DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1470 anti-Pneumocystis therapy in patients with a PO 2
<70 mm Hg or an
alveolar-arterial gradient >35 mm Hg (Centers for Disease Control
and Prevention, 2009). However, the incidence of side effects is high
for both regimens. Prophylaxis with 800 mg sulfamethoxazole and
160 mg trimethoprim once daily or three times a week is effective in
preventing pneumonia caused by this organism in patients with
AIDS (Centers for Disease Control and Prevention, 2009). Adverse
reactions are less frequent with the lower prophylactic doses of
trimethoprim-sulfamethoxazole. The most common problems are
rash, fever, leukopenia, and hepatitis.
Prophylaxis in Neutropenic Patients. Several studies have demonstrated
the effectiveness of low-dose therapy (150 mg/m 2 of body surface
area of trimethoprim and 750 mg/m 2 of body surface area of
sulfamethoxazole) for the prophylaxis of infection by P. jiroveci. In
addition, significant protection against sepsis caused by gram-negative
bacteria was noted when 800 mg sulfamethoxazole and 160 mg
trimethoprim were given twice daily to severely neutropenic patients.
The emergence of resistant bacteria may limit the usefulness of
trimethoprim-sulfamethoxazole for prophylaxis (Hughes et al., 2002).
Miscellaneous Infections. Nocardia infections have been treated successfully
with the combination, but failures also have been reported.
Although a combination of doxycycline and streptomycin or gentamicin
now is considered to be the treatment of choice for brucellosis,
trimethoprim-sulfamethoxazole may be an effective substitute
for the doxycycline combination. Trimethoprim-sulfamethoxazole
also has been used successfully in the treatment of Whipple’s disease,
infection by Stenotrophomonas maltophilia, and infection by
the intestinal parasites Cyclospora and Isospora. Wegener’s granulomatosis
may respond, depending on the stage of the disease.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Untoward Effects. There is no evidence that trimethoprimsulfamethoxazole,
when given in the recommended
doses, induces folate deficiency in normal persons.
However, the margin between toxicity for bacteria and
that for humans may be relatively narrow when the cells
of the patient are deficient in folate. In such cases,
trimethoprim-sulfamethoxazole may cause or precipitate
megaloblastosis, leukopenia, or thrombocytopenia.
In routine use, the combination appears to exert little
toxicity. About 75% of the untoward effects involve the
skin. However, trimethoprim-sulfamethoxazole has
been reported to cause up to three times as many dermatological
reactions as does sulfisoxazole alone (5.9%
versus 1.7%).
Exfoliative dermatitis, Stevens-Johnson syndrome, and toxic
epidermal necrolysis (Lyell’s syndrome) are rare, occurring primarily
in older individuals. Nausea and vomiting constitute the bulk of GI
reactions; diarrhea is rare. Glossitis and stomatitis are relatively common.
Mild and transient jaundice has been noted and appears to have
the histological features of allergic cholestatic hepatitis. Central
nervous system reactions consist of headache, depression, and hallucinations,
manifestations known to be produced by sulfonamides.
Hematological reactions, in addition to those just mentioned, are various
anemias (including aplastic, hemolytic, and macrocytic), coagulation
disorders, granulocytopenia, agranulocytosis, purpura,
Henoch-Schönlein purpura, and sulfhemoglobinemia. Permanent
impairment of renal function may follow the use of trimethoprimsulfamethoxazole
in patients with renal disease, and a reversible
decrease in creatinine clearance has been noted in patients with normal
renal function.
Patients with AIDS frequently have hypersensitivity reactions
to trimethoprim-sulfamethoxazole (rash, neutropenia, Stevens-
Johnson syndrome, Sweet’s syndrome, and pulmonary infiltrates).
It may be possible to continue therapy in such patients following
rapid oral desensitization (Gluckstein and Ruskin, 1995).
THE QUINOLONES
The first quinolone, nalidixic acid, was isolated as a byproduct
of the synthesis of chloroquine and made available
for the treatment of urinary tract infections. The
introduction of fluorinated 4-quinolones, such as
ciprofloxacin (CIPRO, others), and moxifloxacin
(AVELOX), represents a particularly important therapeutic
advance: These agents have broad antimicrobial
activity and are effective after oral administration for
the treatment of a wide variety of infectious diseases
(Table 52–2) (Hooper, 2005a). Rare and potentially
fatal side effects, however, have resulted in the withdrawal
from the U.S. market of lomefloxacin
sparfloxacin (phototoxicity, QTc prolongation), gatifloxacin
(hypoglycemia), temafloxacin (immune
hemolytic anemia), trovafloxacin (hepatotoxicity),
grepafloxacin (cardiotoxicity), and clinafloxacin (phototoxicity).
In all these cases, the side effects were
detected by postmarketing surveillance (Sheehan and
Chew, 2003).
Chemistry. The compounds that are currently available for clinical
use in the U.S. are quinolones containing a carboxylic acid moiety
at position 3 of the primary ring structure. Many of the newer fluoroquinolones
also contain a fluorine substituent at position 6 and a
piperazine moiety at position 7 (Table 52–2).
Mechanism of Action. The quinolone antibiotics target
bacterial DNA gyrase and topoisomerase IV (Hooper,
2005a). For many gram-positive bacteria (such as
S. aureus), topoisomerase IV is the primary activity
inhibited by the quinolones. In contrast, DNA gyrase is
the primary quinolone target in many gram-negative
microbes (such as E. coli) (Alovero et al., 2000;
Hooper, 2005a). Individual strands of double-helical
DNA must be separated to permit DNA replication or
transcription. However, anything that separates the
strands results in “overwinding” or excessive positive
supercoiling of the DNA in front of the point of separation.
To combat this mechanical obstacle, the bacterial
enzyme DNA gyrase is responsible for the
continuous introduction of negative supercoils into