Treatment of typhoid fever using Antibiotics

Class Summary

Definitive treatment of typhoid fever (enteric fever) is based on susceptibility. As a general

principle of antimicrobial treatment, intermediate susceptibility should be regarded as
equivalent to resistance. Between 1999 and 2006, 13% of S typhi isolates collected in the
United States were multidrug resistant.

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Organization (WHO) guidelines to be outdated.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]

History of antibiotic resistance

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]

Mechanisms of antibiotic resistance

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.

The initial strains of antibiotic-resistant S typhi and S paratyphi carried chloramphenicol

acetyltransferase type I, which encodes an enzyme that inactivates chloramphenicol via
acetylation. MDR strains may carry dihydrofolate reductase type VII, which confers
resistance to trimethoprim. Interestingly, in areas where these drugs have fallen out of use, S
typhi has reverted to wild type, and they are often more effective than newer agents.[40, 41, 42,
30]

Resistance to fluoroquinolones is evolving in an ominous direction. Fluoroquinolones target

DNA gyrase and topoisomerase IV, bacterial enzymes that are part of a complex that uncoils
and recoils bacterial DNA for transcription.[43] S typhi most commonly develops
fluoroquinolone resistance through specific mutations in gyrA and parC, which code for the
binding region of DNA gyrase and topoisomerase IV, respectively.

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]

The third-generation fluoroquinolone gatifloxacin appears to be highly effective against all

known clinical strains of S typhi both in vitro and in vivo. due to its unique interface with
gyrA. It achieves better results than cephalosporins even among strains that are considered
fluoroquinolone resistant. However, gatifloxacin is no longer on the market in the United
States, and its use cannot be generalized to any other member of the class.[45, 46]

In any case, as gatifloxacin replaces older fluoroquinolones in high-prevalence resistance is

bound to emerge. Any two of a number of gyrA mutations, when added to the parC mutation,
confer full in vitro resistance. Although such a combination has yet to be discovered in vivo,
all of these mutations exist in various clinic strains, and it seems highly likely that a
gatifloxacin-resistant one will be encountered clinically if selective pressure with
fluoroquinolones continues to be exerted.[44]

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)

Location Severity First-Line Second-Line

Antibiotics Antibiotics
South Asia, East Asia[47] Uncomplicated Cefixime PO Azithromycin PO
Complicated Ceftriaxone IV or Aztreonam IV or

[50, 40]

Cefotaxime IV Imipenem IV

Eastern Europe, Middle East, sub- Uncomplicated Ciprofloxacin PO Cefixime PO or

[48, 51]
Saharan Africa, South America or

Amoxicillin PO or
Ofloxacin PO

TMP-SMZ PO
 or Azithromycin
PO

Complicated Ciprofloxacin IV Ceftriaxone IV or

or

Cefotaxime IV or
Ofloxacin IV

Ampicillin IV

or

TMP-SMZ IV

Unknown geographic origin or Uncomplicated Cefixime PO plus Azithromycin PO*

Southeast Asia[52, 47]

Ciprofloxacin PO
[50, 40, 48, 51]
or

Ofloxacin PO

Complicated Ceftriaxone IV or Aztreonam IV or

Cefotaxime IV, Imipenem IV, plus

plus

Ciprofloxacin IV
Ciprofloxacin IV
or
 or

Ofloxacin IV

Ofloxacin IV

*Note that the combination of azithromycin and fluoroquinolones is not recommended

because it may cause QT prolongation and is relatively contraindicated.

Future directions

A meta-analysis found that azithromycin appeared to be superior to fluoroquinolones and

ceftriaxone with lower rates of clinical failure and relapse respectively. Although the data did
not permit firm conclusions, if further studies confirm the trend, azithromycin could become
a first-line treatment.[53]

View full drug information

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.

Produces rapid improvement in patient's general condition, followed by defervescence in 3-5

d. Reduced preantibiotic-era case-fatality rates from 10%-15% to 1%-4%. Cures
approximately 90% of patients. Administered PO unless patient is nauseous or experiencing
diarrhea; in such cases, IV route should be used initially. IM route should be avoided because
it may result in unsatisfactory blood levels, delaying defervescence.

View full drug information

Amoxicillin (Trimox, Amoxil, Biomox)

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

Trimethoprim and sulfamethoxazole (Bactrim DS, Septra)

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Antibacterial activity of

TMP-SMZ includes common urinary tract pathogens, except Pseudomonas aeruginosa. As
effective as chloramphenicol in defervescence and relapse rate. Trimethoprim alone has been
effective in small groups of patients.

View full drug information

Ciprofloxacin (Cipro)

Fluoroquinolone with activity against pseudomonads, streptococci, MRSA, Staphylococcus

epidermidis, and most gram-negative organisms but no activity against anaerobes. Inhibits
bacterial DNA synthesis and, consequently, growth. Continue treatment for at least 2 d (7-14
d typical) after signs and symptoms have disappeared. Proven to be highly effective for
typhoid and paratyphoid fevers. Defervescence occurs in 3-5 d, and convalescent carriage and
relapses are rare. Other quinolones (eg, ofloxacin, norfloxacin, pefloxacin) usually are
effective. If vomiting or diarrhea is present, should be given IV. Fluoroquinolones are highly
effective against multiresistant strains and have intracellular antibacterial activity.

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.

View full drug information

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.

View full drug information

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.

View full drug information

Ceftriaxone (Rocephin)

Third-generation cephalosporin with broad-spectrum gram-negative activity against gram-

positive organisms; Excellent in vitro activity against S typhi and other salmonellae.

View full drug information

Cefoperazone (Cefobid)

Discontinued in the United States. Third-generation cephalosporin with gram-negative

spectrum. Lower efficacy against gram-positive organisms.

View full drug information

Ofloxacin (Floxin)

A pyridine carboxylic acid derivative with broad-spectrum bactericidal effect.

View full drug information

Levofloxacin (Levaquin)

For pseudomonal infections and infections due to multidrug-resistant gram-negative

organisms.

Next Section: Corticosteroids

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