microbiology – fundamentals of chemotheraphy

Fundamentals of CHEMOTHERAPHYDra. TuanoMicrobiology

Definition of Terms: Antibiotics – a drug used to treat

bacterial infectionso Have no effect on viral infectionso Originally, it was a substance

produced by one microorganism that selectively inhibits the growth of another

o Synthetic antibiotics, usually chemically related to natural antibiotics, have since been produced that accomplish comparable tasks.

Probiotics – are microorganisms that provide health benefits when consumed, as claimed by some.o the term probioticis currently

used to name ingested microorganisms associated with beneficial effects to humans and animals

Chemotherapeutic agents – agent used to treat cancer administered in regimens of one oor more cycles, combining two or more agents over a period of days to weekso Such agents are toxic to cells with

high proliferative rates e.g., to the cancer itself, but also to the GI tract (causing nausea and vomiting), bone marrow (causing various cytopenias) and hair (resulting in baldness

Antimicrobial Chemotherapy: introduction Drugs have been used for the

treatment of infectious diseases since the 17th century (e.g., quinine for malaria, emetine for amebiasis);

However, chemotherapy as a science began in the first decade of the 20th century with understanding of the principles of selective toxicity, the specific chemical relationships between microbial pathogens and drugs, the development of drug resistance and the role of combined therapy

Experiments led to the arsphenamines for syphilis, the first planned chemotherapeutic regimen.

The current era of antimicrobial chemotherapy began in 1935 with the discovery of the sulfonamides. In 1940, it was demonstrated that penicillin discovered in 1929, could be an effective therapeutic substance.

During the next 25 years, research on chemotherapeutic agents centered largely around substances of microbial origin called antibiotics

The isolation, concentration, purification, and mass reduction of penicillin were followed by the development of streptomycin, tetracyclines, chlorampehenicol, and many other agents.

These substances were originally isolated from filtrates of media in which their respective molds had grown

Synthetic modification of previously described drugs has been prominent in the development of new antimicrobial agents

Antimicrobial Chemotherapy: Mechanisms of Action of Antimicrobial Drugs Antimicrobial drugs act in one of

several ways: By selective toxicity, By inhibition of cell membrane synthesis and function, By inhibition of protein synthesis, or By inhibition of nucleic acid synthesis

Selective Toxicity - an ideal antimicrobial agent exhibits selective toxicity, which means that the drug is harmful to a pathogen without being harmful to the host. Often, selective toxicity is relative rather than absolute; this implies that a drug in a concentration tolerated by the host may damage an infecting microorganism.

Selective toxicity may be a function of a specific receptor required for a drug attachment, or it may depend on the inhibition of biochemical events essential to the pathogen but not to the host.

The mechanisms of action of antimicrobial drugs can be discussed under four headings:

Inhibition of cell wall synthesis

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Inhibition of cell membrane function

Inhibition of protein synthesis (ie., inhibition of translation and transcription of genetic material).

Inhibition nucleic acid synthesis.

Inhibition of Cell Wall Synthesis Bacteria have rigid outer

layer, the cell wall. The cell wall maintains the shape and size of the microorganisms, which has a high internal osmotic pressure

Injury to the cell wall (eg. By lysosome) or inhibition of its formation may lead to lysis of the cell. In a hypertonic environments (eg. 20% sucrose), damaged to cell formation leads to formation of spherical bacterial “protoplasts” from gram-positive organisms or “spheroplasts” from gram-negative organisms; these forms are limited by the fragile cytoplasmic membrane.

If such protoplasts or sphheroplasts are placed in an environment of ordinary tonicity, they take up fluid rapidly, swell, and may explode. Specimens from patients being treated with cell wall-active antibiotics often show swollen or misshapen bacteria

The cell wall contains a chemically distinct complex polymer “mucopeptide” (“peptidoglycan”) consisting of polysaccharides and a highly cross-linked polypeptide.

The polysaccharides regularly contain the amino sugars N-acetylglucosamine and acetylmuramic acid. The latter is found only in bacteria.

To the amino sugars are attached short peptide chains.

The final rigidity of the cell wall is imparted by cross-linking of the peptide chains (eg, through pentaglycine bonds) as a result of transpeptidation reaction carried out by several enzymes.

The peptidoglycan layer is much thicker in the cell wall of gram-positive than of gram-negative bacteria.

All β-lactam drugs are selective e inhibitors of bacterial cell wall synthesis & therefore active against growing bacteria/

This inhibition is only one of the several different activities of these drugs, but it is the best understood.

The initial step in drug action consists of binding of the drugs to cell receptors (Penicillin-binding proteins; PBS)

There are 3 to 6 PBPs (MW 4-12 x 105 ), some of which are transpeptidation enzymes.

Different receptors have different affinities for a drug, and each may mediate a different effect.

For example: attachment of Penicillin to one PBP – may result chiefly in abnormal elongation of the cell, whereas attachment to another PBP may lead to a defect in the periphery of the cell wall, with resulting cell lysis.

PBPs are under chromosomal control, & mutations may alter their number or their affinity for β.

After a β-lactam drug has attached to one or more receptors, the transpepdiation reaction is inhibited & peptidoglycan synthesis is blocked.

The next step probably involves removal or inactivation of an inhibitor of autolytic enzymes in the cell wall.

This activates the lytic enzyme and results in lysis if the environment is isotonic

In a markedly hypertonic environment, the microbes change to protoplasts or sphetoplast, covered only by the fragile cell membrane.

In such cells, synthesis of proteins and nucleic acids may continue for some time

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The inhibition of the transpeptidation enzymes by Penicillins & Cephalosphorins may be due to a similarity of these drugs to actl-structural alanine.

The transpeptidation reaction involves loss a D-alanine from the pentapeptide.

The remarkable lack of toxicity of β-lactam drugs to mammalian cells must be attributed to the absence, in animal cells, of a bacterial wall, with its peptidoglycan.

The difference in susceptibility of gram (+) & gram (-) bacteria to various Penicillins or Cephalosphorins probably depends on structural differences in their cell walls (e.g., amount of Peptidoglycan, presence of receptors & lipids, nature of crosslinking activity of autolytic enzymes) that determine penetration, binding, & activity of the drugs.

Resisitance to Penicillin’s may be determined by the organism’s production of penicillin-destroying enzymes (β-lactamases).

Beta-lactamases – open the β-lactam ring of penicillins and Cephalosphorins & abolish their antimicrobial activity.

Beta-lactamases are plasmid-mediated (e.g., penicillinase of Staphylococcus), while others are chromosomally mediated (e.g., many species of gram (-) bacteria.

