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‫السالم‬ ‫عبد‬ ‫أحمد‬

Once a specific cause of infection is identified based
upon specific microbial tests, the following questions
should be considered:
1. If a specific microbial pathogen is identified, can a
narrower spectrum agent be substituted for the initial
empirical therapy?
2. Is one agent or a combination of agents necessary?
3. What is the optimal dose, route of administration, and
duration of therapy?
4. What adjunctive measures can be undertaken to eradicate
the infection? For example is surgery feasible for removal
of devitalized tissue or foreign body or drainage of an
abscess- into which antimicrobial agents may be unable to
penetrate?

Choice of antimicrobial agent depends upon
I. Host factors:
History of allergy- renal and hepatic function-
resistance to infection (ie whether immuno-
compromised)- ability to tolerate drugs by mouth-
severity of illness- age- and if female whether
pregnant, breast-feeding or taking oral contraceptive.
Patients with AIDS have an unacceptably high risk of
allergic and toxic reactions to many antimicrobial
agents.
Patients with severe liver disease have an unacceptably
high risk of developing non-oliguric renal failure with
aminoglycosides.
Prior adverse effects and impaired elimination or
detoxification of the drug- this may be genetically pre-
determined or due to underlying renal or hepatic
disease.

The age of the patient at times may provide
important additional clues to the likely organism
or may affect the choice of the antimicrobial:
In meningitis, neonates are usually infected with
group B streptococcus or enteric organisms.
In children younger than 2 years, H.influenza is
common but S. pneumoniae and Neisseria
meningitidis also occur. The last two organisms
are the most common pathogens in adults.
The duration of therapy, dosage and route of
administration depend on site, type and severity
of infection and response.
The dose varies according to a number of factors
including age, weight, renal function and
severity of infection.

II. Pharmacologic factors:
. The kinetics of absorption, distribution and elimination.
. The ability of the drug to be delivered to the site of
infection.
. The potential toxicity of an agent.
. The pharmacokinetic or pharmcodynamic interaction with
other drug.
Pharmacokinetic differences among agents with similar
antimicrobial spectrum may be exploited to decrease the
frequency of dosing (e.g. ceftriaxone may be conveniently
given every 24 hours).
III. Lastly, increasing consideration is being given to cost
of antimicrobial therapy especially when multiple agents
with comparable efficacy are available for a specific
infection.

Interpretation of culture results
Properly obtained and processed specimens for culture
frequently yield reliable information. The lack of a
confirmatory microbial diagnosis may be due to:
1. Sample error,e.g. obtaining culture after antimicrobial
agents have been administered.
2. Non-cultivable or slowly growing organisms, where
cultures are discarded before sufficient growth.
3. Requesting bacterial cultures when the infection is due
to other organisms.
4. Not recognizing the need for special media or isolation
techniques.

Susceptibility testing
Testing bacterial pathogens in vitro for their
susceptibility, ideally to a narrow-spectrum, non-
toxic antimicrobial drug.
Tests measure the concentration of drug
required to inhibit growth of thr organism
(MIC) or kill the organism (MBC). The results
can be correlated to known drug concentration
in various body compartments.
Only MICs are routinely measured in most
infections, where in infections in which
bactericidal therapy is required for irradication
(e.g. meningitis, endocarditis, sepsis in the
granulocytopenic patient), MBC measurements
may be useful.

Clinical failure of antimicrobial therapy
. Errors in susceptibility testing are rare, but the original
results should be confirmed by repeated testing.
. Drug dosing and absorption should be scrutinized and
tested directly using serum measurements. Pill counting or
directly observed therapy.
. The clinical data should be reviewed to determine whether
the patient’s immune system is adequate, and if not, what
can be done to maximize it. For example, are adequate
number of granulocytes present and are HIV infection,
malnutrition, or underlying malignancy present?
. The presence of abscesses or foreign bodies should also
be considered.
. Culture and susceptibility testing should be repeated to
determine if superinfection has occurred with another
organism- or if the original organism becomes resistant.

Antimicrobial Pharmacodynamics
Pharmacodynamic factors include
1. pathogen susceptibility testing
2. Drug bactericidal versus bacteriostatic activiy
3. Drug synergism or antagonism
4. Post-antibiotic effect
Together with pharmacokinetics, pharmaco-
dynamic information permits the selection of
antimicrobial dosage regimens.

Bacterioststic versus bactericidal activity
. This classification has limitations: Some agents that are
considered bacteriostatic may be bactericidal against
selected microorganisms. For example chloramphenicol
is often bactericidal against pneumococci, meningococci,
and H.influenza. On the other hand, enterococci are
inhibited, but not killed, by vancomycin, penicillin or
ampicillin, used as single drugs.
. Static and cidal agents are equivalent for treatment of
most infections in immunocompetent host. Cidal agents
should be selected over static ones when local or systemic
host defenses are impaired. Cidal agents are required for
treatmnt of meningitis, endocarditis and other
endovascular infections and infections in neutropenic
cancer patients.

