INTRODUCTION TO ANTIMICROBIAL CHEMOTHERAPY (General Principles)

OBJECTIVES: General principles of chemotherapy for other drugs govern antimicrobial chemotherapy also. However, there are principles that are more pertinent to the use of antimicrobial agents as a group. Particular attentions should be directed to the following: 1. Mechanisms of actions of different groups of antibiotics. 2. Mechanisms by which pathogens acquire and express resistance to antibiotics. 3. Combination therapy (use of two or more drugs concomitantly). 4. Host determinants that influence the selection and efficacy of antibiotics.

INTRODUCTION TO ANTIMICROBIAL CHEMOTHERAPY (General Principles)

PR0TOTYPES Penicillin G Rifampin

Polymyxin
Choramphenicol Streptomycin

Ciprofloxacin
Sulfamethoxazole

CONJUGATION
1. A sexual process that requires cell-to-cell contact through pili. The transferable materials consist of two different DNA sequences: (1) R Determinant Plasmid for resistance mechanism (2) Resistant Transfer Factor (RTF) that is needed for conjugation. Combination of the two plasmid is called R-Factor Many Gram (-) organisms acquire resistance to multiple antibiotics by conjugation mechanism. Multiple drugs resistant Enterobacteriaceae became a serious world-wide problem.

2.

3. 4.

EFFECTIVENESS OF COMBINATION THERAPY

1.

Synergistic Effect: When two bactericidal antibiotics are used in combination. One of the two drugs must show at least 4-fold increase in antibacterial activities (or a decrease in MIC to ) for a synergism is said to exist between the two drugs. (e.g. penicillin + streptomycin). Additive Effect: When two bacteriostatic agents with the same mechanisms of action are used. Antagonism: Usually bacteriostatic antibiotics are antagonistic to bactericidal agents. (e.g. Chloramphenicol has been shown to antagonize the bactericidal activities of penicillin in the treatment of Pneumococcal meningitis.

2.

3.

Important Host Determinants

a) Hepatic function: Erythromycin, clindamycin, rifampin, Chloramphenicol, etc depend on liver metabolisms for the inactivation of antimicrobial mechanisms. Patients with impaired liver function may accumulate in the body active form of the drugs to a toxic level if the dosage adjustment is not made. Kidney function: Normal kidney function is essential for disposal of -lactams, aminoglycosides, vancomycin, etc. Active form of these drugs may accumulate in the patient with renal diseases. Host defense mechanism: A chemotherapeutic regimen that is perfectly adequate for immuno-competent patient may be totally ineffective for immuno-incompetent patient. Immunoincompetence may be due to deficiencies in (1) immunoglobulin, (2) phagocytic cells and (3) cellular immune system.

b)

c)

Untoward Effects of Antibiotics

1.
2. 3.

Reactions due to toxic properties of antibiotics. Hypersensitivity reactions Superinfection (or also called Suprainfection)

-LACTAMS (penicillins & cephalosporins) AND -LACTAM RELATED AGENTS

OBJECTIVES: -Lactams constitute one of the most important and most frequently used groups of antibiotics available to combat infectious diseases. Therefore, all practitioners in any field of medicine should be knowledgeable of all aspects of the pharmacology. Particular attentions should be directed to the following: 1. 2. Important pharmacodynamics and pharmacokinetics of the prototypes listed below. Important therapeutic and prophylactic uses and untoward effects of prototypes that are representatives of different categories of -lactams. Significance of -lactam related compounds in antimicrobial chemotherapy

3.