All of more than 30 plasmid-mediated β-lactamases are produced constitutively & have a high propensity to move from one species of bacteria to another (e.g., β-lactamase-producing Neisseria gonorrheae, Hemophilus influenza & Enterococci)

Chromosomally mediated β- lactamases may be

constitutively produced (e.g., Bacteriodes, Acinetobacter) or they may be inducible (e.g., Enterobacter, Citrobacter, Pseudomonas).

There is one group of β-lactamases that is occasionally found in certain species of gram (-) bacilli, usually Klebsiella pneumonia & Escherichia coli.

These enzymes are termed extended-spectrum β-lactamases (ESBLs) because they confer upon the bacteria the additional ability to hydrolyze the β-lactam rings of Cefotaxime, Ceftazidime, or Aztreonam.

The classification of β-lactamases is complex, based upon the genetics, biochemical properties, and substrate affinity for β-lactamase inhibitor (clavulanic acid).

Clavulanic acid, sulbactam & tazobactam are β-lactamase inhibitors that have a high affinity for and irreversibly bind some β-lactamases (e.g., penicillinase of Staphyloccocus aureus) but arenot hydrolyzed by the β-lactamase.

These inhibitors protect simultaneously present hydrolysable penicillins (e.g., ampicillin, amoxicillin, & ticarcillin) from destruction

Certains penicillings (e.g., cloxacillin) also have a high affinity for β-lactamases.

There are two other types of resistance mechanisms:

Due to the absence of some penicillins receptors (penicillin-binding proteins; PBPs) and occurs as a result of chromosomal mutation;

Results from failure of the β-lactam drug to


activate the autolytic enzymes in the cell wall.

As a result, the organism is inhibited but not killed. Such tolerance has been observed especially with staphylococci & certain streptococci.

Examples of agents acting by inhibition of cell wall synthesis: penicillins, the cephalosphorins, vancomycin, and cycloserine.

Several other drugs, including bacitracin, teicoplanin, vancomycin, ristocetin, and novobiocin, inhibit early steps in the biosynthesis of the peptidoglycan.

Since the early stage of synthesis take place inside the cytoplasmic membrane, these drugs must penetrate the membrane to be effective.

Inhibition of Cell Membrane Function

The cytoplasm of all living cells is bounded by the cytoplasmic membrane, which serves as a selective permeability barrier, carries out active transport functions, and thus controls the internal composition of the cell.

If the functional integrity of the cytoplasmic membrane is disrupted, macromolecules and ions escape from the cell, and cell damage or death ensues.

The cytoplasmic membrane of bacteria and fungi has a structure different form that of animal cells, and can be more readily disrupted by certain agents.

Consequently, selective chemotherapy is possible.

Examples of this mechanism are the polymyxins acting on the gram (-) bacteria and polyenes acting on fungi.

Polyenes require binding to a sterol which is present in the fungal cell membrane but lacking in the bacterial cell membrane.

Conversely, Polymyxins are inactive against fungi and polyenes are inactive against bacteria – a striking example of selective toxicity.

Other examples of agents acting by inhibition of cell membrane function are amphotericin B, colistin & the imidazoles &triazoles.

Inhibition of Protein Synthesis It is established that

erythromycins, lincomycins, tetracyclines, aminoglycosides, & chloramphenicol can inhibit protein synthesis in bacteria.

The precise mechanisms of action are not fully established for these drugs.

Bacteria have 70s ribosomes, whereas mammalian cells have 80s ribosomes.

The subunits of each type of ribosome, their chemical composition, and their functional specificities are sufficiently different to explain why antimicrobial drugs can inhibit protein synthesis in bacterial ribosomes without having a major effect on a mammal ribosomes.

In normal microbial protein synthesis, the mRNA message is simultaneously “read” by several ribosomes that are strung out along the mRNA strand. These are called polysomes.

Examples of drug acting by inhibition of protein synthesis are the erythromycins, lincomycins, tetracyclines, aminoglycosides, & chloramphenicol.

Inhibition of Protein Synthesis: Aminoglycosides

The mode of action of Streptomycin has been studied far

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more intensively than that of other aminoglycosides, but all probably act similarly.

The 1st step is the attachment of the aminoglycoside to a specific receptor protein (P 12 in the case of streptomycin) on the 30S subunit of the microbial ribosome.

2nd, the aminoglycoside blocks the normal activity of the “initiation on complex” of peptide formation (mRNA + formyl methicinine + tRNA)

3rd, the mRNA message is misread on the “recognition region” of the ribosome; consequently, the wrong amino acid is inserted into the peptide, resulting in a nonfunctional protein.

4th, aminoglycoside attachment results in the breakup of polysomes and their separation into monosomes incapable of protein synthesis.

o These activities occur more or less simultaneously, and the overall effect is usually an irreversible event – killing of the bacterium

Chromosomal resistance of microbes to aminoglycosides principally depends on the lack of specific protein receptor on the 30S subunit of the ribosome.

Plasmid-dependent resistance to aminoglycosides depends on the production by the microorganism of adenylylating, phosphorylating, or acetylating enzymes that destroy the drugs.

A 3rd type of resistance consist of a “permeability defect”, an outer membrane change that reduces active transport of the aminoglycoside into the cell so that the drug cannot reach the ribosome. Often this is plasmid-mediated.

Inhibition of Protein Synthesis: Macrolides, Azalides

These drugs (erythromycins, azithromycin, and clarithromycin)

bind to the 50S subunit of the ribosome, and the binding site is a 23S rRNA.

They may interfere with formation of initiation complexes for peptide chain synthesis or may interfere with aminoacyl translocation reactions.

Some macrolide-resistant bacteria lack the proper receptor on the ribosome (through methylation of the rRNA). This may be under plasmid or chromosomal control.

Inhibition of Protein Synthesis: Lincomycins

Clindamycin – binds to the 50S subunit of the microbial ribosome and resembles macrolides in binding site, antibacterial activity, and mode of action.

Chromosomal mutants are resistant because they lack the proper binding site on the 50S subunit

Inhibition of Protein Synthesis: Tetracyclines

Bind to the 30S subunit of the microbial ribosomes.

They inhibit protein synthesis by blocking the attachment of charged aminoacyl-tRNA

Thus, they prevent introduction of new amino acids to the nascent peptide chain.

The action is usually inhibitory and reversible upon withdrawal of the drug

Resistance to tetracyclines results from changes in permeability of the microbial cell envelope.

In susceptible cells, the drug is concentrated from the environment and does not readily leave the cell.

In resistant cells, the drug is not actively transported into the cell or leaves it so rapidly that inhibitory concentrations are not maintained.

This is often plasmid-controlled. Mammalian cells do not actively concentrate tetracyclines.

Inhibition of Protein Synthesis: Chloramphenicol

Binds to the 50S subunit of the ribosome.


It interferes with the binding of new amino acids to the nascent peptide chain, largely because chloramphenicol inhibits peptidyl transferase.

