General Principles of Chemotherapy
Many of the same basic principles apply to antimicrobial, antiparasitic and anticancer chemotherapy.
Selective Toxicity:
Selective toxicity refers to the ability of the drug to targets sites that are relative specific to the microorganism responsible for infection.
Sometimes these sites are unique to the microorganism or simply more essential to survival of the microorganism than to the host.
Examples of such specific or relatively specific sites include specific fungal or bacterial cell wall synthesizing enzymes, the bacterial ribosomal or the molecular machinery of viral replication.
Chambers, H.F., Hadley, W. K. and Jawetz, E. Introduction to Antimicrobial Agents in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 723.
Chemotherapeutic Drug Targets
Targets for Antimicrobial/Antiviral Drugs
Bacterial Cell Wall Synthesis Inhibitors
Agents that Increase Cell Membrane Permeability
Protein Synthesis Inhibitors: interfere with 30S or 50S bacterial ribosome function
Drugs that Bind to the 30S bacterial ribosomal subunit, leading to cell death
Agents that interfere with nucleic acid synthesis
Antimetabolites
Inhibitors of Viral Replication
Bacterial cell wall synthesis inhibitors:
penicillins
cephalosporins
cycloserine
vancomycin (Vancocin)
bacitracin
miconazole (Monistat)(imidazole antifungal)
ketoconazole (Nizoral)(imidazole antifungal)
clotrimazole (Mycelex)(imidazole antifungal)
Agents that increase cell membrane permeability
polymixins (detergent)
colistimethate (detergent)
nystatin (Mycostatin)(polyene antifungal)
amphotericin B (Fungizone, Amphotec)(polyene antifungal)
Protein synthesis inhibitors: interfere with 30S or 50S bacterial ribosome function.
Bacteriostatic
chloramphenicol (Chloromycetin)
tetracyclines
erythromycin estolate (Ilosone)
clindamycin (Cleocin)
Drugs that bind to the 30S bacterial ribosomal subunit, leading to cell death.
Bacteriocidal
Aminoglycosides (e.g.gentamicin (Garamycin), tobramycin (Nebcin))
Agents that interfere with nucleic acid synthesis
rifamycins (rifampin (Rimactane)): inhibits DNA-dependent RNA polymerase
quinolones: inhibit gyrase
Antimetabolites
sulfonamides
trimethoprim (generic)
Some Nucleic Acid Analogs (Antivirals): inhibitors of viral replication
zidovudine (Retrovir, AZT, azidothymidine)
ganciclovir (DHPG, Cytovene)
vidarabine (Vira-A)
acyclovir (Zovirax)
Chambers, H.F and Sande, M.A. Antimicrobial Agents in,In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.1029-1030
Disease caused by bacteria and the the role of the host response in outcome of chemotherapeutic intervention.
Importance of Host Response
Host response as manifest in the inflammatory response is crucial for both the interruption resolution of the infection and for the basis of the infection's signs and symptoms.
The ability of effective antibiotic chemotherapy depends not only on appropriate selection of medication(s), dosage, and interval, but also on the host immune response.
Pier, G.B. Molecular Mechanism of Bacterial Pathogenesis., In Harrison's Principles of Internal Medicine (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1994, p. 592.
Disease Manifestations of Bacterial Disease
Disease manifestation of bacterial infection involves:
Colonization
Invasion: Bacterial invasion refers to the presence of bacteria in tissue sites normally sterile.
Examples:
Gram-negative rods in the blood stream result in septisemia and bacteremia without requiring endotoxin involvement
Pneumococcal pneumonia is due the growth of Streptococcus pneumoniae in the lung while bacterial endotoxins do not appear to play a role.
Disease that occurs after bactermia and invasion of the meninges by meningitis-producing bacteria (N. meningitidis, H. influenzae, E. coli, K1 and group B streptococci) is due to tissue destruction secondary to bacterial growth and host inflammation.
Toxin production and release
Toxin Elaboration
Clinicial manifestation of some bacterial infections are primarily due to toxin elaboration.
For example: Botulinum toxin: C. botulinum, Tetanus toxins: C. tetani, Diptheria toxin causes the disease due to infection with C. diphtheriae
Some specific aspects of bacterial disease are caused by elaborated toxins
Enterotoxins cause the diarrhea associated with E. coli, Salmonella, Shigella, Staphylococcus and V. cholerae.
Toxins involved in Toxic shock syndrome caused by Staphylococci, steptococci, P. aeruginosa and Bordatella: include: Toxic shock syndrome toxin (TSST), erythrogenic toxin, exotoxin A and pertussis toxin.