Bactericidal agents can be divided into two groups:
1. Agents that exhibit concentration-dependent killing
(e.g. aminoglycosides, quinolones) with which the rate
and extent of killing increase with increasing drug
concentration, i.e. increasing concentrations kill an
increasing proportion of bacteria and at a more rapid
rate.
Maximizing peak serum concentration of such drugs
results in increased efficacy and decreased selection of
resistant bacteria.
Concentration dependent killing is one of the
pharmacodynamic factors responsible for the efficacy of
once-daily dosing of aminoglycosides.

2. Agents that exhibit time-dependent killing (e.g. Beta
lactams and vancomycin) do not exhibit increasing
killing with increasing concentraion above MBC.
Antibacterial activity is directly related to time above
MBC and becomes independent of concentration once
the MBC has been exceeded. Bactericidal activity
continues so long as serum concentrations are greater
than MBC.
Drug concentration of time-dependent killing agents that
lack a post-antibiotic effect should be maintained above
the MBC for the entire dosage interval.

Postantibiotic effect “PAE”
It is the persistent suppression of bacterial growth after
limited exposure to an antimicrobial agent, ie.
Antimicrobial activity persists beyond the time that
measurable drug is present. It is expressed
mathematically as follows: PAE = T – C
T= time required for the viable count in the test (in vitro)
culture to increase tenfold above the count observed
immediately before drug removal.
C= time required for the count in untreated culture to
increase tenfold above the count observed immediately
after completion of the same procedure used in the test
culture.
The PAE reflects the time required for bacteria to return
to logarithmic growth. It may represent an extension of
the lag phase of bacterial growth.

Proposed mechanisms of PAE:
1. Recovery after reversible non-lethal damage to cell
structures.
2. Persistence of drug at a binding site or within periplasmic
space.
3. The need to synthesize new enzymes before growth.
4. In-vivo PAE is thought to be due to postantibiotic
leukocyte enhancement (PALE).
Most antimicrobials possess in vitro PAE (> 1.5 h) against
susceptible gram positive cocci. Antimicrobials with
significant PAE against susceptible gram negative bacilli
are limited to carbapenems, and agents that inhibit
protein or DNA synthesis.

Antimicrobials with in vitro PAE > 1.5 h
Against gram positive cocci:
Aminoglycosides, carbapenems, cephalosporins,
chloramphenicol, clindamycin, macrolides,
oxazolidinones, penicillins, quinolones,
rifampicin, sulphonamides, tetracyclines,
trimethoprim, vancomycin.
Against gram negative bacilli:
Aminoglycosides, carbapenems,
chloramphenicol, qinolones, rifampicin,
tetracyclines

In-vivo PAEs are usually much longer than in vitro PAEs.
This may be due to postantibiotic leucocyte enhancement
(PALE) and exposure of bacteria to subinhibitory antibiotic
concentrations.
PALE reflects the increased susceptibility of bacteria to the
phagocytic and bactericidal action of neutrophils.
Subinhibitory drug concentrations result in altered bacterial
morphology and decreased rate of growth.
The lowest drug concentration required to induce
morphologic changes is known as the minimal antibacterial
concentration.

Clinical relevance of PAE:
Aminoglycosides have significant PAE that can reach
several hours.
Aminoglycosides and quinolones possess concentration
dependent PAEs; thus high doses of aminoglycosides
given once daily result in enhanced bactericidal activity
and extended PAEs. These pharmacodynamic effects
allow amioglycoside serum concentrations that are below
the MICs of target organisms to remain effective for
extended periods of time.
Aminoglycoside toxicity is both time- and concentration-
dependent. Toxicity is unlikely to occur until a certain
threshold concentration is achieved, but once it is
achieved the time above this threshold becomes critical.
At clinically relevant doses the time above the threshold
is greater with multiple smaller doses than with a single
large dose.

Advantages of once-daily dosing:
1. A single daily dose of aminoglycosides is just as
effective and no more (often less) toxic than multiple
smaller doses.
2. Avoidance of adaptive resistance, a phenomenon in
which reduced bactericidal activity occurs following a
second antibiotic exposure. It is probably caused by a
reduction in energy-dependent aminoglycoside uptake
into bacteria.
3. Lower monitoring cost than conventional dosing. No
need to obtain serum concentrations unless the
intention is to administer aminoglycosides for more
than 4-5 days.
N.B. The use of once-daily dosing does not eliminate
careful monitoring and dose adjustment to minimize
toxicity (accoding to creatinine clearance).