Chloramphenicol is mainly bacteriostatic, and growth of microoganisms resumes when the drug is withdrawn.

Microorganisms resistant to chloramphenicol produce the enzyme chloramphenicol acetyltransferase, which destroys drug activity

The production of this enzyme is usually under control of a plasmid.

Inhibition of Nucleic Acid Synthesis Examples of a drug acting by

inhibition of nucleic acid synthesis are the quinolones, pyrimethamine, rifampin, sulfonamides, trimethoprim, and trimetrexate.

Rifampin inhibits bacterial growth by

binding strongly to the DNA-dependent RNA polymerase of bacteria.

Thus, it inhibits bacterial RNA synthesis.

Rifampin resistance results from a change in RNA polymerase due to a chromosomal mutation that occurs with high frequency.

The mechanism rifampicin action on viruses is different. It blocks a late stage in the assembly of poxviruses

All quinolones and fluoroquinolones inhibit microbial DNA synthesis by blocking DNA gyrase.

For many microorganisms, p-aminobnzoic (PABA) is an essential metabolite.

The specific mode of acion of PABA involves an adenosine triphosphate (ATP)-dependent condensation of a peptide with PABA to yield dihyropteoic acid, which is subsequently converted to folic acid.

PABA is involved in the synthesis of folic acid, an important precursor to the synthesis of nucleic acids.

Inhibition of Nucleic Acid Synthesis: Sulfonamides

Sulfonamides are structural analog of PABA and inhibit dihydrioteroate synthetase

can enter into the reaction in place of PABA and compete for the active center of the enzyme.

As a result, nonfunctional analogs of folic acid are formed, preventing further growth of the bacterial cell.

The inhibiting action of sulfonamides on bacterial growth can be counteracted by an excess of PABA in the environment (competitive inhibition).

Animal cell cannot synthesize folic acid and must depend upon exogenous sources. Some bacteria, like animal cells, are not inhibited by sulfonamides. Many other bacteria, however, synthesize folic acid as mentioned above and consequently are susceptible to action by sulfonamides.

Inhibition of Nucleic Acid Synthesis: Trimethoprim

(3,4,5-trimethoxybenzylpyrimidine)inhibits dihydrofolic acid reductase 50,000 times more efficiently in bacteria than in mammalian cells.

This enzyme reduces dihydrofolic to tetrahydrofolic acid, a stage in the sequence leading to the synthesis of purines and ultimately of DNA.

Sulfonamides and trimethoprim each can be used alone to inhibit bacterial growth.

If used together, they produce sequential blocking, resulting in

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a marked enhancement (synergism) of activity. Such mixtures of sulfonamide

(five pats) plus trimethoprim (one part) have been used in the treatment of pneumocystis pneumonia, malaria, shigella enteritis, systemic salmonella infections, urinary tract infections, and many others.

Inhibition of Nucleic Acid Synthesis: Pyrimethamine

also inhibits dihydrofolate reductase, but it is more active against the enzyme in mammalian cells and therefore I more toxic than trimethoprim

pyrimethamine + sulfonamide or Clindamycin is the current treatment of choice in toxoplasmosis and some other protozoal infections.

Resistance to Antimicrobial Drugs there are many different mechanisms by

which microorganisms might exhibit resistance to drugs:

microorganisms produce enzymes that destroy the active microorganism might exhibit resistance to drugs

Examples: staphylococci resistant to penicillin G produce a β-lactamase that destroys the drug. Other β-lactamases are produced by gram (-) rods.

Gram (-) bacteria resistant to aminoglycoside (by virtue of a plasmid) produce adenylylating, phosphorylating, or acetylating enzymes that destroy drug.

Microorganisms change their permeability to the drug

Examples: tetracylines accumulate in succeptible bacteria but not in resistant bacteria.

Resistance to polymyxins is also associated with change in permeability to the drugs.

Streptococci have a natural permeability barrier to aminoglycosides.

This can be partly overcome by the simultaneous presence of a cell wall-active drug.

E.g., a penicillin Resistance to amikacin and to

some other aminglycsides may depend on a lack of permeability to the drugs, apparently due to an outer membrane change that impairs active transport into the cell.

Microorganisms develop an altered structural target for the rig

Examples: erythromycin-resistant organisms have an altered receptors on the 50S subunit of the ribosome, resulting from methylation of a 23S riboso,al RNA

Resistance to some penicillins and cephalosphorons may be a function of the loss or alteration of PBPs.

Penicillin resistance n Streptococcus pneumonia and enterococcie is due to altered PBPs.

Microorganisms develop an altered metabolic pathway that bypasses the reaction inhibited by the drug.

Example: Some sulfonamine-resistant bacteria do not require extracellular PABA but, like mammalian cells, can utilize preformed folic acid.

Microorganisms develop an altered enzyme that can still perform its metabolic function but is much less affected by the drug.

Example: in trimethoprim-resistant bacteria, the dihydrofolic acid reductase is inhibited far less efficiently than in trimethoprim-susceptible bacteria.

Origin of Drug Resistance: Nongenetic Origin of Drug Resistance


Active replication of bacteria is required for most antibacterial drug actions.

Consequently, microorganisms that are metabolically inactive (nonmultiplying) may be phenotypically resistant to drugs. However, their offspring are fully susceptible.

Example: Mycobacteria often survive in tissues for many years after infection yet are restrained by the host’s defenses and do not multiply.

Such “persisting” organisms are resistant to treatment and cannot be eradicated by drugs. Yet if they start to multiply (e.g., following suppression of cellular immunity in the patient) they are fully susceptible to the same drugs.

Microorganisms may lose the specific target structure for a drug for several generations and thus be resistant.

Example: Penicillin-susceptible organisms may change to cell wall-deficient L forms during penicillin administration.

Lacking cell walls, they are resistant to cell wall-inhibitor drugs (penicillin, cephalosphorins) and may remain so for several generations.

When these organisms revert to their bacterial parent forms by resuming cell wall production, they are again susceptible to penicillin.

Microorganisms may infect the host at sites where antimicrobials are excluded or are not active.

Examples: Aminoglycosides such as gentamicin are not effective in treating salmonella enteric fevers because the salmonellae are intracellular and the aminoglycosides do enter the cells.

Similarly, only drugs that enter cells are effective in treating legionnaires’ disease because of the intracellular location of Legionella pneumophila.

Origin of Drug Resistance: Genetic Origin of Drug Resistance

Most drug-resistant microbes emerge as a result of genetic change and subsequent selection processes by antimicrobial drugs

Origin of Drug Resistance: Chromosomal Resistance This develops as a result of

spontaneous mutation in a locus that controls susceptibility to a given antimicrobial drug.

The presence of the antimicrobial drug serves as a selecting mechanism to suppress susceptible organisms and favor the growth of drug-resistant mutants

Spontaneous mutation occurs with a frequency of 10-12 to 10-7 and thus is an infrequent cause of the emergence of clinical drug resistance in a given patient.