Staphylococcal enterotoxins, TSST-1 and streptococcal exotoxins have been classified as superantigens which are capable of inducing certain T cell proliferation without processing of the protein toxin by antigen-presenting cells.
This process involves, in part, the elaboration of IL-1 and TNF-alpha which may cause many clinical features seen in staphylococcal toxic shock syndrome, scarlet fever, streptococcal toxic shock syndrome.
Pier, G.B. Molecular Mechanism of Bacterial Pathogenesis., In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 855.
Endotoxins (lipid A portion of gram-negative LPS) may cause many clinical presentations seen in gram-negative bacterial sepsis: Toxins involve include: IL-1 and TNF-alpha--
Clinical presentations include:fever, intravascular coagulation, shock, and muscle proteolysis.
Pier, G.B. Molecular Mechanism of Bacterial Pathogenesis., In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 855.
Importance of Host Response
Host response as manifest in the inflammatory response is crucial for both interruption and infection resolution and the infection's signs and symptoms.
The ability of effective antibiotic chemotherapy depends not only on appropriate selection of medication(s), dosage, and interval, but also on the host immune response.
Pier, G.B. Molecular Mechanism of Bacterial Pathogenesis., In Harrison's Principles of Internal Medicine (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1994, p. 592.
Pharmacokinetic barriers that reduce the effectiveness of treatment
Introduction
Pharmacokinetic components include absorption, distribution, biotransformation (metabolism) and excretion.
Pharmacokinetic "profile" of antibacterial describes the drug concentration in tissues and serum as a function of time after administration.
The profile depends on the agent's absorption, distribution, biotransformation and excretion.
In therapeutics "trough" concentration (low) and "peak" concentrations (high) are important.
Pharmcokinetic information is used to establish dose and dosing intervals.
Absorption
Oral Therapy predominates for the following principal reasons: lower costs and fewer adverse effects
Another consideration, however, is that the oral route of administration is associated with a substantial range of bioavailabililty. For example, oral availability is only about 10% to 20% erythromycin estolate (Ilosone) and penicillin G, whereas bioavailability is about 100% for clindamycin (Cleocin), doxycycline (Vibramycin, Doryx) methonidazole, and trimethoprim (generic) sulfamethoxazole (Gantanol).
Bioavailability differences are NOT clinically important if the concentration of drug at the site of infection is sufficient to inhibit (bacteriostatic) or to kill (bacteriocidal).
Factors that can influence oral bioavailability include the presence of food in the digestive tract and drug interactions for example quinolones with metal cations.
Intramuscular
Administration by this route offers 100% bioavailable, but not widely used because of injection site pain can be usually ease of intravenous administration in the hospital inpatient setting.
Intravenous Administration:
Intravenous administration, however, would be appropriate if for example, oral agents proved ineffective, if there is a special concern about bioavailability, if larger doses are required relative to those typically obtained from oral dosing or because the bioavailability will be known to be 100%.
Distribution:
Antibacterial concentrations must exceed that required to inhibit bacterial growth (MIC).
Given that most infections are located outside the blood stream, the drug must distribute to those sites.
Drug concentration at most sites are similar to serum levels.
Some sites are "protected", however. these protected sites include the eye, prostate, and cardiac sites where there may be vegetative growth (e.g. around valves in a bacterial endocarditis setting)
High parentral doses may be required in these circumstances.
Poor efficacy may be related to adequate concentrations, but local unfavorable conditions.
For example, the activity of aminoglycosides is reduced in acidic pH, common at sites of infection. Biological constituants present in absesses may also inhibit the activity of antibacterials, thus requiring surgical dranage prior to efficacious therapy.
Archer,G.L. and Polk, R.E. Treatment and Prophylaxis of Bacterial Infections, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 860.
Mechanisms for chemotherapeutic drugs resistance
Bacterial resistance may occur because the drug does not reach its target site, drug is inactivated, or there is some sort of molecular alteration in the target itself, possibly due to mutation.
Resistance may occur because enzymes at or near the cell surface inactivate the antibiotic; the cell membrane is impermeable to the drug; there is an absence of aqueous channels (porins) through which the drug will reach the cell interior; there is a lack of a necessary transport system to support drug translocation; the transport mechanism is present but inoperative due to anaerobic metabolism; there are target site changes that results in reduced or absent antibacterial drug efficacy.
How Bacteria Acquire Resistance
Resistance may be acquired by vertical transfer, i.e. acquired by mutation and then passed to daughter cells
Mutations: Specific genetic mutations are the molecular basis for resistance to streptomycin (ribosomal mutation), to quinolones (DNA gyrase gene mutation) and to rifampin (Rimactane) (RNA polymerase gene mutation)
The mutation to rifampin (Rimactane) is an example of a single-step mutation: In this case E. coli or Staph. aureus exposure to rifampin results in highly resistant strain due to a point mutation in the RNA polymerase gene such that the polymerase protein no longer binds rifampin.
