ANTIMICROBIAL AGENTS

Suryadi Nattadiputra

Department of Pharmacology
Medical Faculty
Sriwijaya University
 General Consideration

History
The modern era of antimicrobial chemotherapy started with the clinical use of
sulfanilamide in 1936. The golden age of antibiotics began with the production of
penicillin in 1941, when this compound was mass produced and first made available for
limited clinical trial. At least 30% of all hospitalized patients now receive one or more
courses of therapy with antibiotics, and of potentially fatal infections have been cured.
However, at the same time, these agents are among the most misused by the practicing
physician. One result of the widespread use has been the emergence of antibiotic resistant
pathogens, which in turn has fueled an ever-inreasing need for new drugs. These agents
have contributed significantly to the rising cost of medical care.

Definition and Characteristics.

Antibiotics are substances produced by various species of microorganisms (bacteria,
fungi, actinomycetes) that suppress the growth of other microorganisms and eventually
may destroy them. However, common usage often extends the term antibiotics to include
synthetic antibacterial agent, such as sulfonamides and quinolones, which are not
products of microbes.
Antibiotics differ markedly in physical, chemical and pharmacological properties;
antibacterial spectra; and mechanisms of action.

Classification and Mechanism of Action.

The most common classification has been based on chemical structure and proposed
mechanism of action, as follow : (1) agents that inhibit synthesis of bacterial cell walls;
these include the penicillins, and cephalosporins, which are structurally similar and
dissimilar agents such as cycloserine, vancomycin. bacitracin, and imidazol antifungal
agents (miconazole, ketokonazole, and clotrimazole); (2) agents that act directly on the
cell membrane of the microorganism, affecting permeability and leading to leakage of
intracellular compounds; these include detergents, polymyxin and colistimethate, and the
polyene antifungal agents, nystatin and amphotericin B, that bind to cell wall sterols; (3)
agent that affect the function of 30S or 50S ribosomal subunits to cause a reversible
inhibition of protein synthesis; these bacteriostatic drug include chloramphenicol, the
tetracyclines, erythromycin, and clindamycin; (4) agents that bind to the 30S ribosomal
subunit and alter protein synthesis, which eventually leads to cell death; these include the
aminoglycosides ; (5) agents that affect nucleic acid metabolism, such as the rifamycin
which inhibit DNA-dependent RNA polymerase and the quinolones , which inhibit
gyrase ; (6) antimetabolites, including trimethoprim and sulfonamides, which block
specific metabolic steps that essential to microorganisms; (7) nucleic acid analogs, such
as zidovudine, ganciclovir, vidarabine and acyclovir which inhibit viral enzymes that
essential for DNA synthesis, thus halting viral replication; at the present time , the precise
mechanism of action of some antimicrobial agents is unknown.
Factors That Determine the Susceptibility and Resistance of Microorganisms to
Antimicrobial Agents.
When antibiotics are used to treat an infection, a favorable therapeutic outcome depend
upon several factors. In simple terms, success depends on achieving a concentration of
antibiotic at the site of infection that is sufficient to inhibit bacterial growth. When host
defenses are maximally effective, a minimum inhibitory effect may be all that is
necessary, such as that provided by bacteriostatic agents that slow protein synthesis or
prevent microbial cell division. On the other hand, when host defenses are impaired,
complete antibiotic-mediated killing (i.e , a bactericidal effect) may be required to
achieve a successful outcome. The dose of drug utilized must be sufficient to produce the
necessary effect on the microorganism; however, concentration of the drug must be
remain below those that are toxic to human cells. If this can be achieve, the
microorganism is considered to be susceptible to the antibiotic. If the concentration of
drug required to inhibit or kill the microorganism is greater than the concentration that
can be safely achieved, the microorganism is considered to be resistant to the antibiotic.

Resistance to Antimicrobial Agents.

For an antibiotic to be effective, it must reach the target and bind to it. Bacteria can be
resistant to an antimicrobial agent because (1) the drug fails to reach its target; (2) the
drug is inactivated; or (3) the target is altered. Some bacteria produce enzymes that reside
at or within the cell surface an interactive the drug. Others posses impermeable cell
membrane that prevent influx of the drug. Hydrophilic antibiotics traverse the outer
membrane of microbial cell via aqueous channels made up of specific proteins (porin).
Bacteria deficient in these channels can be resistant to such drugs. Since many antibiotics
are organic acids, their penetration may be pH-dependent; in addition, permeation may be
altered by osmolality or by various cation in the external milieu. The transport
mechanism for certain drugs are energy-dependent and are not operative in an anaerobic
environment. Once the drug has gained acces to the target site, it must exert an effect that
is deleterious to microorganism. Natural variation or acquired changes at the target site
that prevent drug binding or action can lead to resistance.