However, chromosomal mutants resistant to rifampin occur with high frequency (about 10-7 to 10-5).

Consequently, treatment of bacterial infections wit rifampin as the sole drug often falls.

Chromosomal mutants are most commonly resistant by virtue of a change in a structural receptor for a drug.

Thus, the P12 protein on the 30S subunit of the bacterial ribosome serves as a receptor for streptomycin attachment.

Mutation in the gene controlling that structural protein results in streptomycin resistant to β-lactam drugs.

Origin of Drug Resistance: Extrachromosomal Resistance

Bacteria often contain extrachromosomal genetic elements called plasmids

Some plasmids carry genes for resistance to one and often several antimicrobial drugs.

Plasmid genes for antimicrobial resistance often control the formation of enzymes capable of destroying the antimicrobial drugs.

Thus, plasmids determine resistance to penicillins and and cephalosporins by carrying genes for the formation of lactamases.

Plasmids code for enzymes that acetylate, adenylylate, or

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phosphorylate various aminoglycosides:

For enzymes that determine the active transport of tetracyclines across the cell membrane; and for others.

Genetic material and plasmids can be transferred by transduction, transformation, and conjugation.

Origin of Drug Resistance: Cross-Resistance

Microorganisms resistant to a certain drug may also be resistant to other drugs that share a mechanism of action.

Such relationship exist mainly between agents that are closely related chemically (e.g., different aminoglycosides) or that have a similar mode of binding or action (e.g., macrolides-lincomycins).

In certain classes of drugs, the active nucleus of the chemical is so similar among many congeners (e.g., tetracyclines) that extensive cross-resistance is to be expected.

Emergence of drug resistance in infections may be minimized in the following ways:

(1.) by maintaining sufficiently high levels of the drug in the tissues to inhibit both the original population and first-step mutants;

(2) by simultaneously administering two drugs that do not give cross-resistance, each of which delays the emergence of mutants resistant to the other drug (e.g., rifampin and isoniazid in the treatment of tuberculosis);

(3) by avoiding exposure if microorganisms to a particularly valuable drug by limiting its use, especially in hospitals

Clinical Implications of Drug Resistance: Gonococci

When sulfonamides were first employed in the late 1930s for the treatment of gonorrhea, virtually all isolates of gonococci were

susceptible and most infections were cured.

A few years later, most strains had become resistant to sulfonamides, and gonorrhea was rarely curable by these drugs.

Most gonococci were still highly susceptible to penicillin

Over the next decades, there was a gradual increase in resistance to penicillin, but large doses of that drug were still curative.

In the 1970s, β-lactamase-producing gonococci appeared, first in the Philippines and in West Africa, and then spread to form endemic foci worldwide.

Such infections could not be treated effectively by penicillin but were treated with spectinomycin.

Resistance to spectinomycin hhas appeared.

Third-generation cephalosporins or quinolones are recommended to treat gonorrhea.

Clinical Implications of Drug Resistance: Meningococci

Until 1962, meningococci were uniformly susceptible to sulfonamides, and these drugs were effective for both prophylaxis and therapy.

Subsequently, sulfonamide-resistant meningococci spread widely, and the sulfonamides have bow lost their usefulness against meningococcal infections.

Penicilllins remain effective for therapy and rifampin is employed for prophylaxis.

However, rifampin-resistant meningococci persist in about 1% of individuals who have received rifampin for prophylaxis.

Clinical Implications of Drug Resistance: Staphylococci

In 1944, most staphylococci were susceptible to penicillin G, though a few resistant strains had been observed.

After massive use of penicillin, 65-85% of staphylococci isolated from hospitals in 1948 were β-lactamase producers and thus resistant to penicillin G.


The advent of β-lactamase-resistant penicillins, (e.g., nafcillin) provided a temporary respite, but infections due to nafcillin-resistant staphylococci are common.

Presently, penicillin-resistant staphylococci include not only those acquired in hospitals but also 80-90% of those isolated in the community.

These organisms also tend to be resistant other drugs, e.g., tetracyclines.

Nafcillin-resistant staphylococci ae common in tertiary hospitals.

Vancomycin has been the major drug used for treatment of nafcillin-resistant S aureus infetions, but some strains of S aureus have become of intermediate susceptibility to vancomycin in vitro and may be clinically resistant in vivo.

Clinical Implications of Drug Resistance: Pneumococci

Streptococcus pneumonia was uniformly susceptible to penicillin G until 1963, when relatively penicillin-resistant strains were found in New Guinea.

Penicillin-resistant pneumococci subsequently were found in South Africa, Japan, Spain, and later worldwide.

In the United States, 5-10% of pneumococci are resistant to penicillin G (MICs of >2 g/mL) and approximately 20% are moderately resistant (MICs of 0.2-2 g/mL).

The penicillin resistance is due to altered penicillin-binding proteins.

Penicillin resistance in pneumococci tends to be clonal.

Pneumococci also are frequently resistant to trimethoprim-sulfamethoxazole and sometimes to erythromycin and tetracycline.

Clinical Implications of Drug Resistance: Enterococci

The enterococci have intrinsic resistance to multiple antimicrobials: Penicillin G and ampicillin with high MICSs; cephalosporins with very high MICs; low-level resistance to aminoglycosides; and resistance to

trimethoprim-sulfamethoxazole in vivo.

The enterococci also have shown acquired resistance to almost all if not all other antimicrobials as follows: altered PBPs and resistane to β-lactams; high-level resistance to aminoglycosides; and resistance to fluoroquinolones, macrolides, azalides, and tetracyclines.

Some enterococci have acquired a plasmid that encodes for β-lactamse and are fully resistant to penicillin and ampicillin.

Of greatest importance is the development of resistance to vancomycin, which has become common in Europe and North America though there is geographic variation in the percentages of enterococci that are vancomycin-resistant.

Enterococcus faecium is the species that is most commonly vancomycin-resistant in outbreaks of infections due to vacomycin-resistant enterococci, the isolates may be clonal genetically diverse.

Resistance to the streptogramins. (quinupristin-dalfopristin) aslo occurs in enterococci.

Clinical Implications of Drug Resistance: Gram-Negative Enteric Bacteria

Most drug resistance in enteric bacteria is attribute to the widespread transmission of resistance plasmids among different genera.

About half the strains of shigella species in many parts of the world are now resistant to multiple drugs.

Salmonallae carried by animals have developed resistance also, particularly to drugs (especially tetracycines) incorporated into animal feeds.

The practice of incorporating drugs unto animals feeds causes farm animals to grow mor rapidly but is associated with an increase in drug-resistant enteric organisms in the fecal flora of farm workers.

