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 typhiisolates 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 recommend combination treatment with ceftriaxone and
ciprofloxacin when neither the sensitivities nor the geographical origin of the bacteria is known.
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.

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 typhior S
paratyphi) developed simultaneous plasmid-mediated resistance to all three of these agents.
Fluoroquinolones 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.[44]

Mechanisms of antibiotic resistance

The genes for antibiotic resistance in S typhi and S paratyphi are acquired fromEscherichia coli and other
gram-negative bacteria via plasmids. The plasmids contain cassettes of resistance genes that are incorporated
into a region of theSalmonella 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.[45, 46, 47, 35]
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.[48] 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 inparC 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. [49]The risk of relapse after bacterial
clearance is higher in both partially and fully resistant strains than in fully susceptible strains. [23]
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.
[50, 51]

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.[49]

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.[52] The authors believe that the IAP recommendations apply to 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 validthat uncomplicated disease should be treated empirically with oral
ciprofloxacin and complicated typhoid fever from these regions should be treated with intravenous
ciprofloxacin.[44, 47, 53, 24, 54]

Resistance in the United States

In the United States in 2012, 68% of S typhi isolates and 95% of S paratyphiisolates were fully resistant to
nalidixic acid. While full resistance to ciprofloxacin was considerably less, intermediate susceptibilities to
ciprofloxacin in both organisms closely matched resistance to nalidixic acid. 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.[44, 22]
The rate of multidrug resistance in 2012 was 9% in S typhi and 0% in S paratyphi. (Multidrug-resistant S
typhi is, by definition, resistant to the original first-line agents, ampicillin, chloramphenicol, and trimethoprimsulfamethoxazole.)
There have been no cases of ceftriaxone-resistant S typhi or S paratyphidocumented in the United States, at
least since 2003.[55]
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. However, in the authors' opinion, if the origin of the infection is unknown, the combination of a firstgeneration fluoroquinolone and a third-generation cephalosporin should be used. This allows for most effective
clearance if the organism is fluoroquinolone-susceptible but still covers strains that are not.
Table 3. Antibiotic Recommendations by Origin and Severity (Open Table in a new window)
Location

Severity

First-Line Antibiotics

Second-Line Antibiotics

South Asia, East Asia[52]

Uncomplicated

Cefixime PO

Azithromycin PO

Complicated

Ceftriaxone IVor

Aztreonam IV or

[56, 45]

Eastern Europe, Middle East, sub-Saharan Africa, South America [53, 57]

Uncomplicated

Cefotaxime IV

Imipenem IV

Ciprofloxacin PO or

Cefixime PO or

Ofloxacin PO

Amoxicillin PO or

TMP-SMZ PO

or Azithromycin PO

Complicated

Ciprofloxacin IVor

Ceftriaxone IV or

Ofloxacin IV

Cefotaxime IV or

Ampicillin IV

or

TMP-SMZ IV

Unknown geographic origin or Southeast Asia[58, 52]

Uncomplicated

[56, 45, 53, 57]

Cefixime POplus

Azithromycin PO*

Ciprofloxacin PO or

Ofloxacin PO

Complicated

Ceftriaxone IVor

Aztreonam IV or

Cefotaxime IV,plus

Imipenem IV,plus

Ciprofloxacin IVor

Ciprofloxacin IV

Ofloxacin IV

or

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. [59]
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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.
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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.
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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, exceptPseudomonas aeruginosa. As effective as chloramphenicol in
defervescence and relapse rate. Trimethoprim alone has been effective in small groups of patients.
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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.

Cefotaxime (Claforan)
Arrests bacterial cell wall synthesis, which inhibits bacterial growth. Third-generation cephalosporin with gramnegative 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-resistantSalmonella infections has been described.
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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.
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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.

Cefoperazone (Cefobid)
Discontinued in the United States. Third-generation cephalosporin with gram-negative spectrum. Lower efficacy
against gram-positive organisms.
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Ofloxacin (Floxin)
A pyridine carboxylic acid derivative with broad-spectrum bactericidal effect.
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Levofloxacin (Levaquin)
For pseudomonal infections and infections due to multidrug-resistant gram-negative organisms.

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