AntibioticsClass SummaryDefinitive 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% ofS 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 resistanceChloramphenicol 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, someS typhiandS paratyphistrains (multidrug resistant [MDR]S typhiorS 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 resistanceThe genes for antibiotic resistance inS typhiandS paratyphiare acquired fromEscherichia coliand other gram-negative bacteria via plasmids. The plasmids contain cassettes of resistance genes that are incorporated into a region of theSalmonellagenome 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 ofS typhiandS paratyphi,often without intermediate strains that have less-extensive resistance.The initial strains of antibiotic-resistantS typhiandS paratyphicarried 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 typhihas 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 typhimost commonly develops fluoroquinolone resistance through specific mutations ingyrAandparC,which code for the binding region of DNA gyrase and topoisomerase IV, respectively.A single point mutationgyrAconfers partial resistance. If a secondgyrApoint mutation is added, the resistance increases somewhat. However, a mutation inparCadded to a singlegyrAmutation 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 ofS typhiboth in vitro and in vivo. due to its unique interface withgyrA. 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 ofgyrAmutations, when added to theparCmutation, 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 resistanceAmongS typhiisolates obtained in the United States between 1999 and 2006, 43% were resistant to at least one antibiotic.Nearly half ofS typhiisolates 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 StatesIn the United States in 2012, 68% ofS typhiisolates and 95% ofS 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 forS typhiinfection.[44, 22]The rate of multidrug resistance in 2012 was 9% inS typhiand 0% inS paratyphi. (Multidrug-resistantS typhiis, by definition, resistant to the original first-line agents, ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole.)There have been no cases of ceftriaxone-resistantS typhiorS 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 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.Table 3. Antibiotic Recommendations by Origin and Severity(Open Table in a new window)LocationSeverityFirst-Line AntibioticsSecond-Line Antibiotics

South Asia, East Asia[52]

[56, 45]

UncomplicatedCefixime POAzithromycin PO

ComplicatedCeftriaxone IVor

Cefotaxime IV

Aztreonam IVor

Imipenem IV

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

Ofloxacin PO

Cefixime POor

Amoxicillin POor

TMP-SMZ PO

or Azithromycin PO

ComplicatedCiprofloxacin IVor

Ofloxacin IV

Ceftriaxone IVor

Cefotaxime IVor

Ampicillin IV

or

TMP-SMZ IV

Unknown geographic origin or Southeast Asia[58, 52]

[56, 45, 53, 57]

UncomplicatedCefixime POplus

Ciprofloxacin POor

Ofloxacin PO

Azithromycin PO*

ComplicatedCeftriaxone IVor

Cefotaxime IV,plus

Ciprofloxacin IVor

Ofloxacin IV

Aztreonam IVor

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 directionsA 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]View full drug informationChloramphenicol (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 typhi 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 informationAmoxicillin (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 informationTrimethoprim 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.View full drug informationCiprofloxacin (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 againstS typhiand other salmonellae and has acceptable efficacy in typhoid fever. Only IV formulations are available. Recently, emergence of domestically acquired ceftriaxone-resistantSalmonellainfections has been described.View full drug informationAzithromycin (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 informationCeftriaxone (Rocephin)Third-generation cephalosporin with broad-spectrum gram-negative activity against gram-positive organisms; Excellent in vitro activity againstS typhiand other salmonellae.Cefoperazone (Cefobid)Discontinued in the United States. Third-generation cephalosporin with gram-negative spectrum. Lower efficacy against gram-positive organisms.View full drug informationOfloxacin (Floxin)A pyridine carboxylic acid derivative with broad-spectrum bactericidal effect.View full drug informationLevofloxacin (Levaquin)For pseudomonal infections and infections due to multidrug-resistant gram-negative organisms.

http://emedicine.medscape.com/article/231135-medication