A concomitant rise in drug-resistant salmonella infections in Britain led to a restriction on antibiotic supplements in animal feeds.

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Continued use of tetracycline supplements in animal feeds in the United States may contribute to the spread of resistance plasmids, and drug-resistant salmonellae.

Plasmids carrying drug resistance genes occur in may gram-negative bacteria of the normal gut flora.

The abundant use of anti-microbial drugs – particularly in hospitalized patients – leads to the suppression of drug – susceptible organisms in the gut flora and favors the persistence and growth of drug-resistant bacteria, including enterobacter, klebsiella, proteus, pseudomonas, and serratia – and fungi.

Such organisms present particularly difficult problems in granulocytopenic and immunocompromised patients.

The closed environments of hospitals favor transmission of such resistant organisms through personnel and fomites as well as by direct contact.

Clinical Implications of Drug Resistance: Mycobacterium Tuberculosis

Primary drug resistance in M tuberculosis occurs in about 10% isolates and most commonly is to isoniazid or streptomycin.

Resistance to rifampin or ethambutol is less common. Isoniazid and rifampin or ethambitol is less common. Isoniazid and rifampin are the primary drugs used in most standard treatment regimen; other first-line drugs are pyrazinamide, ethambutol, and streptomycin.

Resistance to isoniazid and rifampin is considered multiple drug resistance.

In the United States, multiple drug resistance of M tuberculosis ranges from nil to 30%

Worldwide, the highest rates of multidrug-resistant tuberculosis have been reported from Nepal (48%), Gujarat, India (33.8%), New York (30.1%), Bolivia (15.3%), and Korea (14.5%)

Poor compliance with drug treatment is a major factor in the development of drug resistance during therapy.

Control of multidrug-resistant tuberculosis is a significant worldwide problem.

Antimicrobial Activity in Vitro Antimicrobial activity is measured in

vitro in order to determine:o The potency of an

antibacterial agent in solutiono Its concentration in body

fluids or tissue, ando The susceptibility of a given,

microorganism to known concentrations of the drug

Factors affecting Antimicrobial Activity

1. pH of environmento Some drugs are more active at

acid pH (eg, nitrofurantion); other, at alkaline pH (eg, aminoglycosides, sulfonamides)

2. Components of Mediumo Sodium polyanetholsufonate (in

blood culture media) and other anionic detergents inhibits aminoglycosides

o PABA in tissues extracts antagonizes sulphonamides. Serum proteins bind penicillins in varying degrees, ranging from 40% for methicillin to 98% for dicloxacillin

o Addition of NaCl to the medium enhances the detection of methicillin resistance in S. aures

3. Stability of Drugo At incubator temperature,

several antimicrobial agents lose their activity

o Peniciilins are inactivated slowly, whereas aminoglycosides and ciprofloxacin are quite stable for long periods

4. Size of Inoculumo In general, the larger the

bacterial inoculum, the lower the apparent “susceptibility” of the organism

o Large bacterial populations are less promptly and completely inhibited than smaller ones


o In addition, a resistant mutant is more likely to emerge in large populations

5. Length of Incubationo In many instances,

microorganisms are not killed but only inhibited upon short exposure to antimicrobial agents

o The longer incubation continues, the greater the chance for resistant mutants to emerge or for the least susceptible members of the antimicrobial population to begin multiplying as the drug deteriorates

6. Metabolic activity of Microorganismso In general, actively and rapidly

growing organisms are more susceptible to drug action than those in the resting phase

o Metabolically inactive organisms that survive long exposure to a drug may have offspring that are fully susceptible to the same drug

Measurement of Antimicrobial Activity Determination of the susceptibility

of a bacterial pathogen to antimicrobial can be done by one of 2 principal methods: dilution or diffusion

It is important to use a standardized method that controls for all the factors that affect antimicrobial activity; in the United States, the tests are performed according to the methods of the National Committee for Clinical Laboratory Standards (NCCLS)

Using an appropriate standard test organism & a known sample of drug for comparison, these methods can be employed to estimate either the potency of antibiotic in the sample or the susceptibility of the microorganism

Dilution Method: Graded amounts of antimicrobial

substances are incorporated into liquid or solid bacteriologic media

Commonly, twofold (log2) dilutions of the antimicrobial substances are used

The media are subsequently inoculated with test bacteria and incubated

The end point is taken as that amount of antimicrobial substance required to inhibit the growth of or to kill the test bacteria

Agar dilution susceptibility tests are time-consuming, and their use is limited to special circumstances

Broth dilution tests were cumbersome and little used when dilutions had to be made in test tubes; however, the advent of prepared broth dilution series for many different drugs in microdilution plates has greatly enhanced and simplified the method

The advantage of microdilution broth dilution tests:

o They permit a quantitative result to be reported, indicating the amount of a given drug necessary to inhibit (or kill) the microorganisms tested

Diffusion Method:Disk diffusion test – the most widely used method

A filter paper disk containing a measured quantity of a drug is placed on the surface of a solid medium that has been inoculated on the surface of a solid medium that has been inoculated on the surface with the test organism

After incubation, the diameter of the clear zone of inhibition surrounding the disk is taken as a measure of the inhibitory power of the drug against the particular test organism

This method is subject to many physical and chemical factors in addition to the simple interaction of drug and organisms (eg, the nature of the medium and diffusibility, molecular size, and the stability of the drug)

Nevertheless, standardization of conditions permits determination of the susceptibility of the organism

Interpretation of the results of diffusion tests must be based on comparisons between dilution and diffusion methods

Such comparisons have led to the establishment of reference standards

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Linear regression lines can express the relationship between log of minimum inhibitory concentration in dilution tests and diameter of inhibition zones in diffusion tests

Use of a single disk for each antibiotic with careful standardization of the test conditions permits the report of susceptibility or resistant for a microorganism by comparing the size of the inhibition zone against a standard of the same drug

Inhibition around a disk containing a certain amount of antimicrobial drug does not imply susceptibility to the same concentration of drug per millilitre of medium, blood, or urine

Drug-Pathogen Relationships Environment

o In the host, varying environmental influences affect microorganisms located in different tissues and in different parts of the body in contrast to the test tube or Petri dish, where the environment is constant for all members of a microbial population

o Therefore, the response of the microbial population is much less uniform within the host than in the test tube

State of metabolic activityo In the body, the state of

metabolic activity is diverse undoubtedly, many organisms exist at a low level of biosynthetic activity and are thus relatively insusceptible to drug action

o These “dormant” microorganisms often survive exposure to high concentrations of drugs and subsequently may produce a clinical relapse of the infection

Distribution of Drugo In the body, the antimicrobial

agent is unequally distributed in tissues and fluids

o Many drugs do not reach the central nervous system effectively

o The concentration in urine is often much greater than the concentration in blood or other tissue

o The tissue response induced by the microorganism may protect it from the drug

o Necrotic tissue or pus may adsorb the drug and thus prevent its contact with bacteria