PROTOTYPES (-lactams & related agents)

Penicillins:

penicillin G; phenoxymethyl penicillin (pen V) methicillin; oxacillin ampicillin; amoxicillin; carbenicillin; ticarcillin First Gen.: cephalexin; cephalothin Second Gen.: cefoxitin; cefaclor Third Gen.: cefotaxime; cefoperazone; ceftriaxone Fourth Gen.: cefepime

Cephalosporins:

-Lactam related agents:

Antibiotics: imipenem; aztreonam -Lactamase inhibitors: sulbactam; clavulanic acid

Antimicrobial Spectrum (therapeutic uses)

Penicillin G is primarily a narrow spectrum antibiotic, and mainly Gram (+) organisms are susceptible. However, there are Gram (-) organisms that are very sensitive to the agent. a) b) c) Sensitive G(+) cocci: Pneumococci, Strep. Pneumoniae, Sensitive G(-) cocci: N. meningitidis N. gonorrhea, Other cocci and G(+) and G(-) bacilli require test for the drug sensitivity because of frequent resistance to penicillin G. However, Treponema pallidum (syphillis), Treponema pertenue and Actinomyces israeli etc are still sensitive to the agent.

ANTIBACTERIAL ACTION MECHANISMS OF LACTAM

1.

Competitive inhibition of TRANSPEPTIDASE. --The last step of peptidoglycan synthesis Alteration of bacterial morphology. --Inhibition of SEPTUM formation (Penicillin Binding Protein mechanism) Inhibition of availability of Autolysin Inhibitor. --Stimulation of bacterial cell lysis (PBP mechanism)

2.

3.

MECHANISMS UNDERLYING BACTERIAL RESISTANCE TO -LACTAMS

1. 2. 3. Production of -LACTAMASE Alteration in penicillin binding proteins (PBP) Decreased entry of -lactams (cell membrane and cell wall structure; porin mechanism) Increased efflux of -lactams

4.

Semisynthetic Penicillins
1. Those stable in acid and absorbed well from GI tract, but penicillinase sensitive. (penicillin V; phenethicillin) Those resistant to penicillinase and unstable in acid or poorly absorbed from GI tract--i.e. Suitable only for parental administration. (methicillin) Those resistant to penicillinase, stable in acid and absorbed well from GI. (oxacillin; cloxacillin; etc.) Extended spectrum (or broad spectrum) penicillins that are effective against G(-) organisms such as H. influenza, E. coli, Proteus, Pseudomonas, Klebsiella, etc: -Ampicillin; amoxacillin; hetacillin (amino-pen.) -Carbenicillin; ticarcillin (carboxy-pen.) -Azocillin; piperacillin (ureido-pen.)

2.

3.

4.

HYPERSENSITIVITY REACTION TO -LACTAMS

1. 2. Antigenic properties reside in -lactam ring structure. --i.e. Cross-reactivity between penicillins and cephalosporins. Skin-test materials are of two types: (a) MAJOR DETERMINANTS; (b) MINOR DETERMINANTS. (a) Major Determinants: Benzylpenicilloyl-polylysine (penicilloylpolylysine, PPL or pre-pen), available commercially. Patients showing positive tests to major determinants are likely to react to therapeutic doses of -lactams and more likely to manifest slow onset type reactions. Minor Determinants: Penicillin G and some of its hydrolyzates. Usually penicillin G is used for skin test. Positive tests indicate a high-risk for an immediate, anaphylactic reaction.

(b)

**Even negative tests to either or both determinants do not exclude the possibility of serious, immediate type reactions. **The major and minor refer to the frequency of reaction and not the seriousness of reaction (i.e. patients having positive reaction to minor determinants are likely to have more serious reactions)

SOME PRECAUTIONS FOR POTENTIAL -LACTAM ALLERGY

1. Always ask patients about previous allergic reactions 2. Patients should be kept in the office for at least 30 min after an injection of -lactam. 3. It is prudent to give a skin test with penicillin G 30 min before the injection of procaine or benzathine penicillin. 4. Always have a syringe of epinephrine on hand. 5. Perform skin test with PPL and penicillin G for high-risk patient. 6. In the presence of positive test to skin test, preferably -lactams not be used. If used, be prepared for an emergency situation.

-Lactam Related Compounds

A.

Compounds with antimicrobial activities: Imipenem, meropenem, aztreonam, etc: structurally similar to -lactam, but lacks the classical ring structures of -lactam. In terms of antimicrobial activities they share those of other antibiotics. -LACTAMASE Inhibitors: Clavulanic acid; Sulbactam: by inactivating the enzyme these compounds enhance the antibacterial activity when used in combination with other -lactam antibiotics.