More usually, acquired by horizontal transfer of resistance factors from a donor cell, perhaps of a different species by transformation which involves the incorporation of DNA found free environment into the bacterial genome.
An example of this process is the basis of penicillin resistance in. pneumococci and Neisseria gonorrhoeae.
Penicillin-resistant pneumococci produce different PBPs (penicillin-binding proteins). These different PBPs exhibit relatively low affinity for penicillin compared to wild type pneumococci.
These different PBPs arise from integration of foreign DNA which were most likely from a closely related streptococcal strain into the PBP gene by a process of homologous recombination.
Transduction-based resistance occurs when a bacteriophage which includes bacterial DNA in its protein coat infects the bacteria. This bacterial DNA may contain a gene confiring resistance to antibacterial drugs.
Examples of this process:
Staphylococcus aureus strain resistance development to penicillin may occur by transduction (Some bacteriophages carry plasmids [extrachromosomal self-replicating DNA] that code for penicillinase
Other phages can transfer genes which confer resistance to tetracycline (Achromycin), erythromycin estolate (Ilosone), and chloramphenicol (Chloromycetin).
Conjugation is another important mechanism for single and multi-drug resistance development. In conjugation direct passage of resistance-confering DNA between bacteria proceeds by way of a bridge
The genetic material transfer in conjugation requires two elements: an R-determinant plasmid which codes for the resistance and a resistance-transfer factor (RTF) plasmid which contains the genes necessary for the bacterial conjugation process. Occasionally two plasmids join to form a complete R factor
Some genes that are responsible for resistance are located on transposons which can move from location to location within plasmid and bacterial genomes.
Conjugation mediated resistance is particularly important in gram-negative bacilli.
Enterococci may contain plasmids that spread resistance among gram-positive organisms
Vancomycin (Vancocin) resistance in enterococcal strains appears to occur as a result of the conjugation mechanism.
Conjugation is not a high efficiency mechanism for resistance development. Unfortunately, antibiotic use provides selection pressures which facilitate the elaboration of resistance bacteria. Furthermore, enteric bacteria carrying plasmids for multidrug resistance is now a worldwide, serious concern.
Resistance acquired by horizontal transfer can disseminate rapidly through the bacterial population by clonal spread as well as by continuing genetic material exchange between cells of the same or different susceptible strains.
Chambers, H.F and Sande, M.A. Antimicrobial Agents in,In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.1031.
Microbial Resistance and Specific Drugs
Resistance: ß-Lactams
Most common among several mechanisms by which bacteria develop resistance to ß-Lactam antibiotics is by elaboration of the enzyme ß-lactamase, which hydrolyzes the ß-lactam ring.
Beta-lactamase genes may be found in both gram-positive and gram-negative bacteria. Resistance may be reduced by agents which bind to some beta-lactamases. Examples of these drugs include clavulanic acid and sulbactam.
Another mechanism by which bacteria may develop resistance to beta-lactam antibiotics is by changes in penicillin-binding proteins (PBPs). These changes may occur either by mutation of existing PBP genes or more often by the acquisition of new PBP genes. For the latter case, unimportant example is staphylococcal resistance to methicillin (Staphcillin).
In addition to mutation of existing PBP genes, bacterial also acquiring new "pieces or segments" of PBP genes. This process appears important in resistance development for certain pneumococcal, gonococcal, and meningococcal strains)
Yet another mechanism is observed in gram-negative bacteria and follows from alteration of genes that code for certain outer membrane proteins (porins). The expression of altered porins reduce membrane permeability to penicillins. This process appears important in cephalosporin-resistance of Enterbacteriaceae and that of Pseudomonas species to ureidopenicillins.
Multiple resistance mechanisms can exist within the same bacterial cell.
Archer,G.L. and Polk, R.E. Treatment and Prophylaxis of Bacterial Infections, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 859.
Chloramphenicol (Chloromycetin) resistance:
This resistance occurs because of the formation of an acetylated chloramphenicol (Chloromycetin) derivative which is not biologically active.
A plasmid-encoded enzyme, chloramphenicol acetyltransferase catalyzes the acetyl group transfer which would otherwise not occur
Vancomycin (Vancocin) resistance is an important problem in antibiotic chemotherapy. For example, vancomycin (Vancocin)-resistant enterococci strains are worldwide.
