S subunit of the ribosome, which is the binding site for aminoglycosides, may be altered due to chromosomal mutation. Mechanisms of bacterial resistance to antibiotics

3. Decreased drug accumulation in the bacterium e.g. tetracyclines Reduction of drug uptake by the bacterium. Resistance genes code for inducible proteins in the bacterial membrane which promote efflux of tetracyclines. 4. Development of altered metabolic pathway Resistance to trimethoprim is the result of the synthesis of dihydrofolate reductase which is insensitive to trimethoprim. Mechanisms of bacterial resistance to antibiotics

Clinical Relevance The clinician may be forced to abandon a FIRST choice drug and turn to a second-line drug

Drug Selection for Individual Patients

Major factors to be considered are: Identification of organism Sensitivity of organism to antibiotics Bactericidal versus bacteriostatic Host status

Identification of Organisms Before initiating antimicrobial therapy, it is highly desirable to determine the possible pathogen or pathogens in the infection site. Antibacterial therapy is effective only for bacterial infections, therefore it is important to restrict the use of antibiotics to those situations caused by bacterial infections.

Bactericidal Versus Bacteriostatic Drug A bacteriostatic agent often is adequate in uncomplicated infections because the host defences will help eradicate the micro-organism For example, in pneumonococcal pneumonia, tetracyclines, which are bacteriostatic agents, suppress the multiplication of the pneumococci. The pneumococci are eventually destroyed by the interaction of alveolar macrophages and polymorphonuclear leukocytes. For a neutropenic individual, such as a bacteriostatic agent might prove ineffective and a bactericidal agent would be necessary.

Thus the status of the host influences whether a bactericidal or bacteriostatic agent is selected

Host Status Factors Site of infection Allergy history Age Renal and Hepatic function Pregnancy status Genetic or metabolic abnormalities

Host Status: Site of Infection It is essential that the antibiotic reaches the site of infection. Only a few antibiotics are able to enter the CNS in therapeutic concentrations to treat meningitis; urinary tract infections must be treated with drugs that are excreted in active forms. The site of infection often determines not only the antimicrobial agent used, but also the dose, route, and duration of drug administration.

Allergy History A history of any previous allergic reaction is important in selecting an antimicrobial agent, because a similar reaction to other members of the same drug class may occur. Allergy to penicillins is an important factor. Anaphylactic reactions to any penicillin compound prevent the subsequent use of penicillins.

Host Status: Age Factors Many antibiotics are removed from the body by renal elimination, which may change with age. Certain antibiotics should not be given to children.

Host Status: Renal Function Many antimicrobial agents are eliminated from the body by renal filtration or secretion. Dosage adjustments required for those agents eliminated by glomerular filtration. Toxicity may affect the kidney or other organs.

Host Status: Hepatic Function Antimicrobials that are metabolized in the liver include chloramphenicol, erythromycin, clarithromycin, rifampin, nitroimidazoles and some of the quinolones. It may be necessary to reduce the doses of these agents to avoid toxic reactions in patients with impaired hepatic function.

Host Status: Pregnancy Pregnant patients or nursing mothers may have important problems when it comes to the use of antimicrobial agents, because most of these drugs cross the placenta to some degree. Use of tetracyclines in pregnancy should be avoided because they alter fetal dentition and bone growth. Many antibiotics are excreted in breast milk and can cause the newborn‘s microflora to be distorted.

Host Status: Genetic and Metabolic Factors Genetic abnormalities of enzyme function may affect the potential for toxicity of certain agents (Pharmaco-genetics/genomics).