B.

SULFONAMIDES, TRIMETHOPRIM-SULFAMETHOXAZOLE, QUINOLONES, URINARY TRACT ANTISEPTICS

OBJECTIVES: This chapter describes 4 different groups of chemotherapeutic agents. These groups are discussed together mainly because these drugs are frequently used for the same types of infectionsmainly urinary tract infections. Particular attentions should be directed to the following. Sulfonamides and quinolones 1. Mechanisms of actions 2. Pharmacological properties of prototypes that represent different groups 3. Currently important therapeutic uses of specific drugs 4. Significant untoward effects

Trimethoprim-sulfamethoxazole 1. Mechanism of action (advantages of the combination) 2. Currently important therapeutic uses 3. Significant untoward effects Urinary tract antiseptics and related agents 1. Definition 2. Nomenclatures of common prototype

(sulfonamide, etc) PROTOTYPES: SULFONAMIDES: sulfadiazine; silver sulfadiazine; sulfacetamide; sulfisoxazole; sulfasalazine; sulfadoxine.

TRIMETHOPRIM-SULFAMETHOXAZOLE:
QUINOLONES: nalidixic acid; ciprofloxacin; ofloxacin; sparfloxacin URINARY TRACT ANTISEPTIC: methenamine URINARY TRACT ANTISEPTIC RELATED AGENT: phenazopyridine

Sulfonamide used for specific purposes

(a)

Sulfacetamide: sodium salt is water-soluble and is used in eye-drops.

Silversulfadiazine: for management of burn wounds. Patient acceptance is better than mafenide. Sulfasalazine: very useful for treating ulcerative colitis Sulfadoxine: extra long acting sulfonamide. Useful for prophylaxis of chloroquine resistant P. falciparum malaria.

(b)

(c) (d)

Untoward effects of sulfonamides

1. Hematopoietic system: Hemolytic anemia (in glucose-6-phosphate dehydrogenase deficient patients); aplastic anemia; thrombocytopenia; eosinophylia. 2. Urinary tract: Occlusions due to precipitates and hypersensitivity reactions. 3. Drug interaction: Due to the high affinity to plasma proteins, some of the newer products may free other drugs from their binding proteins, thereby may potentiate activities of the freed drugs. These include anticoagulants, hydantoin and hypoglycemic agents of sulfonylurea group. 4. Sulfonamides are used only when a particular agent is known to be equal to or better than other antibiotics for a particular infection. 5. When sulfonamide is used systemically: (a) the hematopoietic system and renal function must be monitored closely; (b) the patient must be given sufficient amount of water to produce 1.2 liter/day of urine (i.e. 3-4 liter of water/day).

ACTION MECHANISM OF TRIMETHOPRIMSULFAMETHOXAZOLE

1. 2. 3. Sulfamethoxazole inhibits dihydrofolate synthase. Trimethoprim inhibits dihydrofolate reductase. Inhibition of these two enzymes interferes with 2 serial steps in folic acid synthesis, and thereby inhibits synthesis of nucleic acids and proteins. The two agents exhibit synergism: (a) (b) Reduction in MIC of each drug Extension of antimicrobial spectrum

4.

Therapeutic uses

1.

Trimethoprim-sulfamethoxazole is very effective for the treatment of: (a) uncomplicated infection of the lower urinary tract infection (b) chronic and recurrent urinary tract infections (including enterobacteriaceae) Some of the susceptible organisms include: (a) gonococci in urethritis (b) E. coli (in urinary tract) (c) Yersinia (d) Shigella (e) Pneumocystis carinii (pneumonia) for both therapeutic and prophylactic purposes in AIDS patients (neutropenic patients). (f) Methicillin resistant organisms (Staph.)

2.

POSSIBLE UNTOWARD EFFECTS OF tm-sm

1. 2.

Susceptible to untoward effects of both agents. Trimethoprim can inhibit human dihydrofolate reductase. However affinity of trimethoprim to bacterial enzyme is more than 1000-fold higher than its affinity to mammalian enzyme. Therein the margin of safety. Nonetheless, it may cause folic acid deficiency in patients suffering from malnutrition to begin with. It may precipitate MEGALOBLASTOSIS, LEUKOPENIA, or THROMBOCYTOPENIA.