Mutation.
Mutation occurring in a previously susceptible cell. Mutation may occur in the gene encoding the target
protein, altering its structure so that it no longer binds the drug; in a protein involved in drug transport; or in
regulatory gene or promoter leading to altered expression of the target, a transport protein, or inactivating
enzyme. Any large population of antibiotic-susceptible bacteria is likely to contain some mutants that are
relatively resistant to the drug. There is no evidence that these mutation are the result of exposure to the
particular drug;; rather such mutations are random events that confer a selective advantage to the cell upon
reexposure to the drug. In some instace a single step mutations result in high degree of resistance. For
example for E.Coli or Staph.aureus is exposed to rifampicin, highly resistant mutants emerge due to a point
of mutation in RNA polymerase such that the protein does not bind the drug. In other cases the emergence
of resistant mutants may require several steps, each step conferring only slight alterations in susceptibility.
Cefotaxime resistance in pneumococci passage in vitro in increasing concentrations of drug is an example
of resistance due to multiple stepwise mutations.

Transduction
Transduction occurs by the intervention of a bacteriophage ( a virus that infects bacteria) that contains
bacteria DNA incorporated within its protein coat. If this genetic material includes a gene for drug
resistance, a newly infected banterial cell may become resistant to the agent and capable of passing the trait
on to its progeny. Transduction is particularly important in the transfer of antibiotic resistance among
strains of Staph.aureus, where some phages can carry plasmids that code for penicillinase, while others
transfer genes encoding resistance to erythromycin, tetracycline, or chloramphenicol.

Transformation
This method of transferring genetic information involves incorporation of DNA that free in the environment
into bancteria. Transformation is the molecular basis of penicillin resistance in pneumococci and Neisseria.
Penicillin resistant pneumococci produce altered penicillin-binding proteins (PBPs) that have low-affinity
binding of penicillin. Nucleotide sequence analysis of the genes encoding these altered PBPs indicates that
they are mosaics in which block of foreign DNA from an unknown, but probably closely related, species of
streptococcus have been imported and incorporated into then resisdent PBP gene by homologous
recombination .

Conjugation
The passage of genes from cell by direct contact through a sex pilus or bridge is termed conjugation. This is
now recognized as an extremely important mechanism for spread of antibiotic resistance, since DNA that
codes for resistance to multiple drug may be so transferred. Genetic transfer by conjugation occurs
predominantly among gram-negative bacilli, and resistance is conferred on a susceptible cell as a single
event. However, enterococci also contain broad host range conjugative plasmids which are involved in the
transfer and spread of resistance genes among gram-positive organism.

The recent emergence of antibiotic resistance in bacterial pathogens, both nosocomially and in the
community setting, is a very serious development that threatens the end of the antibiotic era.

A more responsible approach to the use of antibiotics, both those that are now available and new agents that
might be developed in the future, is essential if the end of the antibiotic era is to be averted.

Selection of an Antimicrobial Agent

Optimal and judicious selection of antimicrobial agents for the therapy of infectious
diseases requires clinical judgment and detail knowledge of pharmacological and
microbiological factors. Unfortunately, the decision to use antibiotics frequently is made
lightly, without regard to the potential infecting microorganism or to the pharmacological
features of the drug. Antibiotics are used in two general ways as empirical, or initial
therapy and as definitive therapy. When used as empirical, or initial, therapy, the
antibiotic must cover all of likely pathogens, since the infecting organism(s) has not yet
been defined. Combination therapy or treatment with a single broad-spectrum agent
often is employed. However, once the infecting microorganism is identified, definitive
antimicrobial therapy should be instituted a narrow spectrum, low-toxicity regimen to
complete the course of treatment. When an antimicrobial agent is indicated, the goal is to
choose a drug that is selectively active for the most likely infecting microorganism(s) and
that has the least potential to cause toxicity or allergic reactions in the individual being
treated.