Location of organismso In the body, microorganisms

often are located within tissue cells

o Drugs enter tissue cells at different rates. Some (eg, tetracylcines) reach about the same concentration inside monocytes as in the extracellular fluid

o With others (eg, gentamicin), the drug probably does not enter host cells at all

o This is in contrast to the test tube, where microorganisms come into direct contact with the drug

Interfering subtanceso The biochemical environmental

of microorganisms in the body is very complex and results in significant interference with drug action

o The drug may be bound by blood and tissue proteins or phospholipids; it may also react with nucleic acids in pus and may be physically adsorbed onto exudated, cells, and necrotic debris

o In necrotic tissue, the pH may be highly acid and thus unfavourable for drug action (eg, aminoglycosides)

o The biochemical environment of microorganisms in the body is very complex and results in significant interference with drug action

o The drug may be bound by blood and tissue proteins or phospholipids; it may also react with nucleic acids in pus and may be physically adsorbed onto exudates, cells, and necrotic debris


o In necrotic tissue, the pH may be highly acid and thus unfavourable for drug action (eg, aminoglycosides)

Concentrationo In the body, microorganisms are

not exposed to a constant concentration of drug; in the test tube they are

Absorptiono The absorption of drugs from the

intestinal tract (if taken by mouth) or from tissues (if injected) is irregular

o There is also a continuous excretion as well as inactivation of the drug

o Consequently, the levels of drug in body compartments fluctuate continually, and the microorganisms are exposed to varying concentrations of the antimicrobial agent

Distributiono The distribution of drugs varies

greatly with different tissues. Some drugs penetrate certain tissues poorly (eg, CNS, prostate)

o Drug concentrations following systemic administration may therefore be inadequate for effective treatment

o On surface wounds or mucous membranes such as the conjunctivas, local (topical) application of poorly absorbed drugs permits highly effective local concentrations without toxic side effects

o Alternatively, some drugs applied topically on surface wounds are well absorbed

o Drug concentrations in urine are often much higher than in blood

Variability of concentrationo It is critical to maintain an

effective concentration of a drug where the infecting microorganisms proliferate

o This concentration must be maintained for a sufficient length of time to eradicate the microorganisms

o Because the drug is administered intermittently and is absorbed and excreted irregularly, the

levels constantly fluctuate at the site of infection

o In order to maintain sufficient drug concentrations for a sufficient time, the time-dose relationship must be considered

o The larger each individual drug dose, the longer the permissible interval between doses

o The smaller the individual dose, the shorter the interval that will ensure adequate drug levels

Post antibiotic effecto The post antibiotic effect is the

delayed regrowth of bacteria after exposure to antimicrobial agents

o It is properly of most antimicrobials, except that most β-lactams do not show the post antibiotic effect with gram negative bacilli

o The carbapenems do have a post antibiotic effect with the gram negative bacilli

Host-Pathogen Relationship Alteration of tissue response

o The inflammatory response of the tissue to infections may be altered if the drug suppresses the multiplication of microorganisms but does not eliminate the from the body

o And acute process may in this way be transformed into a chronic one

o Conversely, the suppression of inflammatory reactions in tissues by impairment of cell-mediated immunity in recipients of tissue transplants or antineoplastic therapy or by immune compromise as a result disease (eg, AIDS) cause enhanced susceptibility to infection and impaired responsiveness to antimicrobial drugs

Alteration of immune reponseo If an infection is modified by an

antimicrobial drug, the immune response of the host may also be altered- One example illustrates this

phenomenon: Pharyngeal

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infection with haemolytic group A streptococci is followed frequently by the development of anti-streptococcal antibodies, and if there is a hyper immune response the infection may be followed by rheumatic fever

o If the infective process can be interrupted early and completely with antimicrobial drugs, the development of an immune response and of rheumatic fever can be prevented (presumably by rapid elimination of the antigen)

o Drugs and dosages that rapidly eradicate the infecting streptococci (eg, penicillin) are more effective in preventing rheumatic fever than those which merely suppress the microorganisms temporarily (eg, tetracycline)

Alteration of microbial florao Antimicrobial drugs affect not

only the microorganisms causing disease but also susceptible members of the normal microbial flora

o An imbalance is thus created that in itself may lead to disease. A few examples are of interest1. In hospitalized patients who

receive antimicrobials, the normal microbial flora Is suppressed This creates a partial void

that Is filled by the organisms most prevalent in the environment, particularly drug resistant gram negative aerobic bacteria (eg, pseudomonads, staphylococci)

Such superinfecting organisms subsequently may produce serious drug-resistant infections

2. In women taking antibiotics by mouth, the normal vaginal flora may be suppressed, permitting marked overgrowth of candida

This leads to unpleasant local inflammation (vulvo vaginitis) and itching that are difficult to control

3. In the presence of urinary tract obstruction, the tendency to bladder infection is great When such urinary tract

infection due to a sensitive microorganism (eg, Escherichia coli) is treated with an appropriate drug, the organism may be eradicated

However, it often happens that reinfection due to another drug-resistant gram negative bacillus occurs after the drug sensitive microorganisms are eliminated

A similar process accounts for respiratory tract super infections in patients given antimicrobials for chronic bronchitis

4. In persons receiving antimicrobial drugs for several days, parts of the normal intense flora may be suppressed Drug resistant organisms

may establish themselves in the bowel in great numbers and may precipitate serious enterocolitis (Clostridium difficile, etc)

Clinical Use of AntibioticsSelection of antibiotics

o Diagnosiso A specific etiologic diagnosis

must be formulatedo This can often be done on the

basis of a clinical impressiono Thus, in typical lobar pneumonia

or acute urinary tract infection, the relationship between clinical picture and causative agent is sufficiently constant to permit selection of the antibiotic of choice on the basis of clinical impression alone


o Even in these cases, however, as a safeguard against diagnostic error, it is preferable to obtain a representative specimen for bacteriologic study before giving antimicrobial drugs

o In most infections, the relationship between causative agent and clinical picture is not constant

o It is therefore important to obtain proper specimens for bacteriologic identification of the causative agent

o As soon as such specimens have been secured, chemotherapy can be started on the basis of the “best guess”

o Once the causative agent has been identified by laboratory procedures, the initial regimen can be modified as necessary

o The “best guess” of a causative organism is based on the following considerations, among others:1. The site of infection (eg,

pneumonia, UTI)2. The age of the patient (eg,

meningitis: neonatal, young child, adult)

