Download CLINICAL PHARMACOLOGY OF ANTIBACTERIAL AGENTS

Clinical and pharmaceutical
aspects of the use of
antibacterial drugs in the
clinic of internal diseases
Actions of antibacterial drugs on
bacterial cells
Mechanisms of Action
1. Inhibition of bacterial cell wall synthesis or activation of enzymes that
disrupt bacterial cell walls (eg, penicillins, cephalosporins,
vancomycin)
2. Inhibition of protein synthesis by bacteria or production of abnormal
bacterial proteins (eg, aminoglycosides, clindamycin, erythromycin,
tetracyclines). These drugs bind irreversibly to bacterial ribosomes,
intracellular structures that synthesize proteins. When antimicrobial
drugs are bound to the ribosomes, bacteria cannot synthesize the
proteins necessary for cell walls and other structures.
3. Disruption of microbial cell membranes (eg, antifungals)
4. Inhibition of organism reproduction by interfering with nucleic acid
synthesis (eg, fluoroquinolones, rifampin, anti–acquired
immunodeficiency syndrome antivirals)
5. Inhibition of cell metabolism and growth (eg, sulfonamides,
trimethoprim)
Antibiotic Combination Therapy
Antimicrobial drugs are often used in combination.
Indications for combination therapy may include:
• Infections caused by multiple microorganisms (eg,
abdominal and pelvic infections)
• Nosocomial infections, which may be caused by many
different organisms
• Serious infections in which a combination is synergistic
(eg, an aminoglycoside and an antipseudomonal
penicillin for pseudomonal infections)
• Likely emergence of drug-resistant organisms if a single
drug is used (eg, tuberculosis). Although drug
combinations to prevent resistance are widely used, the
only clearly effective use is for treatment of tuberculosis.
• Fever or other signs of infection in clients whose immune
systems are suppressed. Combinations of antibacterial
plus antiviral and/or antifungal drugs may be needed
PENICILLINS
Indications for Use
• Clinical indications for use of penicillins include
bacterial infections caused by susceptible
microorganisms. As a class, penicillins usually are more
effective in infections caused by gram-positive bacteria
than those caused by gram-negative bacteria. However,
their clinical uses vary significantly according to the
subgroup or individual drug and microbial patterns of
resistance. The drugs are often useful in skin/ soft
tissue, respiratory, gastrointestinal, and genitourinary
infections. However, the incidence of resistance among
streptococci, staphylococci, and other microorganisms
continues to grow.
Aminopenicillins
Piperacillin
Augmentin contains amoxicillin and
clavulanate. It is available in 250-,
500-, and 875-mg tablets, each of
which contains 125 mg of
clavulanate.
MACROLIDES
Cephalosporins
Indications for Use
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Clinical indications for the use of cephalosporins include surgical
prophylaxis and treatment of infections of the respiratory tract, skin
and soft tissues, bones and joints, urinary tract, brain and spinal
cord, and bloodstream (septicemia). In most infections with
streptococci and staphylococci, penicillins are more effective and
less expensive. In infections caused by methicillin-resistant S.
aureus, cephalosporins are not clinically effective even if in vitro
testing indicates susceptibility. Infections caused by Neiserria
gonorrhoeae, once susceptible to penicillin, are now preferentially
treated with a third-generation cephalosporin such as ceftriaxone.
Cefepime is indicated for use in severe infections of the lower
respiratory and urinary tracts, skin and soft tissue, female
reproductive tract, and infebrile neutropenic clients. It may be used
as monotherapy for all infections caused by susceptible organisms
except P. aeruginosa; a combination of drugs should be used for
serious pseudomonal infections.
Aminoglycosides
Contraindications to Use
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Aminoglycosides are contraindicated in infections
for which less toxic drugs are effective. The
drugs are nephrotoxic and ototoxic and must be
used very cautiously in the presence of renal
impairment. Dosages are adjusted according to
serum drug levels and creatinine clearance. The
drugs must also be used cautiously in clients
with myasthenia gravis and other neuromuscular
disorders because muscle weakness may be
increased.
PRINCIPLES OF THERAPY WITH
TETRACYCLINES
1. Culture and susceptibility studies are needed before
tetracycline therapy is started because many strains
of organisms are either resistant or vary greatly in
drug susceptibility. Cross-sensitivity and crossresistance are common among tetracyclines.
2. The oral route of administration is usually effective
and preferred. Intravenous (IV) therapy is used
when oral administration is contraindicated or for
initial treatment of severe infections.
3. Tetracyclines decompose with age, exposure to
light, and extreme heat and humidity. Because the
breakdown products may be toxic, it is important to
store these drugs correctly. Also, the manufacturer’s
expiration dates on containers should be noted and
outdated drugs should be discarded.
Lincosamides
Clindamycin is indicated for treatment of
anaerobic infection caused by
bacteroides and other anaerobes that
often participate in mixed infections.
Clindamycin, sometimes in combination
with an aminoglycoside or cephalosporin,
is used to treat penetrating wounds of the
abdomen and the gut; infections
originating in the female genital tract, eg,
septic abortion and pelvic abscesses; and
aspiration pneumonia. Clindamycin is
now recommended rather than
erythromycin for prophylaxis of
endocarditis in patients with valvular
heart disease who are undergoing certain
dental procedures. Clindamycin plus
primaquine is an effective alternative to
trimethoprim-sulfamethoxazole for
moderate to moderately severe
Pneumocystis jiroveci pneumonia in AIDS
patients. It is also used in combination
with pyrimethamine for AIDS-related
toxoplasmosis of the brain.