The first decision to be made is wether administration of an antimicrobial agent is truly

indicated. Many physicians reflexly associate fever with treatable infections and prescribe
antimicrobial therapy, without further evaluation. This practice is irrational and
potentially dangerous; the diagnosis may be masked if appropriate cultures are not
obtained prior to to therapy, and antibiotics can cause serious toxicity. As noted above,
injudicious use of antimicrobial agents also can result in the selection of resistant
microorganisms. Of course, one does not always have the luxury of identification of a
bacterial infection before treatment must be initiated. In the absence of a clear indication,
antibiotics often may be used if disease is severe and if it seems likely that withholding
therapy will result in failure to manage potentially life-threatening infection.

Initiation of optimal empirical antibiotic therapy require a knowledge of most likely

infecting microorganisms and their susceptibilities ro antimicrobial drugs. The clinical
picture may sugest the specific microorganism. The therapist must know the
microorganism most likely to cause specific infection in a given host. In addition, simple
and rapid laboratory techniques are available for the examination of infected tissues. The
most valuable and time-tested method for immediate identification of bacteria is the
examination of the infected secretion or body fluid with Grams stain. Test such as this
one help to narrow the list of potential pathogens and permit more rational selection of
initial antibiotic therapy. However in most situations, identification of the morphology of
the infecting microorganism is not adequate to arrive at a specific bacteriological
diagnosis, and the selection of a single narrow-spectrum antibiotic may be inappropriate,
particularly if the infection is life-threatening. Broad antimicrobial coverage is then
indicated, pending isolation and identification of the microorganism. Whenever the
clinician is faced with initiating therapy on a presumptive bacteriological diagnosis,
cultures of blood and certain other body fluid should be taken prior to the
institution of drug therapy. For definitive therapy the regimen should be changed to a
more specific (narrow-spectrum) antimicrobial agent. Many factors need to be
considered before this change is made.

Testing for Microbial Sensitivity to Antimicrobial Agents.

Several tests now available for determination of bacterial sensitivity to antimicrobial

agents. The two that most commonly used are disk-diffusion and agar or broth-dilution
tests.
The disk-diffusion technique is simple to perform and relatively inexpensive. It provides only qualitative or
semiquantitative information on the susceptibility of a given microorganism to a given antibiotic. The test
is performed by applying commercially available filter-paper disk impregnated with specific quantities of
the drug onto the surface of agar plates over which a culture of microorganism has been streaked. After 18
24 hours of incubation, the size of a clear zone of inhibition around the disk is determined ; this is related
to the activity of the drug against the test strain. Standards for sensitivity vary for each microorganism, and
they are based on the concentration of drug that can be achieved safely in plasma without producing
toxicity. Even though the concentration of the antibiotic in plasma is the standard used for these test. it may
not always reflect the drug concentration at the site of infection. There are several notable exceptions where
the disk-diffusion test may not accurately predict therapeutic effectiveness: (1) methicillin-resistant
Staph.aureus, which may appear to be sensitive to cephalosporins; (2) enterococci, which may appear to
be sensitive to cephalosporin and trimethoprim-sulfamethoxazole ; (3) Shigella species which may appear
to be sensitive to cephalosporins. These drug have proven not to be useful in such infections.

Dilution test employ antibiotics in serially diluted concentrations in solid or broth media containing a
culture of the test microorganism. The lowest concentration of the agent that prevent visible growth after 18
24 hours of incubation is known as the minimal inhibitory concentration (MIC), and the lowest
concentration that result in a 99,9% decline in bacterial numbers known as minimal bactericidal
concentration (MBC). The value of MBC as a clinical test has not been established, but it may be useful in
special instances where very precise knowledge of the ability of a given antimicrobial agent to kill a
specific clinical isolate is critical, as in the therapy of bacterial endocarditis.
Pharmacokinetic Factors.

Successful therapy depends upon achieving antibacterial activity at the site of infection
without significant toxicity to the host. To accomplish this therapeutic goal, several
pharmacokinetic and host factors must be evaluated.

The location of infection may, to a large extent, dictate the choice of drug and route of
administration. The minimal drug concentration achieved at the infected site should be
approximately equal to the MIC for the infecting organism, although in most instances it
advisable to achieve multiples of this concentration if possible. However there is
evidence to suggest that even subinhibitory concentrations of antibiotics may enhance
phagocytosis and may be effective. Although these and related observations may explain
why some infections are cured even when inhibitory concentration are not achieved, it
should be the aim of antimicrobial therapy to produce antibacterial concentration of drug
at the site of infection during the dosing interval.