3. The place where the infection was acquired (hospital vs community)

4. Mechanical predisposing factors (intravenous drip, urinary catheter, respirator, exposure to vector)

5. Predisposing host factors (immunodeficiency, corticosteroids, transplant, cancerchemotherapy)

o Susceptibility testso Laboratory tests for antibiotic

susceptibility are indicated in the following circumstances1. When the microorganism

recovered is of a type that is often resistant to antimicrobial drugs (eg, gram negative enteric bacteria)

2. When an infectious process is likely to be fatal unless treated specifically (eg, mengitis, septicaemia)

3. In certain infections where eradication of the infectious organisms requires the use of drugs that are rapidly bactericidal, not merely bacteriostatic (eg, infective endocarditis)

Dangers of Indiscriminate Useo The indications for administration of

antibiotics must sometimes be qualified by the following concerns1. Widespread sensitization of the

population, with resulting hypersensitivity, anaphylaxis, rashes, fever, blood disorders, cholestatic hepatitis,, and perhaps collagen-vascular diseases

2. Changes in the normal flora of the body, with disease resulting from “superinfection” due to overgrowth of drug-resistant organisms

3. Wala pic4. Wala pic5. Development of drug resistance

in microbial populations, chiefly through the elimination of drug-sensitive microorganisms from antibiotic-saturated environments (eg, hospitals) and their replacement by drug-resistant microorganisms

Antimicrobial Drugs Used in CombinationIndications:

o Possible reasons for employing two or more antimicrobials simultaneously instead of a single drug are as follows:1. To give prompt treatment in

desperately ill patients suspected of having a serious microbial infectiono A good guess about the most

probable two or three pathogens is made, and drugs are aimed at those organisms

o Before such treatment is started, it is essential that adequate specimens be obtained for identifying the etiologic agent in the laboratory

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o Suspected gram-negative or staphylococcal sepsis in immunocompromised patients and bacterial meningitis in children are foremost indications in this category

2. To delay the emergence of microbial mutants resistance to one drug in chronic infections by the use of a second or third non-cross-reacting drug. The most prominent example is active tuberculosis

3. To treat mixed infections, particularly those following massive trauma or those involving vascular structures, each drug is aimed at an important pathogenic microorganisms

4. To achieve bactericidal synergism or to provide bactericidal actiono In a few infections, eg,

enterococcal sepsis, a combination of drugs is more likely to eradicate the infection than either drug used alone

5. Such synergism is only partially predictable, and a given drug pair may be synergistic for only a single microbial staino Occasionally, simultaneous

use of two drugs permits significant reduction in dose and thus avoids toxicity but still provides satisfactory antimicrobial action

Disadvantages:o The following disadvantages of

using antimicrobial drugs in combinations must always be considered:1. The physician may feel that since

several drugs are already being given, everything possible has been done for the patient, leading to relaxation of the effort to establish a specific diagnosis. It may also give a false sense of security

2. The more drugs that are administered, the greater the chance for drug reactions to

occur or for the patient to become sensitized to drugs

3. The cost is unnecessarily high4. Antimicrobial combinations

usually accomplish no more than an effective single drug

5. Very rarely, one drug may antagonize a second drug given simultaneously

Mechanisms:o When two antimicrobial agents act

simultaneously on a homogenous microbial population, the effect may be one of the following:1. Indifference, ie, the combined

action is no greater than that of the more effective agent when used alone

2. Addition, ie, the combined action is equivalent to the sum of the actions of each drug when used alone

3. Synergism, ie, the combined action is significantly greater than the sum of both effects

4. Antagonism, ie, the combined action is less than that of the more effective agent when used alone. All these effects may be observed in vitro (particularly in terms of bactericidal rate) and in vivo

o The effects that can be achieved with combinations of antimicrobial drugs vary with different combinations and are specific for each strain of microorganism

o Thus, no combination is uniformly synergisitic

o Combined therapy should be made to employ the single antibiotic of choice

o In resistant infections, detailed laboratory study can at times define synergistic drug combinations that may be essential to eradicate the microorganisms

Mechanisms: Antimicrobialsynergismo Can occur in several types of

situations. Synergistic drug combinations must be selected by complex laboratory procedures1. Two drugs may sequentially

block a microbial metabolic


pathway. Sulfonamides inhibit the use of extracellular p-aminobenzoic acid by some microbes for the synthesis of folic acido Trimethoprim or

pyrimethamine inhibits the next metabolic step, the reduction of dihydro- to tetrahydrofolic acid

o The simultaneous use of a sulphonamide plus trimethoprim is effective in some bacterial (shigellosis, salmonellosis, serratia) and some other infections (pneumocystosis, malaria)

o Pyrimethamine plus a sulfonamide or clindamycin is used in toxoplasmosis

2. A drug such as a cell inhibitor (a penicillin or cephalosporin) may enhance the entry of an aminoglycoside into bacteria and thus produce synergistic effectso Penicillins enhance the

uptake of gentamicin or streptomycin by enterococci

o Thus, ampicillin plus gentamicin may be essential for the eradication of Enterococcus faecalis, particularly in endocarditis

o Similarly, piperacillin plus tobramycin may be synergistic against some strains of pseudomonas

3. One drug may affect the cell membrane and facilitate the entry of the second drugo The combined effect may

then be greater than the sum of its parts

o For example, amphotericin has been synergistic with flucytosine against certain fungi (eg, Cryptococcus, candida)

4. One drug may prevent the inactivation of a second drug by microbial enzymeso Thus, inhibitors of β-

lactamase (eg, clavulanic acid, sulbactam, tazobactam) can protect amoxicillin, ticarcilliin, or piperacillin from inactivation by β-lactamases

o In such circumstances, a form of synergism takes place

Mechanisms: Antimicrobial antagonismo Is sharply limited by time-dose

relationships and is therefore a rare event in clinical antimicrobial therapy

o Antagonism resulting in higher morbidity and mortality rates has been most clearly demonstrated in bacterial meningitis

o It occurred when bacteriostatic drug (which inhibited protein synthesis in bacteria) such as chloramphenicol or tetracycline was given with a bactericidal drug such as a penicillin or an aminoglycoside

o Antagonism occurred mainly if the bacteriostatic drug reached the site of infection before the bactericidal drug; if the killing of bacteria was essential for cure; and if only minimal effective doses of either drug in the pair were present

o Another example is combining β-lactam drugs in treatment of P aeruginosa infections (eg, imipenem and piperacillin, where imipenem is a potent β-lactamase inducer and the β-lactamase breaks down the less stable piperacillin)

Antimicrobial Chemoprophylaxiso Anti-infective chemoprophylaxis

implies the administration of antimicrobial drugs to prevent infection

o In a broader sense, it also includes the use of antimicrobial drugs soon after the acquisition of pathogenic microorganisms (eg, after compound fracture) but before the development of signs of infection

o Useful chemoprophylaxis is limited to the action of a specific drug on a specific organism

o An effort to prevent all types of microorganisms in the environment from establishing themselves only selects the most drug resistant organisms as the cause of a subsequent infection

o In all proposed uses of prophylactic antimicrobials, the risk of the patient’s acquiring an infection must be weighed against the toxicity,