The resistance mechanism involves transfer between cells and is plasmid mediated.
The specific alteration is a change in the peptidoglycan stem peptide which causes a loss of the vancomycin (Vancocin) binding target.
Often significant vancomycin (Vancocin) resistance is observed with enterococci strains all the same time most staphylococci aureus and staphylococci epidermis remain vancomycin (Vancocin) sensitive.
Resistance to tetracyclines:
The most common mechanism for gram-negative bacterial resistance follows from insertion of a plasmid-encoded active-efflux pump which translocates tetracycline (Achromycin) out of the cell.
For gram-positive bacteria, resistance may follow from the above mechanism (active efflux) or is a result of changes in the tetracycline ribosomal target site.
Aminoglycoside resistance:
The most common resistance mechanism is antibiotic inactivation by enzyme-mediated covalent bond modification. Modifications occur as a result of acetyl, adenyl or phosphate group transfer.
Enzymes which catalyze these group transfers and confer antibody resistance are plasmid localized.
As a consequence of these molecular modifications, the modified antibiotic becomes less active secondary to reduced transport and attenuated ribosomal target site binding.
Aminoglycoside-modifying enzymes occur in both gram-negative and gram-positive bacteria.
Mupirocin resistance: Resistance to this topical drug is due to alteration in the target site which is an isoleucine tRNA synthetase enzyme. Following modification, the enzyme no longer binds mupirocin (Bactriban)
Macrolides and Licosamides resistance. Antibiotic from these categories target gram-positive bacteria.
Resistance to these antibiotics result from plasmid-mediated ribosomal RNA methylation that interferes with antibiotic binding.
Specific antibiotic susceptible to this type of resistance include erythromycin, newer macrolides and clindamycin (Cleocin).
Quinolone-resistance:
Quinone resistance including resistance to newer fluoroquinolones has developed quickly in Staphylococcus and Pseudomonas strains.
The resistance mechanism involves a mutation in the drug target site, which is DNA gyrases. The mediated DNA gyrases are not susceptible to inhibition by quinolones.
Other resistance mechanisms involve in gram-negative strains, mutations in porins that cause the bacterial membrane to lose its permeability to the drug.in gram-positive organisms, resistance follows the development of the capability that enables the cell to actively pump out the drug from the cell.
Rifampin (Rimactane) resistance can rapidly develop as a result of target site mutations. The target in this case is RNA polymerase. Following mutation of the polymerase, rifampin (Rimactane) no longer binds.
Rapid strain resistance development has become a major limiting factor in rifampin (Rimactane) use in management of susceptible staphylococci thus requiring rifampin (Rimactane) to be combined with another antistaphylococcal drug.
Multiple Antibiotic Resistance Summary
It is increasingly common for one bacterium to be resistant to several antibacterial drugs.
Mechanisms:
Acquisition of multiple, unrelated resistance genes (several steps required)
Mutation in a single gene which results in resistance to unrelated drugs. (single step)
Bacteria resistant due to acquisition of new genes:
hospital-associated gram-negative bacteria
enterococci
staphylococci
community-acquired salmonellae strains
gonococci
pneumococci.
Single gene mutations: usually affecting porins of gram-negative bacteria involve:
ß-lactams
quinolones
tetracycline
chloramphenicol (Chloromycetin)
trimethoprim (generic)
Strains resistant to all known antibacterial drugs have been identified.
Archer,G.L. and Polk, R.E. Treatment and Prophylaxis of Bacterial Infections, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 859.
Clinical indications and rationale for the use of multiple drugs at the same time (combination chemotherapy)
Single Agent Chemotherapy
Single most specific drug is preferable if the infecting bacteria has been identified.
Administration of a single drug with a narrow spectrum of action is desirable because (a) alteration of normal flora is minimized (which in turn reduces the likelihood of overgrowth of resistant nosocomial bacteria (e.g. Candida albicans, enterococci, Clostridium difficile), (b) reduces toxicity which may be associated with multiple drug regimens and (c) reduces cost.
Archer,G.L. and Polk, R.E. Treatment and Prophylaxis of Bacterial Infections, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 862.
Combination Chemotherapy
Combination chemotherapy may be warrented to:
Decrease the likelihood of emergence of resistant mutants. A single agent will be effective against sensitive organisms, but not against those that have developed a mutated "target" site, which is no longer susceptible or has diminished susceptibility to the drug. In this case the single drug will select out the mutant, resistant strain. This effect is more likely when the concentration of the antibacterial agent approximates the MIC (minimum inhibitory concentration).
