Typhoid Fever Medication

Updated: Aug 19, 2019
  • Author: John L Brusch, MD, FACP; Chief Editor: Michael Stuart Bronze, MD  more...
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Medication

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 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 typhi or 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.

H58 type S typhi has become the predominant multidrug-resistant (MDR) isolate throughout Asia and Africa, 75% of all resistant strains. [47] However, MDR isolates can be very localized. Most isolates of S typhi and S paratyphi from Pakistan exhibited a high degree of multidrug resistance, while isolates from Bangladesh, India, and Nepal showed a low rate. [48]

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. [49]

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. [50, 51, 52, 36]

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. [53] 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. [54] The risk of relapse after bacterial clearance is higher in both partially and fully resistant strains than in fully susceptible strains. [24]

The third-generation fluoroquinolone gatifloxacin appears to be highly effective against all known clinical strains of S typhi both in vitro and in vivo owing 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. [55, 56]

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. [54]

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. [57] 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 valid—that uncomplicated disease should be treated empirically with oral ciprofloxacin and complicated typhoid fever from these regions should be treated with intravenous ciprofloxacin. [49, 52, 58, 25, 59]

Resistance in the United States

In the United States in 2012, 68% of S typhi isolates and 95% of S paratyphi isolates 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. [49, 23]

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 trimethoprim-sulfamethoxazole.)

There have been no cases of ceftriaxone-resistant S typhi or S paratyphi documented in the United States, at least since 2003. [60]

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 first-generation 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.

Ceftriaxone and azithromycin continue to be effective against most isolates of S typhi and S paratyphi, although resistance to ceftriaxone appears to be increasing, especially in extensively drug-resistant (XDR) strain of S typhi identified in Pakistan in 2016. [61] This variant continues to remain sensitive to azithromycin and to the carbapenems.

Antibiotic treatment of typhoid fever

Severe or complicated infections

For infections that are not acquired in Pakistan, ceftriaxone should be started empirically. In this setting, resistance to ceftriaxone is unusual. In cases that do not originate in southern Asia, a fluoroquinolone should be considered because of its potential advantage of hastening defervesce then is achievable by cephalosporins.

For infections that are acquired in Pakistan, a carbapenem should be administered because of the risk of XDR strains.

Mild or uncomplicated infections

In less-severe uncomplicated infections, it is appropriate to begin oral therapy. Unless the risk of fluoroquinolone resistance is significant, ciprofloxacin or ofloxacin is preferred. Azithromycin offers dual advantages of low risk of resistance and excellent oral absorption.

Because of the risk of developing antibiotic resistance, the concept of using dual antibiotic therapy has been revived. In addition, some evidence shows that the clinical course is improved with such combinations. Specifically, the combination of cefixime-ofloxacin has been approved by the Indian Regulatory Authority for the treatment of typhoid fever. [62]

Table 3. Antibiotic Recommendations by Origin and Severity

Location

Severity

First-Line Antibiotics

Second-Line Antibiotics

South Asia, East Asia [57]

[63, 50]

Uncomplicated

Cefixime PO

Azithromycin PO

Complicated

Ceftriaxone IV or

Cefotaxime IV

Aztreonam IV or

Imipenem IV

Eastern Europe, Middle East, sub-Saharan Africa, South America [58, 64]

Uncomplicated

Ciprofloxacin PO or

Ofloxacin PO

Cefixime PO or

Amoxicillin PO or

TMP-SMZ PO

or Azithromycin PO

Complicated

Ciprofloxacin IV or

Ofloxacin IV

Ceftriaxone IV or

Cefotaxime IV or

Ampicillin IV

or

TMP-SMZ IV

Unknown geographic origin or Southeast Asia [65, 57]

[63, 50, 58, 64]

Uncomplicated

Cefixime PO plus

Ciprofloxacin PO or

Ofloxacin PO

Azithromycin PO*

Complicated

Ceftriaxone IV or

Cefotaxime IV, plus

Ciprofloxacin IV or

Ofloxacin IV

Aztreonam IV or

Imipenem IV, plus

Ciprofloxacin 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. [66]

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.

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.

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.

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 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)

Third-generation cephalosporin with broad-spectrum gram-negative activity against gram-positive organisms; Excellent in vitro activity against S typhi and other salmonellae.

Levofloxacin (Levaquin)

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

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Corticosteroids

Class Summary

Dexamethasone may decrease the likelihood of mortality in severe typhoid fever cases complicated by delirium, obtundation, stupor, coma, or shock if bacterial meningitis has been definitively ruled out by cerebrospinal fluid studies. To date, the most systematic trial of this has been a randomized controlled study in patients aged 3-56 years with severe typhoid fever who were receiving chloramphenicol therapy. This study compared outcomes in 18 patients given placebo with outcomes in 20 patients given dexamethasone 3 mg/kg IV over 30 minutes followed by dexamethasone 1 mg/kg every 6 hours for 8 doses. The fatality rate in the dexamethasone arm was 10% versus 55.6% in the placebo arm (P =.003). [67]

Nonetheless, this point is still debated. A 2003 WHO statement endorsed the use of steroids as described above, but reviews by eminent authors in the New England Journal of Medicine (2002) [4] and the British Medical Journal (2006) [68] do not refer to steroids at all. A 1991 trial compared patients treated with 12 doses of dexamethasone 400 mg or 100 mg to a retrospective cohort in whom steroids were not administered. This trial found no difference in outcomes among the groups. [69]

The data are sparse, but the authors of this article agree with the WHO that dexamethasone should be used in cases of severe typhoid fever.

Dexamethasone (Decadron)

Prompt administration of high-dose dexamethasone reduces mortality in patients with severe typhoid fever without increasing incidence of complications, carrier states, or relapse among survivors.

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