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cost, inconvenience, and enhances risk of superinfection resulting from the prophylactic drug

Prophylaxis in persons of normal susceptibility exposed to a specific pathogen

In this category, a specific drug is administered to prevent one specific infectiono Outstanding examples are the

injection of benzathine penicillin G intramuscularly once every 3-4 weeks to prevent reinfection with group A haemolytic streptococci in rheumatic patients

o Prevention of meningitis by eradicating the meningococcal carrier state with rifampin

o Prevention of syphilis by the injection of benzathine penicillin G

o Prevention of plague pneumonia by oral administration of tetracycline in persons exposed to infections droplets

o Prevention of clinical rickettsial disease (but not of infection) by the daily ingestion of tetracycline during exposure

o Prevention of leptospirosis with oral administration of doxycycline in a hyper endemic environment

o Early treatment of an asymptomatic infections is sometimes called prophylaxis

o Thus, administration of isoniazid, 6-10mg/kg/day (maximum, 300mg/day) orally for 6-12 months, to an asymptomatic person who converts from a negative to a positive tuberculin skin test may prevent later clinically active tuberculosis

Prophylaxis in persons of increased susceptibility

Certain anatomic or functional abnormalities predispose to serious infections

It may be feasible to prevent or abort such infections by giving a specific drug for short period

Prophylaxis in persons of increased susceptibility:Heart Disease

Persons with heart valve abnormalities or with prosthetic heart valves are unusually susceptible to implantation of microorganisms circulating in the bloodstream

This infective endocarditis can sometimes be prevented if the proper drug can be used during periods of bacteremia

Large numbers of viridants streptococci are pushed into the circulation during dental procedures and operations on the mouth or throat

At such times, the increased risk warrants the use of a prophylactic antimicrobial during aimed at viridans streptococcio for example, amoxicillin taken

orally before the procedure and 2 hrs later can be effective

o persons allergic to penicillin can take erythromycin orally

o other oral and parenteral dosage schedules can be effective

enterococci cause 5-15% of cases if infective endocarditis

they reach the bloodstream from the urinary, gastrointestinal or female genital tract

during procedures in these areas, persons with prostheses or heart valve abnormalities can be given ampicillin combined with an aminoglycoside (eg, gentamicin), both administered intramuscularly or intravenously 30 minutes before the procedure

during and after cardiac catheterization, blood cultures may be positive in 10-20% of patients

many of these persons also have fever, but very few acquire endocarditis

prophylactic antimicrobials do not appear to influence these events

Prophylaxis in persons of increased susceptibility:Respiratory Tract Disease

persons with functional and anatomic abnormalities of the


respiratory tract – eg, chronic obstructive pulmonary disease (COPD) or bronchiectasis – are subject to attacks of chronic bronchitis

this is a recurrent bacterial infection, often precipitated by acute viral infection and resulting in respiratory decompensation

the most common organisms are pneumococci & H. influenza

antibiotics may be given to patients with COPD in the following clinical setting: as prophylaxis for patients with frequent recurrences of chronic bronchitis, to treat an acute episode of bronchitis, or to treat severe exacerbations of COPD

there is little evidence supporting the use of prophylactic antibiotics, but patients with acute exacerbations of chronic bronchitis with changes in the character or quantity of their sputum do benefit from antibiotic therapy

simple prophylaxis of bacterial infection has been applied to children with cystic fibrosis who are not hospitalized

in spite of this, such children contract complicating infections caused by pseudomonads and staphylococci

trimethoprim-sulfamethoxazole orally or pentamidine by aerosol is used for prophylaxis for pneumocystis pneumonia in AIDS patients

for certain women who are subject to frequently recurring urinary tract infections, the oral intake either daily or three times weekly of nitrofurantion or trimethoprim-sulfamethoxazole cane markedly reduce that frequency of symptomatic recurrences over long periods

certain women tend to develop symptoms of cystitis after sexual intercourse

the ingestion of a single dose of antimicrobial drug (nitrofurantion, trimethoprim-sulfamethoxazole, etc) can prevent post coital cystitis by early inhibition of growth of bacteria moved from the introitus into the proximal urethra or bladder during intercourse

Prophylaxis in persons of increased susceptibility:Oppotunistic Infections in Severe Granulocytopenia

immunocompromised patients receiving organ transplants or antineoplastic chemotherapy often develop profound leukopenia

when the neutrophil count falls below 1000/L, they become unusually susceptible to opportunistic infections, most often gram-negative sepsis

such persons are sometimes given a fluoroquinolone or cephalosphorin or a drug combination (eg, vancomycin, gentamicin, cephalosporin) directed at the most prevalent opportunists at the earlieast sign or even without clinical evidence of infection

this is continued for several days until the granulocyte count rises again

Prophylaxis in Surgery a major portion of all antimicrobial

drug used in hospitals Is employed on surgical services with the stated intent of prophylaxis

several general features of surgical prophylaxis merit consideration:1. in clean elective surgical

procedures (ie, procedures during which no tissue bearing normal flora is traversed other than the prepared skin), the disadvantages of “routine” antibiotic prophylaxis (allergy, toxicity, superinfection) may outweigh the possible benefits except when hardware (eg. Artificial hip joint) is being placed however, even in “clean”

herniorrhaphy, a single preoperative dose of a cephalosporin resulted in measurable benefit

2. prophylactic administration of antibiotics should generally be considered only if the expected rate of infectious complications is 3-5% an exception to this rule is

the elective insertion of prostheses (cardiovascular, orthopaedic), where a

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possible infection would have a catastrophic effect

3. The initial dose of systemic prophylactic antibiotic should be given at the time of induction of anesthesia. An exception is elective colonic surgery, in which case oral antibiotics should be given before the procedure

4. Prolonged administration of antimicrobial drugs tends to alter the normal flora of organ systems, suppressing the susceptible microorganisms and favouring the implantation of drug-resistant ones Thus, antimicrobial

prophylaxis should usually continue for no more than 1 day after the procedure and ideally should be given only preoperatively

5. Systemic levels of antimicrobial drugs usually do not prevent wound infection, pneumonia, or urinary tract infection if physiologic abnormalities or foreign bodies are present Topical antimicrobials for

prophylaxis (intravenous catheter site, closed urinary drainage, within a surgical wound, acrylic bone cement, etc) have limited usefulness

Disinfectants Disinfectants and antiseptics differ

from systematically active antimicrobials in that they possess little selective toxicity: They are toxic not only for microbial pathogens but for host cells as well

Therefore, they can be used only to inactivate microorganisms in the inanimate environment or to a limited extent, on skin surfaces

They cannot be administered systematically


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