Antibiotics 4 pharmacology
Antimetabolites:
Sulfonamides
Sulfonamides can be divided into three major groups:
(1) oral, absorbable;
(2) oral, nonabsorbable
(3) topical.
The oral, absorbable sulfonamides can be classified as short-, medium-, or long acting on the
basis of their half-lives.
Mechanism and activity:
Sulfonamides are structural analogs of para-aminobenzoic acid (PABA) that competitively
inhibit dihydropteroate synthase. They inhibit growth by reversibly blocking folic acid
synthesis.
Sulfonamides inhibit both gram-positive and gram-negative bacteria,
Nocardia, Chlamydia
trachomatis,
and some protozoa. Some enteric bacteria, such
as E coli, Klebsiella, Salmonella,
Shigella, and Enterobacter
, are inhibited.
Ristance:
Sulfonamide resistance may occur as a result of mutations that
(1) cause overproduction of PABA,
(2) cause production of a folic acid-synthesizing enzyme that has low affinity for sulfonamides,
(3) impair permeability to the sulfonamide. Dihydropteroate synthase with low sulfonamide
affinity is often encoded on a plasmid that is transmissible and can disseminate rapidly and
widely.
Clinical Uses
Oral Absorbable Agents:
Sulfisoxazole and sulfamethoxazole are short- to medium-acting
agents that are used to treat urinary tract infections, respiratory tract infections, sinusitis,
bronchitis, pneumonia, otitis media, and dysentery.
Sulfadiazine in combination with pyrimethamine is first-line therapy for treatment of acute
toxoplasmosis.
Sulfadoxine, long acting sulfonamide, in combination with pyrimethamine used as a second-
line agent in treatment for malaria.
Oral nonabsorbable
agents:
Sulfasalazine is widely used in ulcerative colitis, enteritis, and
other inflammatory bowel disease. Sulfasalazine is split by intestinal microflora to yield
sulfapyridine and 5-aminosalicylate. Salicylate released in the colon in high concentration is
responsible for an antiinflammatory effect. Comparably high concentrations of salicylate
cannot be achieved in the colon by oral intake of ordinary formulations of salicylates because
of severe gastrointestinal toxicity.
Topical Agents:
Sodium sulfacetamide ophthalmic solution or ointment is effective treatment
for bacterial conjunctivitis and as adjunctive therapy for trachoma.
Silver sulfadiazine is a much less toxic topical sulfonamide and is preferred to for prevention
of infection of burn wounds.
Adverse Reactions:
The most common adverse effects are fever, skin rashes, exfoliative dermatitis,
photosensitivity, urticaria, nausea, vomiting, and diarrhea.
Stevens-Johnson syndrome, crystalluria, hematuria, hemolytic or aplastic anemia,
granulocytopenia, and thrombocytopenia occur less frequently.
Sulfonamides taken near the end of pregnancy increase the risk of kernicterus in newborns.
Trimethoprim:
Trimethoprim is an inhibitor of bacterial dihydrofolic acid reductase. Pyrimethamine is an
excellent inhibitor of dihydrofolic acid reductase in protozoa
These reductases are required for the synthesis of purines and hence DNA. Inhibition of these
enzymes are responsible for bacteriostatic and bacteriocidal activities. When trimethoprim or
pyrimethamine is combined with sulfonamides (sulfamethoxazole) there is sequential blocking
of the biosynthetic pathway leading to drug synergism and enhanced antimicrobial activity.
Resistance to trimethoprim: usually by plasmid encoded trimethoprim-resistant dihydrofolate
reductases. Trimethoprim typically used orally often in combination with sulfamethoxazole, a
sulfonamide with a similar half-life.
Clinical Uses:
Oral trimethoprim: Acute urinary tract infections.
Oral trimethoprim-sulfamethoxazole (Bactrim) combination: Pneumocystis carinii pneumonia,
shigellosis,systemic Salmonella infection, some nontuberculous mycobacterial infections.
Respiratory tract pathogens: pneumococcus, Haemophilus, Moraxella catarrhalis, Klebsiella
pneumoniae
By I.V. administration trimethoprim - sulfamethoxazole: agent of choice for moderately
severe to severe infections with Pneumocystis carinii pneumonia, especially in patients with
HIV. May be used for gram-negative sepsis
Adverse effects:
Trimethoprim adverse effects referable to antifolate properties: megaloblastic anemia,
leukopenia granulocytopenia (avoided by coadminstration of folinic acid) . Combination of
Trimethoprim-Sulfamethoxazole cause in addition, sulfonamide side effects--nausea,
vomiting, vasculitis, renal damage.
DNA gyrase inhibitors
Fluroquinolines
Quinolones are synthetic fluorinated analogs of nalidixic acid.
They are active against a variety of gram-positive and gram-negative bacteria.
Mechanism of Action
Quinolones block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase)
and topoisomerase IV. Inhibition of DNA gyrase prevents the relaxation of positively
supercoiled DNA that is required for normal transcription and replication.
Inhibition of topoisomerase IV interferes with separation of replicated chromosomal
DNA into the respective daughter cells during cell division.
Antibacterial Activity
The old quinolones, nalidixic acid did not achieve systemic antibacterial levels and
were useful only in the treatment of lower urinary tract infections.
Fluorinated derivatives (ciprofloxacin, levofloxacin, enoxacin, lomefloxacin,
ofloxacin, and pefloxacin) have greatly improved antibacterial activity compared
with nalidixic acid and achieve bactericidal levels in blood and tissues.
excellent activity against gram-negative aerobic bacteria; they had limited activity
against gram-positive organisms.