Chloramphenicol
 Because of potential
toxicity, bacterial
resistance, and the
availability of many other
effective alternatives,
chloramphenicol is rarely
used. It may be considered
for treatment of serious
rickettsial infections such
as typhus and Rocky
Mountain spotted fever. It is
an alternative to a b-lactam
antibiotic for treatment of
meningococcal meningitis
occurring in patients who
have major hypersensitivity
reactions to penicillin or
bacterial meningitis caused
by penicillin-resistant
strains of pneumococci. The
dosage is 50-100 mg/kg/d in
four divided doses.
OXAZOLIDINONES
Antibiotic
resistance
Factors that encourage the spread
of resistance
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The emergence and spread of antimicrobial resistance are complex problems
driven by numerous interconnected factors, many of which are linked to the
misuse of antimicrobials and thus amenable to change. In turn, antimicrobial use
is influenced by an interplay of the knowledge, expectations, and interactions of
prescribers and patients, economic incentives, characteristics of a country's
health system, and the regulatory environment.
Patient-related factors are major drivers of inappropriate antimicrobial use. For
example, many patients believe that new and expensive medications are more
efficacious than older agents. In addition to causing unnecessary health care
expenditure, this perception encourages the selection of resistance to these
newer agents as well as to older agents in their class.
Self-medication with antimicrobials is another major factor contributing to
resistance. Self-medicated antimicrobials may be unnecessary, are often
inadequately dosed, or may not contain adequate amounts of active drug,
especially if they are counterfeit drugs. In many developing countries, antimicrobials are purchased in single doses and taken only until the patient feels
better, which may occur before the pathogen has been eliminated. Inappropriate
demand can also be stimulated by marketing practices. Direct-to-consumer
advertising allows pharmaceutical manufacturers to market medicines directly to
the public via television, radio, print media, and the Internet. In particular,
advertising on the Internet is gaining market penetration, yet it is difficult to
control with legislation due to poor enforceability.
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Prescribers' perceptions regarding patient expectations and demands
substantially influence prescribing practice. Physicians can be pressured
by patient expectations to prescribe antimicrobials even in the absence of
appropriate indications. In some cultural settings, antimicrobials given by
injection are considered more efficacious than oral formulations. Such
perceptions tend to be associated with the over-prescribing of broadspectrum injectable agents when a narrow-spectrum oral agent would be
more appropriate. Prescribing “just to be on the safe side" increases when
there is diagnostic uncertainty, lack of prescriber knowledge regarding
optimal diagnostic approaches, lack of opportunity for patient follow-up, or
fear of possible litigation. In many countries, antimicrobials can be easily
obtained in pharmacies and markets without a prescription.
Patient compliance with recommended treatment is another major
problem. Patients forget to take medication, interrupt their treatment when
they begin to feel better, or may be unable to afford a full course, thereby
creating an ideal environment for microbes to adapt rather than be killed.
In some countries, low quality antibiotics (poorly formulated or manufactured, counterfeited or expired) are still sold and used for selfmedication or prophylaxis.
Hospitals are a critical component of the antimicrobial resistance problem
worldwide. The combination of highly susceptible patients, intensive and
prolonged antimicrobial use, and cross-infection has resulted in
nosocomial infections with highly resistant bacterial pathogens. Resistant
hospital-acquired infections are expensive to control and extremely difficult to eradicate. Failure to implement simple infection control practices,
such as handwashing and changing gloves before and after contact with
patients, is a common cause of infection spread in hospitals throughout
the world. Hospitals are also the eventual site of treatment for many
patients with severe infections due to resistant pathogens acquired in the
community. In the wake of the AIDS epidemic, the prevalence of such
infections can be expected to increase.
Adverse Effects
of Sulfonamides
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Adverse effects can result from oral and sometimes topical
sulfonamides; effects include
Hypersensitivity reactions, such as rashes, Stevens-Johnson
syndrome (see Hypersensitivity and Inflammatory Disorders:
Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis
(TEN)), vasculitis, serum sickness, drug fever, anaphylaxis, and
angioedema
Crystalluria, oliguria, and anuria
Hematologic reactions, such as agranulocytosis, thrombocytopenia,
and, in patients with G6PD deficiency, hemolytic anemia
Kernicterus in neonates
Photosensitivity
Neurologic effects, such as insomnia, and headache
Hypothyroidism, hepatitis, and activation of quiescent SLE may
occur in patients taking sulfonamides. These drugs can exacerbate
porphyrias.
FLUOROQUINOLONES
ciprofloxacin (Cipro, Ciloxan), gatifloxacin (Tequin)
levofloxacin (Levaquin, Tavanic), lomefloxacin (Maxaquin)
moxifloxacin (Avelox), norfloxacin (Noroxin), ofloxacin (Floxin, Tarivid)
ANTIVIRAL DRUGS
ANTIVIRAL DRUGS
Antiretrovirals
Therapy
of
HIV
Infection:
Nucleoside-Analog Reverse Transcriptase Inhibitors (NRTI). These
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drugs inhibit viral RNA-dependent DNA polymerase (reverse
transcriptase) and are incorporated into viral DNA (they are chainterminating drugs).
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Zidovudine (AZT = ZDV, Retrovir) first approved in 1987
Didanosine (ddI, Videx)
Zalcitabine (ddC, Hivid)
Stavudine (d4T, Zerit)
Lamivudine (3TC, Epivir)
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). In
contrast to NRTIs, NNRTIs are not incorporated into viral DNA; they
inhibit HIV replication directly by binding non-competitively to reverse
transcriptase.
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Nevirapine (Viramune)
Delavirdine (Rescriptor)
Protease Inhibitors. These drugs are specific for the HIV-1 protease
and competitively inhibit the enzyme, preventing the maturation of virions
capable of infecting other cells.
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Saquinavir (Invirase) first approved in 1995
Ritonavir (Norvir)
Indinavir (Crixivan)
Nelfinavir (Viracept)
Antifungal Drug Mechanisms