Pharmacokinetic considerations
Route of administration
In critically ill patients oral or IM absorption is unreliable.
The IV route is preferred in such patients. IV therapy is
also preferred in bacterial meningitis or endocarditis.
Parenteral therapy should be selected in patients with
nausea, vomiting, gastrectomy or diseases that affect GI
absorption. This route is also preferred for drugs such as
vancomycin and antipsudomonas penicillin which are
poorly absorbed from GIT.
However, many antimicrobials have similar
pharmacokinetic properties when given orally or
parenterally (tetracycline, cotrimoxazole, quinolones,
chloramphenicol, metronidazole, clindamycin, rifampin,
fluconazole). In most cases, oral therapy with these drugs is
equally effective, less costly and with fewer complications.

Conditions that alter antimicrobial pharmacokinetics
Various diseases and physiologic states alter the
pharmacokinetics of antimicrobial drugs.
Impairment of renal or hepatic function may result in
decreased elimination. Dosage adjustment is necessary
in these situations to avoid toxicity.
Conversely patients with burns, cystic fibrosis, or
trauma may have increased dosage requirements for
selected agents.
The pharmacokinetics of antimicrobialsare also altered
in the eldely, in neonates and in pregnancy.
Dosage adjustment needed in hepatic impairment:
Chloramphenicol, clindamycin, erythromycin,
amprenavir, indinavir, rimantadine, metronidazole.

Dosage adjustment needed in renal impairment
Acyclovir, amantadine, aminoglycosides, aztreonam,
cephalosporins (except cefoperazone and ceftriaxone),
clathromycin, cycloserine, didanosine, ethambutol,
famciclovir, fluconazole, flucytosine, foscarnet,
ganciclovir, imipenem, lamivudine, meropenem,
penicillins (except antistaph, e.g. nafcillin and
dicloxacillin), quinolones, rimantadine, atavudine,
terbenafine, cotrimoxazole, valacyclovir, vancomycin,
zalcitabine, zidovudine.
Antimicrobials contraindicated in renal impairment:
Cidovovir, methenamine, nalidixic acid, nitrofurantoin,
sulfonamides (long acting), tetracyclines (except
doxycycline and possibly minocycline).

Drug concentrations in body fluids:
Most antimicrobial agents are well distributed to most
body tissues and fluids. Penetration into the CSF is one
important exception; clindamycin, aminoglycosides and
first and some second generation cephalosporins
penetrate poorly.
Many antibiotics do not penetrate uninflamed meninges
to an appreciable extent. In the presence of meningitis,
however the CSF concentration of many antibiotics
increase.
Two other sites of poor penetration are the prostate and
the obstructed biliary tree.
The pH of the site of infection may affect antibiotic
activity: Aminoglycosides are much more effective at
physiologic pH (7.4) than in acid environment (e.g
abscess). In pus or sputum, an acid pH may alter the
activity of these antibiotics.

CSF penetration of selected antimicrobials (percent of
serm concentration):
Antimicrobial uninflamed inflamed meninges
Ampicillin 2-3 2-100
Aztreonam 2 5
Cefotaxime 22.5 27-36
Ceftazidime 0.7 20-40
Ceftriaxone 0.8-1.6 16
Cefuroxime 20 17-88
Ciprofloxacin 6-27 26-37
Imipenem 3.1 11-41
Meropenem 0-7 1-52
Nafcillin 2-15 5-27
Penicillin-G 1-2 8-18
Sulphamethoxazole 40 12-47
Trimethoprim <41 12-69
Vancomycin 0 1-53

Pregnancy and Lactation:
Certain drugs may pose special problems (e.g. the
tetracycline which may cause hepatotoxicity to the
mother and dentition problems in the infant).
Placental transfer of antibiotics:
Whenever possible, pregnant women should avoid all
drugs because of the risk of fetal toxicity:
. Antibiotics considered safe in pregnancy include the
penicillins, cephalosporins, erythromycin base and
probably aztreonam
. Antibiotics to be used with caution include the
aminoglycosides, vancomycin, clindamycin, imipenem-
cilastatin, trimethoprim and nitrofurantoin.
. Antibiotics contraindicated in pregnancy include
chloramphenicol, erythromycin estolate, tetracycline,
fluoroquinolnes, cotrimozazole, metronidazole and
sulfonamides.

