Beruflich Dokumente
Kultur Dokumente
Class Summary
Until susceptibilities are determined, antibiotics should be empiric, for which there are
various recommendations. The authors of this article consider the 2003 World Health
Organization (WHO) guidelines to be outdated. These recommend fluoroquinolone treatment
for both complicated and uncomplicated cases of typhoid fever, but 38% of S typhi isolates
taken in the United States in 2006 were fluoroquinolone resistant (nalidixic acid–resistant S
typhi [NARST]), and the rate of multidrug resistance was 13%. (Multidrug-resistant S typhi
is, by definition, resistant to the original first-line agents, ampicillin, chloramphenicol, and
trimethoprim-sulfamethoxazole.)
The particular sensitivity pattern of the organism in its area of acquisition should be the major
basis of empiric antibiotic choice. It may soon become necessary to treat all cases
presumptively for multidrug resistance until sensitivities are obtained.
Note that nalidixic acid is a nontherapeutic drug that is used outside of the United States as a
stand-in for fluoroquinolones in sensitivity assays. In the United States, it is still used
specifically for S typhi infection.[39, 17]
Chloramphenicol was used universally to treat typhoid fever from 1948 until the 1970s, when
widespread resistance occurred. Ampicillin and trimethoprim-sulfamethoxazole (TMP-SMZ)
then became treatments of choice. However, in the late 1980s, some S typhi and S paratyphi
strains (multidrug resistant [MDR] S typhi or S paratyphi) developed simultaneous plasmid-
mediated resistance to all three of these agents.
Fluoroquinolones are now recommended by most authorities for the treatment of typhoid
fever. They are highly effective against susceptible organisms, yielding a better cure rate than
cephalosporins. Unfortunately, resistance to first-generation fluoroquinolones is widespread
in many parts of Asia.
In recent years, third-generation cephalosporins have been used in regions with high
fluoroquinolone resistance rates, particularly in south Asia and Vietnam. Unfortunately,
sporadic resistance has been reported, so it is expected that these will become less useful over
time.[39]
The genes for antibiotic resistance in S typhi and S paratyphi are acquired from Escherichia
coli and other gram-negative bacteria via plasmids. The plasmids contain cassettes of
resistance genes that are incorporated into a region of the Salmonella genome called an
integron. Some plasmids carry multiple cassettes and immediately confer resistance to
multiple classes of antibiotics. This explains the sudden appearance of MDR strains of S typhi
and S paratyphi, often without intermediate strains that have less-extensive resistance.
A single point mutation gyrA confers partial resistance. If a second gyrA point mutation is
added, the resistance increases somewhat. However, a mutation in parC added to a single
gyrA mutation confers full in vitro resistance to first-generation fluoroquinolones. Clinically,
these resistant strains show a 36% failure rate when treated with a first-generation
fluoroquinolone such as ciprofloxacin.[44] The risk of relapse after bacterial clearance is
higher in both partially and fully resistant strains than in fully susceptible strains.[18]
Geography of resistance
Among S typhi isolates obtained in the United States between 1999 and 2006, 43% were
resistant to at least one antibiotic.
Nearly half of S typhi isolates found in the United States now come from travelers to the
Indian subcontinent, where fluoroquinolone resistance is endemic (see Table 3). The rate of
fluoroquinolone resistance in south and Southeast Asia and, to some extent, in East Asia is
generally high and rising (see Table 3). Susceptibility to chloramphenicol, TMP-SMZ, and
ampicillin in South Asia is rebounding. In Southeast Asia, MDR strains remain predominant,
and some acquired resistance to fluoroquinolones by the early 2000s.