Acces of antibiotics to sites of infection depends on multiple factors. If the infection is in

the cerebrospinal fluid (CSF), the drug must pass the blood-brain barrier, and many
antimicrobial agent that are polar at physiological pH do so poorly; some, such as
penicillin G, are actively transported out of CSF by an anion transport mechanism in
choroids plexus. The concentration of penicillins and cephalosporins in the CSF are
usually only 0,5% -to 5% of steady-state concentrations determine simultaneously in
plasma. However, the integrity of the blood-brain barrier is diminished during active
bacterial infection; tight junctions in cerebral capillaries open, leading to marked increase
in the penetration of even polar drugs. As the infection is eradicated and the inflammatory
reaction subsides, penetration reverts toward normal.

Penetration of drugs into infected loci almost always depends on passive diffusion. The
rate of penetration is thus proportional to the concentration of free drug in the plasma or
extracellular fluid. Drugs that are extensively bound to protein thus may not penetrate to
the same extent as those that are bound to a lesser extent. Drugs that are highly protein
bound also may have reduced activity, because only the unbound fraction of drug is free
to interact with its target.

Knowledge of the status of individual patients mechanisms for elimination of drugs also
essential especially when execcive plasma or tissue concentration of the drugs may cause
serious toxicity. Most antimicrobial agents and their metabolites are eliminated primarily
by the kidneys. One must be particularly careful when using aminoglycosides,
vancomycin, or flucytocine in patients with impaired renal function, since these drugs are
eliminated exlusively by renal mechanism, and their toxicity appears to correlate with
their concentration in plasma and tissue. Furthermore, since the toxicity of certain drugs
is particularly manifested on the kidney, a vicious cycle may ensue if care is not
exercised.

For drugs that are metabolized or excreted by the liver (erythromycin, chloramphenicol,
metronidazole, clindamycin), dosages must be reduced in patients with hepatic failure.
Rifampin and isoniazid also have prolonged half-lives in patients with cirrhosis. If there
is infection in the biliary tract, hepatic desease or biliary obstruction may reduce the acces
of the drug to the site of action. This has been shown to occur with ampicillin and other
drugs that are normally excreted into the bile.

Route of Administration

While oral administration is preferred whenever possible, parenteral administration of

antibiotics usually is recommended in seriously ill patients in whom predictable
concentration of drug must be achieved.

Host Factors.