Placental transfer of antibiotics (infant-maternal serum
concentration):
50-100% :
Ampicillin, carbenicillin, chloramphenicol, methicillin,
nitrofurantoin, penicillin-G, sulphonamides,
tetracyclines, trimethoprim.
30-50% :
Amphotericin-B, cefamandole, cephalothin, clindamycin,
gentamycin, kanamycin, streptomycin.
0-30% :
Amikacin, cefazolin, ceftriaxone, dicloxacillin,
erythromycin, nafcillin, oxacillin, tobramycin

Antibiotics in breast milk:
Minimal data are available regarding adverse effects in
nursing neonates.
If possible nursing mothers should avoid all drugs.
The total daily dose a nursing baby receives is often
probably not toxicologically significant.
As in pregnancy, chloramphenicol, tetracycline,
sulphonamides and metronidazole should be avoided.
Until further data are available, it is suggested to avoid
the use of fluoroquinolones.

Maternal milk Antibiotic milk conc
Plasma conc (ug/ml)
50-100% Ampicillin NA
Chloramphenicol* 16-25
Clindamycin NA
Erythromycin 0.4-1.6
Isoniazid 6-12
Metronidazole* NA
Sulfapyridne* 30-130
Tetracycline* 0.5-2.6
Cotrimoxazole NA
<30% Cefotaxime NA
Cefazolin 1.5
Kanamycin* 18.4
Nalidixic scid* 4
Oxacillin 0.2
Penicillin-G 0.01-0.04
Streptomycin* 0.3-1.3
--------------------------------------------------------------------------------
*Potential toxicity to the mother NA= not available

Monitoring serum concentration of antimicrobial agent
For most antimicrobial agents, the relationship between dose
and therapeutic outcome is well established and serum
concentration monitoring is unnecessary for these drugs.
In clinical practice, serum concentration monitoring is
routinely performed on patients receiving aminoglycosides.
Despite the lack of supporting evidence for its utility or
need, serum vancomycin concentration monitoring is also
performed.
Flucytosine serum concentration monitoring has been
shown to reduce toxicity when doses are adjusted to
maintain peak concentration below 100ug/ml.

Antimicrobial combination
Although indications for combination therapy exists,
antimicrobial combinations are often overused in
clinical practice.
Current indications:
1. To provide broad spectrum empirical therapy in
seriously ill patients.
2. To treat polymicrobial infections such as
intrabdominal sepsis or pelvic abscess.
3. Limiting or preventing the emergence of resistant
strains as in tuberculosis.
4. Synergism: Mechanisms:
a) Blockade of sequential steps in a metabolic
sequence, eg. Cotrimoxazole.
b) Inhibition of enzymatic activation.
c) Enhancement of antimicrobial uptake, e.g. cell wall
active agents increase the uptake of aminoglycosides.

Commonly used antimicrobial combinations:
1. Penicillin and gentamycin are synergistic against S.
especially S.viridans and enterococci.
2. Antipseudomonas penicillins and aminoglycosides are
synergistic.
3. Cephalosporins and aminoglycosides are synergistic
against K. pneumoniae.
4. Sulfamethoxazole and trimethoprim are synergistic
against some gram positive and negative organisms.
5. Penicillins and cephalosporins are synergistic with beta-
lactamase inhibitorsas clavulanic acid and sulbactam.
6. Flucytosine and Amphotericin-B in cryptococcal
meningitis to reduce the dose of amphotericin-B.
7. Unique dug combination; imipenem-cilastatin. The
enzyme inhibitor cilastatin prevents metabolic
breakdown of imipenem by the kidney.

Disadvantages of multiple antibiotics:
1. An increased risk of drug sensitivities or toxicity.
2. Increased cost.
3. False sense of security: The use of multiple agents to
cover all possible organisms is often not possible,
practical or necessary and may be associated with
significant complications.
4. An increased risk of colonization with a resistant
organism may occur. If superinfection develops, this
organism is difficult to treat.
5. Possibility of antagonism:
The most striking example was reported in a study of
patients with pneumococcal meningitis who were
treated with a combination of penicillin and
chlortetracycline. The mortality rate was 79% versus
21% in patients who received penicillin monotherapy.

Mechanisms of antagonistic action:
1. Inhibition of cidal activity by static action:
a) Tetracycline and chloramphenicol can antagonize
the action of bactericidal of cell wall active agents
(beta-lactam antibiotics) whose action requires that
the bacteria be actively growing and dividing.
b) Tetracycline and chloramphenicaol can also
antagonize the bactericidal action of
aminoglycosides by inhibition of active
aminoglycoside uptake by susceptible organisms.
2. Induction of enzymatic activation:
Some gram negative bacilli possess inducible beta-
lactamases. Beta-lactam antibiotics as imipenem,
cefoxitin and ampicillin are potent inducers of beta-
lactamase production. If an inducing agent is
combined with hydrolyzable beta-lactam, such as
piperacillin, antagonism may occur.