Examples:
rifampin (Rimactane) : staphylococci
ciprofloxacin (Cipro): staphylococci and Pseudomonas.
imipenem: Pseudomonas
aminoglycosides: staphylococci
A second agent, which acts by a different mechanism, may prevent the emergence of the resistant strain (e.g. impenem + aminoglycoside for systemic Pseudomonas).
To take advantage of additive/synergistic action against some bacteria. Synergistic or additive activity occurs if the MIC or MBC of each agent is lowered in the presence of the other. Accordingly, each drug is more efficacious when combined with the other. (1) Certain ß-lactam-aminoglycoside combinations are effective against enterococci, viridans streptococci, and P. aeruginosa. (2) Combination of trimethoprim-sulfamethoxazole (Bactrim) is effective against many enteric gram negative bacteria. (3) Most other combinations are not clinically surperior compared to administration of the more efficacious single drug component.
Some combinations are less effective than a single agent: penicillin plus tetracycline (Achromycin) against pneumonococci.
To provide therapy when multiple pathogens may be or are known to be present . If a mixture of pathogens is thought to be present and/or the patient is critically ill, combination therapy may be warrented. [Multiple Pathogens may be present in intra-abdominal or brain abscesses and limb infection in diabetic patients; in critical illness fevers in neutropenic patients, acute aspiration pneumonia (oral flora) by hospitalized patients, septic shock or sepsis syndrome. However, monotherapy should be started if a single infecting bacterium that can be appropriately treated with a single drug has been identified
Archer,G.L. and Polk, R.E. Treatment and Prophylaxis of Bacterial Infections, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 862.
Rationale for chemoprophylaxis
Chemoprophylaxis
A manifestation of antibiotic misuse is that 30% to 50% of the time, the antibiotic is prescribed to prevent rather treat an infection.
Prophylaxis is more likely to be effective if a single, effective, nontoxic drug is used to prevent infection by a specific organism or to eliminate a recently established infection.
Examples of effective chemoprophylaxis:
Penicillin G prevents infection by group-A streptococci.
Intermittent use of trimethoprim (generic) sulfamethoxazole (Gantanol) prevents recurrent urinary tract infections
Prevention of endocarditis in patients with valvular heart lesions who are to undergo a surgical procedure.
The most extensive use of chemoprophylaxis is prevention of wound infections following surgery.
Chambers, H.F and Sande, M.A. Antimicrobial Agents in,In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.1049-1050
Appropriate and Inappropriate Uses of Chemotherapy
Appropriate Use
Before the organism is identified: either combination therapy or a single broad spectrum agent may be used.
After the organism is identified, a low-toxicity regimen with a narrow-spectrum drug is indicated.
Selection of the drug should be goverened by its selectivity for the most likely involved bacteria and its toxicity.
First decide if an antibiotic is indicated since antibiotics may be toxic. Inappropriate use may hinder diagnosis, and can result in development of resistant bacterial strains
Some Clinical Issues
Optimal empirical treatment requires knowledge of the antibiotic sensitivity of the organisms which is most likely causing the infection.
Assessment with Gram's stain and other tests must be used to narrow the list of pathogens.
In life threatening situations, the selection of a single narrow-spectrum agent may not be possible and broad coverage would be indicated until a definitive identification is possible.
Chambers, H.F and Sande, M.A. Antimicrobial Agents in,In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.1054-1055
Inappropriate Uses
Treatment of Untreatable Infections:
The infection is viral.
Antimicrobial treatment of measles, mumps and 90% of upper respiratory infections are inappropriate.
Treatment of fever of unknown origin:
Antimicrobials are not antipyretic agents.
Pyrexia of short duration, without localizaing signs, is most likely due to viral infection.
Three infections may be associated with prolonged fever:
tuberculosis
hidden intra-abdominal abscesses
infective endocarditis.
other causes: cancer metabolic disorders hepatitis atypical rheumatoid arthritis
Improper dosage:
Some drugs, such as the aminoglycosides, are frequently administered at subtherapeutic dosages because of concern about toxicity.
Clinical treatment failure and selection of resistant strains may result.
Inappropriate Dependence on Chemotherapy Alone:
Some disorders require both chemotherapy and a surgical procedure, especially if significant amount of necrotic tissue is present.
Example : Pneumonia in a patient with empyema (accumulation of pus) may be effectively manage following drainage
Lack of Adquate Bacteriological Information:
About one-half of antimicrobial therapy is given to hospitalized patients without support from microbiological data. [clinical judgment alone];
Antimicrobial therapy must be individualized, not administered based on prescribing habit alone.
Chambers, H.F and Sande, M.A. Antimicrobial Agents in,In, Goodman and Gillman's The Pharmacological Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.1054-1055