Innate host factors, which may seem unrelated to infectious disorder being treated, often
are the prime determinants not only of the type of drug selected but also of its dosage,
route of administration, risk and nature of untoward effects, and therapeutic effectiveness.
Host Defense Mechanisms.
A critical determinant of therapeutic effectiveness of antimicrobial agents is the
functional stage of host mechanisms. Both humoral and cellular immunity are important.
Frequently, successful treatment of infection with antimicrobial agents may be achieved
in the immunocompetent host merely by halting multiplication the microorganisms (a
bacteriostatic effect). If host defenses are impaired, this action may be inadequate and
rapidly bactericidal antimicrobial agents have been shown to be essential for cure.
Patients with AIDS have impaired cellular immune responses, and therapy for various
opportunistic infections in these patients is usually suppressive but not curative. For
example, most AIDS patients with bacteremia due to Salmonella will respond to
conventional therapy, but this infection will relapse even after prolonged treatment.
Local Factors.
Pus with consist of phagocytes, cellular debris, fibrin, protein, binds aminoglycosides and
vancomycin, resulting in a reduction in their antimicrobial activity. Large accumulations
of hemoglobin in infected hematomas can binds penicillin and tetracyclines and may thus
reduce the effectiveness of the drugs. The pH in abscess cavities and in other confined
infected sites (pleura space, CSF, and urine) is usually low, resulting in a marked loss of
antimicrobial activity of aminoglycosides, erythromycin, and clindamycin. However,
some drugs such as chlortetracycline, nitrofurantoin, and methenamine, are more active
in such an acidic environment. The anaerobic conditions found in abscess cavities are
also impair activity of the aminoglycosides. Penetration of antimicrobial agents into
infected areas such as abscess cavities is impaired, since the vascular supply is reduced.
Successful therapy of abscesses usually requires drainage.
The presence of a foreign body in an infected site markedly reduces the likelihood
of successful antimicrobial therapy. This factor has become increasingly important in the
present era of prosthetic cardiac valves, prosthetic joints, pacemakers, vascular
prostheses, and various vascular and central nervus system shunts. The prosthesis
apparently is perceived by the phagocytic cells as foreign. In an attempt to phagocytize
and destroy it, degranulation occurs, resulting in the depletion of intracellular bactericidal
substances. Thus, these phagocytes are relatively inefficient in killing bacterial
pathogens.; in fact, microbes may even reside within phagocytes, protected from most
antimicrobial agents. In addition, microbes may attach to foreign bodies by elaboration
of glycocalyx substrate. When embedded in this substrate, they are relatively resistant to
the actions of most antimicrobial agents, Infections associated with foreign bodies are
thus characterized by frequent relaps and failure, even with long-term, high-dose
antibiotic therapy. Successful therapy usually requires removal of the foreign material.
Infectious agents that reside within phagocytic cells (intracellular parasite) also
may be relatively resistant to the action of antimicrobial agents, since many of these
drugs penetrate into cell only poorly. This may be a problem in infections with
Salmonella, Brucella, Toxoplasma, Listeria, and M. Tuberculosis, and in some instances,
even in infections cause by Staph. aureus , Rifampin and fluoroquinolones can penetrate
cells well and can kill many intraleukocytic microbes.
Age.
The age of the patient is an important determinant of pharmacokinetic properties of antimicrobial agents.
Mechanism of elimination, especially renal excretion and hepatic biotransformation, are poorly developed
in the newborn, especially the premature infant. Failure to make adjustments for such differences can have
disastrous consequences. Elderly patients also may have significantly reduced rates of creatinine clearance
and drug metabolism. Also elderly patients are particularly susceptible to the ototoxic effect of
aminoglycosides
Developmental factors also may determine the type of untoward response to a drug. Tetracycline
bind avidly to developing teeth and bones, and their use in young children can result in retardation of bone
growth and discoloration or hypoplasia of tooth enamel. Fluoroquinolones accumulate in cartilage of
developing bone, affecting its growth. Kernicterus may follow the use of sulfonamides in new born infants,
because this class of drugs compete effectively with bilirubin for binding sites on plasma albumin.
Achlorhydria in young children and in the elderly or antacid therapy may alter absorption of orally
administered antimicrobial agents (e.g. increased absorption of penicillin G and decreased absorption of
ketoconazole.)
Genetic Factors.
Certain genetic factor or metabolic abnormalities must be considered when prescribing antibiotics. A
number of drug, including the sulfonamides, nitrofurantoin, chloamphenicol and nalidixic acid, may
produce acute hemolysis in patients with glucose-6-phosphate dehyrogenase deficiency. More common in
black males, the defect also occasionally found in Caucasians. . Patients who acetylate isoniazid rapidly
may have suboptimal concentrations of the drug in plasma.
Pregnancy.
Pregnancy imposes an increased risk of reaction to some antimicrobial agents for both mother and fetus.
For example, hearing loss in the child has been associated with administration of streptomycin to the
mother during pregnancy. Tetracyclin can affect the bones and teeth of the fetus and also can be particularly
toxic to the pregnant female. Pregnant women receiving these drugs may develop fatal acute fatty necrosis
of the liver, pancreatitis, and associated renal damage. Pregnancy also may affect the pharmacokinetics of
various antibiotics.
The lactating female can pass antimicrobial agent to her nursing child. Both nalidixic acid and
sulfonamides in breast milk have been associated with hemolysis in children with glucose-6-phosphate
dehydrogenase deficiency. In addition, sulfonamides, even in the small amounts received from breast
milk, may predispose the nursing child to kernicterus.
Drug Allergy.
Antibiotics, especially the beta-lactam derivatives and their degradation product, are notorious for
provoking allergic reactions. Patients with a history of atopic allergy seem particularly susceptible to the
development of these reactions. The sulfonamides, trimethoprim, nitrofurantoin, and erythromycin also
have been associated with hypersensitivity reactions, especially rash.. When use of a penicillin is
contemplated, a history of anaphylaxis (immediate reaction) or hives and laryngeal edema (accelerated
reaction) precludes the use of the drug in all but extreme life-threatening. Skin testing, particularly of the
penicillins may be of value in predicting life-threatening reactions. However, the controvercy over the
utility of such tests is only partly resolved. It also should be noted that antimicrobial agents and other drugs
can cause drug fever , which can be mistaken for a sign of continued infection.
Disorders of the Nervous System
Patients with diseases of the nervous system that predispose them to a seizures are at risk for localized or
major motor seizures while taking high doses of penicillin G. Neurotoxicity of penicillin and other beta
lactam antibiotics correlates with high concentration of drug in the CSF and usually occurs in patients with
renal insufficiency who are receiving large doses of these drugs. Decreased renal function increases
concentrations of penicillin in CSF by two mechanisms: reduction of renal elimination of penicillin from
plasma, which result in a higher concentration gradient for passive diffusion into CSF; and accumulation of
organic acids (in uremic state), which competitively inhibit the transport mechanism in the choroids plexus
that removes penicillin and other organic acids from CSF. Patients with myasthenia gravis or other
neuromuscular problems are susceptible to the neuromuscular blocking effect of the aminglycosides,
polymyxins, and colistin. Patients undergoing general anesthesia who receive a neuromuscular blocking
agent also particularly susceptible to such antibiotic toxicity.