The most recent professional guideline for the treatment of typhoid fever in south Asia was
issued by the Indian Association of Pediatrics (IAP) in October 2006. Although these
guidelines were published for pediatric typhoid fever, the authors feel that they are also
applicable to adult cases. For empiric treatment of uncomplicated typhoid fever, the IAP
recommends cefixime and, as a second-line agent, azithromycin. For complicated typhoid
fever, they recommend ceftriaxone. Aztreonam and imipenem are second-line agents for
complicated cases.[47] The authors believe that the IAP recommendations have more validity
than the WHO recommendations for empiric treatments of typhoid fever in both adults and
children.
In high-prevalence areas outside the areas discussed above, the rate of intermediate
sensitivity or resistance to fluoroquinolones is 3.7% in the Americas (P =.132), 4.7% (P
=.144) in sub-Saharan Africa, and 10.8% (P =.706) in the Middle East. Therefore, for strains
that originate outside of south or Southeast Asia, the WHO recommendations may still be
valid—that uncomplicated disease should be treated empirically with oral ciprofloxacin and
complicated typhoid fever from these regions should be treated with intravenous
ciprofloxacin.[39, 42, 48, 19, 49]
Antibiotic resistance is a moving target. Reports are quickly outdated, and surveys of
resistance may have limited geographic scope. Therefore, any recommendation regarding
antibiotic treatment must be taken with a grain of salt. In the authors' opinion, if the origin of
the infection is unknown, the combination of a first-generation fluoroquinolone and a third-
generation cephalosporin should be used.
Table 3. Antibiotic Recommendations by Origin and Severity (Open Table in a new window)
[50, 40]
Cefotaxime IV Imipenem IV
Amoxicillin PO or
Ofloxacin PO
TMP-SMZ PO
or Azithromycin
PO
Cefotaxime IV or
Ofloxacin IV
Ampicillin IV
or
TMP-SMZ IV
Ciprofloxacin PO
[50, 40, 48, 51]
or
Ofloxacin PO
Ciprofloxacin IV
Ciprofloxacin IV
or
or
Ofloxacin IV
Ofloxacin IV
Future directions
Chloramphenicol (Chloromycetin)
Binds to 50S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein
synthesis. Effective against gram-negative and gram-positive bacteria. Since its introduction
in 1948, has proven to be remarkably effective for enteric fever worldwide. For sensitive
strains, still most widely used antibiotic to treat typhoid fever. In the 1960s, S typh i strains
with plasmid-mediated resistance to chloramphenicol began to appear and later became
widespread in many endemic countries of the Americas and Southeast Asia, highlighting
need for alternative agents.
Interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in
bactericidal activity against susceptible bacteria. At least as effective as chloramphenicol in
rapidity of defervescence and relapse rate. Convalescence carriage occurs less commonly
than with other agents when organisms are fully susceptible. Usually given PO with a daily
dose of 75-100 mg/kg tid for 14 d.
View full drug information
Ciprofloxacin (Cipro)
Not currently recommended for use in children and pregnant women because of observed
potential for causing cartilage damage in growing animals. However, arthropathy has not
been reported in children following use of nalidixic acid (an earlier quinolone known to
produce similar joint damage in young animals) or in children with cystic fibrosis, despite
high-dose treatment.
Cefotaxime (Claforan)
Arrests bacterial cell wall synthesis, which inhibits bacterial growth. Third-generation
cephalosporin with gram-negative spectrum. Lower efficacy against gram-positive
organisms. Excellent in vitro activity against S typhi and other salmonellae and has
acceptable efficacy in typhoid fever. Only IV formulations are available. Recently,
emergence of domestically acquired ceftriaxone-resistant Salmonella infections has been
described.
Azithromycin (Zithromax)
Treats mild to moderate microbial infections. Administered PO at 10 mg/kg/d (not exceeding
500 mg), appears to be effective to treat uncomplicated typhoid fever in children 4-17 y.
Confirmation of these results could provide an alternative for treatment of typhoid fever in
children in developing countries, where medical resources are scarce.
Ceftriaxone (Rocephin)
Cefoperazone (Cefobid)
Ofloxacin (Floxin)
Levofloxacin (Levaquin)