We described the serovar distribution and antibiotic susceptibility of 72 Salmonella enterica BSI isolates from Cambodian adults, and noted a predominance of S. Typhi and S. Choleraesuis. Besides MDR, S. Typhi in particular displayed high rates of DCS, while S. Choleraesuis was associated with advanced HIV-infection and remarkably high azithromycin resistance rates.
Our findings have several limitations. The study describes Salmonella
BSI mainly in adults. As Salmonella
spp. is an important pediatric pathogen in tropical low-resource settings 
, data on its invasive infections in children are essential to complement the epidemiological picture of salmonellosis in Cambodia. Next, our clinical hospital data did not allow calculations of incidence and/or the true burden of disease because the population denominator and referral pattern were not known. In addition, the presence of an HIV-treatment center in the hospital may have led to a patient selection bias. In spite of these limitations our data shed new light on invasive Salmonella
infections in Cambodia.
In HIV-negative patients, S.
Typhi was the most common serovar, with very high rates of MDR (75.0%) and DCS (90.0%). This confirms earlier trends from Cambodia as noted by Kasper and coworkers in 2009 
describing 56% of MDR and 80% DCS in S.
Typhi. The presence of MDR and DCS has been observed in other Asian countries, albeit with important differences. A survey on typhoid fever in five countries 
revealed MDR rates as variable as 65% in Pakistan, 22% in Vietnam, 7% in India and 0% in China/Indonesia whereas rates of NA resistant S. Typhi (NARST) ranged similarly between 57–59% (India, Pakistan), 44% (Vietnam) and 0% (China, Indonesia). Since the early 1990's, Southern Vietnam has been particularly mentioned as a regional ‘typhoid resistance hotspot’ with NARST/DCS rates as high as 90–98% 
. The geographical location of Cambodia in the vicinity of this regional ‘hotspot’ may be one of the explanations for the high rates of DCS among our patients with typhoid fever, given the intense cross-border traffic between the two countries. In addition, the uncontrolled use of ciprofloxacin and other antibiotics and the limited access to safe water and sanitation services 
probably add to selection and spread of MDR and DCS isolates.
In Vietnam, the Ser83→Phe substitution in gyrA
was described as the predominant underlying resistance mechanism for DCS 
. We observed this mutation also in all S.
Typhi isolates with combined DCS and NA resistance and to a lesser extent in S.
Choleraesuis and other NTS. According to the Cambodian National Treatment Guidelines 
ciprofloxacin is the first choice treatment for presumed typhoid fever with ceftriaxone as alternative. Given the failure risk of a treatment course with ciprofloxacin for invasive salmonellosis with DCS as high as 36% 
, we think the empiric treatment of typhoid fever with ciprofloxacin should be abandoned in Cambodia. Alternatives could be azithromycin for uncomplicated cases and ceftriaxone for hospitalized patients. Gatifloxacin proved to be a safe, cheap and effective alternative treatment in Nepal 
and Vietnam 
, but it is not widely distributed in Cambodia, and caution remains regarding its use in the elderly and in a setting with increasing rates of MDR tuberculosis.
In addition, these data and their subsequent therapeutic challenges urge the need for more and better yet affordable diagnostic microbiology in Cambodia. More and adequately working microbiology laboratories across the country are essential for the improvement of clinical care and for surveillance of bacterial resistance.
Among HIV-infected patients, S.
Choleraesuis was the most common serovar. It is a zoonotic pathogen causing paratyphoid in pigs and is an emerging cause of invasive infections in immune compromised patients in Southeast and Eastern Asia 
. The prevalence of S.
Choleraesuis was not yet described in Cambodia in swine nor in humans but it is a well-known pathogen in neighboring Thailand 
All isolates in patients with recurrent S.
Choleraesuis BSI had PFGE profiles which were identical to the first isolate, which is suggestive for relapse rather than for reinfection although the small number of pulsotypes and the limited discriminatory power of PFGE using XbaI 
should be taken into account. Given the context of advanced HIV-infection, relapse is the more likely interpretation 
Choleraesuis isolates (70.8%) had azithromycin MIC-values exceeding 16 µg/mL. To our knowledge, this has not yet been described in a series of clinical Salmonella
isolates from a single setting. Of note, also one S.
Typhi and S.
Enteritidis isolate displayed high azithromycin MIC-values. This contrasts with the low azithromycin MIC data for S.
Typhi reported from Vietnam (MIC90 8–16 µg/mL 
), India and Egypt (MIC90 8 µg/mL 
). Azithromycin MIC-values up to 64 µg/mL in S.
Typhi and Paratyphi A from India were recently described 
, and a Finnish study revealed azithromycin MIC-values ≥32 µg/mL in 1.9% of 1237 NTS isolates; half of them were isolated after travel to Thailand 
. While considering the azithromycin resistance ‘epidemiological cutoff’ of 16 µg/mL 
, azithromycin resistance apparently presents an emerging problem as treatment failures have been described 
Possible mechanisms of azithromycin resistance include the presence of specific resistance genes (e.g. mph
B), a mutation in rlp
D or rlp
V, or the acquisition of an efflux pump 
. In Cambodia, generic azithromycin can be purchased over the counter of private clinics and pharmacies; local prices vary between 1 to 5 US $ per tablet. It is commonly used for respiratory tract infections, and often prescribed when all other treatments have failed (personal communication Thong Phe). No local data about macrolide use in animals are available, but a recent report from Vietnam showed that antibiotics such as macrolides, lincomycin, colistin, and aminoglycosides are actually used in livestock 
As the above mentioned azithromycin resistance in our study is most prevalent in S.
Choleraesuis, our findings may firstly affect empiric treatment choices for fever and presumed BSI in HIV-infected patients. Given the complex resistance patterns in S.
Choleraesuis, neither ciprofloxacin nor azithromycin appear to be safe choices; the most likely alternative in the Cambodian setting is probably a third generation cephalosporin. However, in two S.
Choleraesuis isolates the presence of ESBL was found. Extensive antibiotic resistance, including ESBL has been reported before for S.
Choleraesuis in East Asia 
. Even though ESBL prevalence in Salmonella enterica
is still low compared to the very high rates in community-acquired Escherichia coli
and Klebsiella pneumoniae
isolates in the same study population 
, this is a very worrisome trend, as the potential for transmission of resistance genes is expected.
These results warrant further surveillance of resistance in invasive bacterial pathogens and Salmonella spp. in particular in Cambodia. More in depth research of the causes and molecular mechanisms of this in vitro measured azithromycin resistance are needed. In addition, integrated research on the human and veterinary epidemiology of S. Choleraesuis in Cambodia is essential for better understanding of the disease dynamics and planning of public health interventions.