Therapy with Combined Antimicrobial Agents.

The simultaneous use of two or more antimicrobial agents has a certain rationale and is
recommended in specifically defined situations. However, selection of an appropriate
combination requires an understanding of the potential for interaction between the
antimicrobial agents. Such interaction may have consequences for both the
microorganism and the host. Since the various classes of antimicrobial agents exert
different action on microorganism, one drug has the potential to either enhance or inhibit
the effect of the second. Similarly, combinations of drugs that rationally might be used to
cure infections may have additive or supraadditive toxicities. For example, vancomycin
when given alone usually has minimal nephrotoxicity, as does tobramycin; however,
when the drugs are given in combination they may cause marked impairment of renal
function.

Methods of Testing Antimicrobial Activity of Drug Combinations.

To predict the potential therapeutic efficacy of combination of antibiotics, methods have
been developed to quantitate their effects on bacterial growth in vitro . Two distinctly
different method are used. The first employs two fold dilution of antibiotics in broth
inoculated with a standard number of the test microorganism in a checkerboard fashion,
so that a large number of antibiotic concentrations in different proportions be tested
simultaneously. Inhibition of bacterial growth is quantified after 18 hours of incubation.
This test determines wether the MIC of one drug is reduced, unchanged or increased in
the presence of another drug. Synergism is defined as inhibition of growth with a
combination of drugs when their concentration are less than or equal to 25% of the MIC
of each drug acting alone. This implies that one drug is affecting the microorganism in
such a way that it becomes more sensitive to the inhibitory effect of the other. If one- half
of the inhibitory concentration of each drug is required to produce inhibition, the result is
called additive (fractional inhibitory concentration FIC index = 1, suggesting that the two
drugs are working independently of each other. If more than one-half of the MIC of each
drug is necessary to produce the inhibitory effect, the drug are said to be antagonistic
(FIC index >1). A potential limitation of this method is that its end point is growth
inhibition, not killing, and consequently synergism may not indicate enhanced
bactericidal effect.
 The second method for evaluating drug combinations involves quantitation of
their rate of bactericidal action. Identical cultures are incubated simultaneously with
antibiotics added singly or in combination. If a combination of antibiotics is more rapidly
bactericidal than either drug alone, the result is term synergism . If the bactericidal rate of
the combination is less than that for either drug alone, antagonism is said to occur. If the
bactericidal rate is as rapid as that for the more bactericidal drug, the result is called
indifference.

Indications for the Clinical Use of Combinations of Antimicrobial Agents.

Numerous reasons have been given to justify the use of combinations of antimicrobial
agents. These will be considered individually.

Treatment of Mixed Bacterial Infections

Some infections are caused by two or more microorganisms. These include
intraabdominal, hepatic, and brain abscesses and some genital tract infections. In such
situations it may be necessary to administer different antibiotics with different
antimicrobial spectra to obtain the necessary breadth of activity.

Following perforation of a viscus such as the colon, one can expect contamination and infection
with aerobic Enterobacteriaceae, anaerobic and aerobic gram-positive cocci (streptococci), anaerobic bacilli
such as Bacteroides fragilis, and anaerobic gram-positive rods such as Clostridium species. Since a single
drug may be ineffective against this mixed infection, a rational combination would be an aminoglycoside
for Enterobacteriaceae and either clindamycin or metronidazole for the anaerobic microorganisms,
including B.fragilis.