Pharmacokinetics of quinolones

1.

All quinolones are well absorbed after oral administration. Food may delay the time to reach the peak serum concentration. A significant portion of ingested amount of the drugs is excreted through kidney in original form, and thereby all quinolones are good urinary tract antibiotics (except norfloxacin). Patients with renal insufficiency may need dose adjustments during ciprofloxacin, ofloxacin or other fluoroquinolone therapy.

2.

3.

4.

Unfluorinated quinolone, nalidixic acid, has a high affinity for protein, and over 90% of plasma concentration are protein bound form. An effective antibacterial concentration in plasma cannot be attained.

Therapeutic uses of quinolones

CIPROFLOXACIN; OFLOXACIN; SPARFLOXACIN 1. 2. 3. 4. 5. Urinary tract infection and prostatitis Acute diarrheal diseases by E. coli, Shigella and Campylobacter Staphylococcal infection including those of methicillin-resistant strains. Anaerobes Mycobacterial infections in multiple drugs therapy. (N.B. the later chapter on Tuberculosis and Leprosy.)

Untoward effects of quinolones

1. 2. 3. 4.

All quinolones are well tolerated. Common side effects include nausea, abdominal discomfort, headache, etc. Quinolones are not recommended for prepuberal children and pregnant woman due to possible arthropathy in children. Some preparation (ciprofloxacin) may inhibit metabolism of theophyline---hence possible toxicity from elevated concentration of methylxanthines.

MISCELLANEOUS ANTIBIOTICS

OBJECTIVES: Antibiotics discussed in this chapter are considered preferred agents in limited types of infection. Some of these agents are exquisitely effective for the respective limited purposes. Particular attentions should be directed to the following with respect to the prototypes that represent different groups:

1. 2. 3. 4.

Mechanism of action Pharmokinetics pertinent to therapeutic uses Therapeutic uses Significant untoward effects

Prototypes: Macrolides: Clindamycin Spectinomycin Vancomycin Polymyxin Bacitracin (erythromycin; azithromycin; clarithromycin)

Summary of Miscellaneous Antibiotics (1):

Therapeutic Uses (a) Drugs Erythromycin Azithromycin* Clarithromycin* Therapeutic Use a) Alternative to Penicillin & Tetracycline b) Does not penetrate meninge c)* Useful for Mycobact. avium Complex

Clindamycin

a) G(+) cocci (but not 1st choice due to AAPMC) b) Valuable anti-ANAEROBES (B. fragiris; fecal spillage in gun shot wounds etc)
a) Gonococcal infection (-lactam resistant strains; patient allergic to -lactam) a) usually reserved for methicillin-resistant Infection and patient allergic to -lactam

Spectinomycin

Vancomycin

Summary of Miscellaneous Antibiotics (2):

Therapeutic Uses (b) Drugs Polymyxin* Therapeutic Use a) Antimicrobial activity is limited to G(-) organisms b) Topical use for skin, eye, ear and mucous membranes a) Ophthalmological use (can be effective if the organism is sensitive)

Bacitracin*

*Mixtures of different combinations of polymyxin, bacitracin and neomycin for topical use are available over-the-counter.

Summary of Miscellaneous Antibiotics (3):

Action Mechanisms & Untoward Effects (a) Drugs Erythromycin Azithromycin) Clarithromycin Act. Mech. 50s Ribosm Untoward Effects (UE) a) epigastric and/or gustatory distress b) auditory impairment

Clindamycin

50s Ribosm

a) AAPMC* (or Clostridium difficile Colitis)

Minor neuropathy

Spectinomycin Vancomycin

30s Ribosm

Cell wall synth a) nephrotoxicity b) ototoxicity

*Antibiotic Associated PseudoMembranous Colitis

Summary of Miscellaneous Antibiotics (4):

Action Mechanisms & Untoward Effects (b) Drugs Polymyxin Act. Mech. Cell membrane function Cell wall Untoward Effects (UE) Extreme nephrotoxicity

Bacitracin

Extreme nephrotoxicity synthesis

AGENTS THAT MAY REPLACE METHICILLIN WHEN RESISTANCE TO METHICILLIN DEVELOPS

1. 2. 3. 4.