Several newer agents have improved activity against gram-positive cocci.
Norfloxacin
is the least active against both gram-negative and gram-positive
organisms .
Ciprofloxacin, enoxacin, lomefloxacin, levofloxacin, ofloxacin, and pefloxacin
comprise a second group of similar agents possessing excellent gram-negative
activity and moderate to good activity against gram-positive bacteria.
MICs for
gram-negative cocci and bacilli, including
Enterobacter
sp,
P aeruginosa
,
Neisseria
meningitides
,
H aemophilus
sp, and
C ampylobacter jejuni
, are 1–2 mcg/mL and
often less.
Methicillin-susceptible strains of
S aureus
are generally susceptible to these
fluoroquinolones, but methicillin-resistant strains of staphylococci are often
resistant.
Streptococci and enterococci tend to be less susceptible than staphylococci, and
efficacy in infections caused by these organisms is limited.
Ciprofloxacin is the most active agent of this group against gram-negative
organisms,
P aeruginosa
in particular. Levofloxacin, the L-isomer of ofloxacin, has
superior activity against gram-positive organisms, including
Streptococcus
pneumoniae.
Gatifloxacin, gemifloxacin, and moxifloxacin (a third group) of fluoroquinolones
with improved activity against gram positive organisms, particularly
S pneumoniae
and some staphylococci.
Fluoroquinolones also are active against agents of atypical pneumonia (eg,
mycoplasmas and chlamydiae) and against intracellular pathogens such as
Legionella pneumophila
and some mycobacteria, including
Mycobacterium
tuberculosis
and
Mycobacterium avium
complex.
Moxifloxacin also has modest activity against anaerobic bacteria. Because of
toxicity, it is no longer use.
Pharmacokinetics
After oral administration, the fluoroquinolones are well absorbed (bioavailability of 80–95%)
and distributed widely in body fluids and tissues . Serum half-lives range from 3 to 10 hours.
The relatively long half-lives of levofloxacin, gemifloxacin, gatifloxacin,
and moxifloxacin permit once-daily dosing.
Oral absorption is impaired by divalent and trivalent cations, including those
in antacids. Therefore, oral fluoroquinolones should be taken 2 hours before or 4 hours after
any products containing these cations.
Serum concentrations of intravenously administered drug are similar to those of orally
administered drug.
Most fluoroquinolones are eliminated by renal mechanisms, either tubular secretion or
glomerular filtration. Dosage adjustment is required for patients with creatinine clearances
less than 50 mL/min. Dosage adjustment
for renal impairment is not necessary for moxifloxacin.
Nonrenally cleared fluoroquinolones are relatively contraindicated in patients
with hepatic failure.
Clinical Uses
Fluoroquinolones (other than moxifloxacin, which achieves relatively low urinary levels) are
effective in
urinary tract infections
caused by many organisms, including
P aeruginosa
. These
agents are also effective for bacterial diarrhea caused by
Shigella
,
Salmonella
, toxigenic
E coli,
and
Campylobacter
. Fluoroquinolones (except norfloxacin, which does not achieve adequate
systemic concentrations) have been used in infections of
soft tissues, bones, and joints
and in
intra-abdominal and respiratory tract infections
, including those caused by multidrug-
resistant organisms such as
Pseudomonas
and
Enterobacter
.
Ciprofloxacin is a drug of choice for prophylaxis and treatment of anthrax, Ciprofloxacin and
levofloxacin are no longer recommended for the treatment of gonococcal infection. However,
both drugs are effective in treating
chlamydial urethritis or cervicitis.
Ciprofloxacin, levofloxacin, or moxifloxacin is occasionally used for treatment of tuberculosis
and atypical mycobacterial infections. These agents may be suitable for eradication of
meningococci from carriers or for prophylaxis of infection in neutropenic cancer patients.
With their enhanced gram-positive activity and activity against atypical
pneumonia agents
(chlamydiae,
Mycoplasma
, and
Legionella
), levofloxacin, gatifloxacin, gemifloxacin, and
moxifloxacin— so-called respiratory fluoroquinolones—are effective and used increasingly for
treatment of upper and lower respiratory tract infections.
Adverse Effects
Fluoroquinolones are generally well tolerated.
The most common effects are
nausea, vomiting, and diarrhea. Occasionally, headache,
dizziness, insomnia, skin rash, or abnormal liver function tests develop
.
Photosensitivity
has been reported with lomefloxacin and pefloxacin.
QT c prolongation
may occur with gatifloxacin, levofloxacin, gemifloxacin, and moxifloxacin,
which should be avoided or used with caution in patients with known QT c interval
prolongation or uncorrected hypokalemia; in those receiving class IA (eg, quinidine or
procainamide) or class III antiarrhythmic agents (sotalol, ibutilide, amiodarone); and in
patients receiving other agents known to increase the QT c interval (eg, erythromycin, tricyclic
antidepressants).
Gatifloxacin has been associated with hyperglycemia in diabetic patients and with
hypoglycemia in patients also receiving oral hypoglycemic agents. Because of these serious
effects (including some fatalities.
Fluoroquinolones
may damage growing cartilage and cause an arthropathy
. Thus, these drugs
are not routinely recommended for patients under 18 years of age. However, the arthropathy
is reversible.
Fluoroquinolones
should be avoided during pregnancy.