Therapy of Severe Infections in Which a Specific Cause Is Unknown.

Combination chemotherapy is used probably most frequently in the empirical therapy of
infections in which the causative agent has not been or cannot be identified. In these
situations, the goal of treatment is to select antibiotic coverage for microorganisms that
are most likely involved. The breadth of the antibiotic coverage that is selected for
treatment is narrowed by the ability to reduce the list of potential infectious agents, but
the severity of illness also must be taken into account.

Enhancement of Antibacterial Activity in the Treatment of Specific Infections.

As mentioned above, when two antimicrobial agents are administered together, they may
produce a synergistic effect. There are specific clinical indication for the use of
combination of antimicrobial agents, and they are based on documented proof of efficacy.

Perhaps the best- documented example of the utility of a synergistic combination of antimicrobial agents is
in the treatment of endocarditis. In vitro penicillin alone is bacteriostatic against most strain of E.faecalis,
whereas a combination of penicillin and streptomycin or gentamycin is bactericidal. Treatment of
enterococcal endocarditis with penicillin alone frequently result in relapses, while combination therapy is
curative.
Sulfonamides combined with trimethoprim are synergistic in vitro and are effective against
infections caused by microorganisms that may be resistant to sulfonamides alone. A fixed combination of
trimethoprim and sulfamethoxazole is effective treatment of recurrent urinary tract infections.
Combination of an inhibitor of beta-lactamase (clavulanate, sulbactam, or tazobactam), which has
little or no intrinsic antimicrobial activity, and a beta-lactam antibiotic that susceptible to beta-lactamase
(amoxicillin, ampicillin, ticarcillin, or piperacillin) allow successful treatment of infections caused by beta-
lactamase-producing H.influenzae may be treatable with ampicillin-sulbactam or amoxicillin-clavulanate.
Prevention of the Emergence of Resistant Microorganism.
The use of combination of antimicrobial agents was first proposed as a method to prevent
the emergence of resistant mutant during therapy. If spontaneous mutation were the
predominant means by which microorganism acquires resistance to antibiotics,
combination chemotherapy would in theory, be an effective means of prevention. The
approach has been most extensively used in the treatment of tuberculosis, where the
concomitant use of two or more appropriate agents strikingly reduces the development of
drug resistance by the tubercle bacillus.

Disadvantages of Combination of Antimicrobial Agents.

The most obvious are the risk of toxicity from two or more agents, the selection of
microorganism that are resistant to antibiotics that may not have been necessary, and
increase cost to the patient. In addition, as noted above, antagonism of antibiotics effect
may result when bacteriostatic and bactericidal agents are given concurrently.

The Prophylaxis of Infection with Antibiotics.

A large percentage (30% -50%) of antibiotics administered in the United States are given
to prevent infection rather than to treat established disease. This practice accounts for
some of the most flagrant misuses of these drugs.
Clinical studies have demonstrated that there are some situations in which
chemoprophylaxis is highly effective and others in which it is totally without value and
may in fact be deleterious. There are still numerous situations where the attempt to use
antimicrobial compounds to prevent bacterial infections is controversial. In general, if a
single, effective, nontoxic drug is used to prevent infection by a specific microorganism
or to eradicate infection immediately or soon after it has become established, then
chemoprophylaxis frequently is successful. On the orher hand, if the aim of
prophylaxis is to prevent colonization or infection by any or all microorganisms
present in the environment of a patient, then prophylaxis often fails.
Prophylaxis may be used to protect healthy persons from acquisition of or
invasion by specific microorganisms to which they are exposed. Successful example of
this practice include the following: The use of penicillin G to prevent infection by group-
A Streptococci; prevention of gonorrhea or syphilis after contact with an infected person;
the intermittent use of trimethoprim-sulfamethoxazole to prevent recurrent urinary tract
infection usually caused by E.coli.
Chemoprophylaxis should be employed to prevent endocarditis in patients with
valvular or other structural lesion of the heart who are undergoing dental, surgical, or
other procedures that produce a high incidence of bacteremia. Therapy should not begin
until immediately before the procedure, since prolong administration of antibiotics can
lead to colonization by resistant strains.
The most extensive use of chemoprophylaxis is to prevent wound infections after
various surgical procedures. Wound infection results when a critical number of bacteria
are present in the wound at time of closure. Antimicrobial agents directed against the
invading microorganisms may reduce the number of viable bacteria below the critical
level and thus prevent infection.
Superinfections.
Antibiotics can cause unique reactions that result from alterations of the microbial flora
of the host.
All individuals who receive therapeutic doses of these agents undergo alterations
in the normal microbial population of the intestinal, upper respiratory. and genitourinary
tracts; some develop superinfection as a result of such changes. Superinfection may be
defined as the appearance of bacteriological and clinical evidence of a new infection
during the chemotherapy of a primary one. This phenomenon is relatively common and
potentially very dangerous because the microorganisms responsible for the new infection
are, in many cases, Enterobacteriaceae, Pseudomonas, and Candida or other fungi; these
may be very difficult to eradicate with the presently available antiinfective drugs.
Superinfection by these microorganisms is due to removal of inhibitory influence of the
flora that normally inhabits the oropharynx and other body orifices. The most specific
antimicrobial agent to treat a given infection should be chosen whenever possible. The
incidence of superinfection also increases when administration of antibiotics is
prolonged.