Vancomycin Trimethoprim-sulfamethoxazole Quinolones (ciprofloxacin, ofloxacin, sparfloxacin) Rifampin, Rifabutin

AGENTS FOR VANCOMYCIN RESISTANT INFECTIONS (New Classes of Antibiotics)

1. OXAZOLIDINONES: Linezolid (Zyvox) Inhibits functions of 30s and 50s ribosomal fractions

2. STREPTOGRAMINS:

Quinupristin-Dalfopristin combination form (Synercid) Inhibits functions of 50s ribosomal fraction

CHEMOTHERAPY OF MYCOBACTERIAL DISEASES

OBJECTIVES:

The chemotherapy of Mycobacterial diseases presents special problems mainly due to the inherent nature of the bacteria. The organisms grow slowly, and the diseases are usually chronic. The invading organisms are hard to eradicate. The duration of therapy tends to be months and years. Thereby emergence of drug resistant bacterial strains and manifestation of drug toxicities during the therapy are common problems. The therapy entails many different groups of drugs in combination regimen. Many of the drugs useful for the treatment have already been discussed elsewhere in the syllabus. Particular attention should be directed to the following:
1. 2. First line drugs for different Mycobacterial diseases. Important pharmacodynamics, pharmacokinetics and untoward effects of the first line drugs. Rationale and the current status of drug combinations.

3.

PROTOTYPES & FIRST LINE DRUGS

M. tuberculosis and M. kansasii: Isoniazid; rifampin; ethambutol; pyrazinamide; streptomycin* M. avium complex: Clarithromycin*; ethambutol; clofazimine; amikacin*; ciprofloxacin* M. leprae: Dapsone; rifampin; clofazimine M. fortuitum complex: Amikacin*; doxycycline*

M. marinum: Rifampin; ethambutol

*Discussed elsewhere in the syllabus

MECHANISM OF ACTION:
1. Those that inhibit cell wall synthesis: (a) Isoniazid; pyrizinamide: Mycolic acid synthesis inhibitors (b) Ethambutol: Inhibits MA incorporation to cell wall Those that affect nucleic acid metabolism: (a) Rifampin; rifabutin: DNA dependent RNA polymerase inhibitors (b) Clofazimine: Binds to DNA and inhibits the template function of DNA Those that inhibits intermediary metabolism: (a) Dapsone; sulfoxone: The same as that of sulfonamides.

2.

3.

Other agents have been discussed in other chapters.

UNTOWARD EFFECTS
ISONIAZID: Peripheral neuritis if pyridoxine (Vit.B6) is not given concomitantly. Hepatitis: Age related. Not given to patient over 35 years old for prophylactic purpose. Optical neuritis: inability to distinguish red -green color; optical acuity test must be given before and during therapy. Hepatitis; Febrile reaction; Imparts orange-red color to body fluids, urine and feces (warning to patients!) Hepatotoxicity (used for only short-term therapy) Hyperuricemia Red discoloration of skin

ETHAMBUTOL:

RIFAMPIN:

PYRAZINAMIDE:

CLOFAZIMINE:

CURRENT STATUS OF COMBINATION THERAPY

1. None of the drugs is used alone to treat active diseases. Always use 2 or more drugs to which the invading organisms are sensitive.

2. Isoniazid, or if it is inappropriate, rifampin is used alone for prevention of active tuberculosis for patients showing positive tuberculin test.
3. For M. tuberculosis or M. kansasii of serious cases or patients who had previous treatments for these infections,up to 6 different drugs may be used in combination at least during the drug sensitivity tests are being conducted. 4. For M. tuberculosis and M. kansasii, combination of isoniazid and rifampin is considered the most effective. If possible isoniazid and/or rifampin should be included in any regimen. 5. For M. avium complex (in AIDS patients) isoniazid and pyrazinamide are totally useless.