Misuses of Antibiotics.

Treatment of Untreatable Infections.

A common misuse of these agents is in infections that have been proved by experimental
and clinical observation to be untreatable. The majority of the diseases caused by the
viruses are self limited and do not respond to any of currently available antiinfective
compounds. Thus, antimicrobial therapy of measles, mumps, and at least 90% of
infections of the upper respiratory tract is ineffective and therefore, useless.

Therapy of Fever of Undetermined Origin.

Fever of undetermined cause may be of two types: ane that is present for only a few days
to a week and another that persists for an extended period. Both of these are frequently
treated with antimicrobial agents. Most instances pyrexia of short duration, in the absence
of localizing signs, are probably associated with undefined viral infections, and do not
respond to antibiotics. Studies of prolong fever have shown that three common infectious
causes are tuberculosis, often of the disseminated variety, hidden pyogenic
intraabdominal abscess, and, less commonly, infectious endocarditis. Also, the so called
collagen-vasculer disorders and various neoplasms, especially lymphoma, are frequently
responsible for prolonged and significant degree of fever.
It must be stress that antiinfective agents are not antipyretics.

Improper Dosage.
Erroneous dosage of antimicrobial agents is of two types: administration of excessive
amounts and use of suboptimal quantities. The difficulties that may arise from drug
overdose in patients with impairment of drug elimination. Drug such as aminoglycosides
frequently are administered at subtherapeutic doses, probably because of fear of toxicity.
Inappropriate Reliance on Chemotherapy Alone.
Patient with pneumonia and empyema often fails to be cured by the administration of
large doses of an effective drug until drainage of the involved area is established. The
patient with renal lithiasis frequently will suffer recurrent episodes of acute
pyelonephritis, regardless of the number of times antimicrobial agents are given, until the
stones are removed. As a general rule, when an appreciable quantity of pus, necrotic
tissue, or foreign body is present, the most effective treatment is a combination of an
antimicrobial agent given in adequate dose plus a properly performed surgical procedure.

Lack of Adequate Bacteriological Information.

One half of the courses of antimicrobial therapy administered to hospitalized patients
appear to be given in the absence of support from the microbiological laboratory. A great
proportion of the use of these drugs is based on so called clinical judgment alone.
Bacterial cultures and Gram stains of infected material are obtained too infrequently, and
the results, when available, are often disregarded in the selection and application of drug
therapy. Frequent use of drug combination or drug with broadest spectra is a cover for
diagnostic imprecision. The agents are selected more likely of habit than for specific
indications, and the dosages employed are routine.
Antimicrobial drug therapy must be individualized on the basis of clinical
situation, microbiological information and pharmacological consideration.

Learning objectives.
- To know the definition of antibiotic
- To know classification & mechanism of action of antimicrobials
- To know factors that determine the susceptibility & resistance of microorganisms to
antimicrobial agents
- To know how bacterial can be resistant to antimicrobial agents
- To know how to select an antibacterial agent
- To know susceptibility test (disk diffusion test)
- To know host factors that determine selection of antimicrobial agents
- To understand therapy with combined antimicrobial agents
- To know the prophylaxis of infection with antibiotics
- To understand superinfection
- To understand about antibiotics drug misused