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U.S. Department of Health and Human Services

Animal & Veterinary

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Typhi and Paratyphoidal Salmonellae by Felicita Medalla, M.D., M.S.

DR. MEDALLA: Good afternoon. I am happy to be talking about Typhi and Paratyphoidal Salmonella which often we do not talk about. So this is an opportunity for me to talk about these serotypes.


Although these serotypes account for less than two percent of Salmonella infections that are reported to CDC, they are important serotypes and they do cause serious infections. Salmonella Typhicauses typhoid fever and Paratyphoid A,B, and C cause paratyphoid fever and collectively these infections are referred to as enteric fever which is a systemic illness characterized by fever, headache and abdominal pain.

Humans are the only known host for Salmonella Typhi and probably also for the Paratyphoidal serotypes. These infections have been rare in the United States and in many countries in the developing world since implementation of good sanitation and access to drinking water. However, these infections are still important causes of febrile illness in populations that are exposed to unsafe food and water. 

They remain to be important risk factors for travelers who are visiting countries where these infections are endemic. The majority of typhoid cases in the United States are travel associated. In a recent study that was published, 79 percent of cases from 1999 to 2006 were travel associated and the proportion of travel associated cases increased from 64 percent to 85 percent.


The good news is mortality is low with prompt antimicrobial therapy. But with increasing use of antimicrobial agents, we are seeing increasing resistance. Traditional agents are ampicillin, chloramphenicol, and trimethoprim and resistance to these agents is typically referred to as multidrug resistance. 

We have seen resistance to these agents, this multidrug resistance to be widespread in Typhi. Low rates have been detected in the paratyphoidal serotypes.

Because of increasing multi-drug resistance, fluoroquinolones soon became the first-line agents. As expected, we started seeing increasing quinolone resistance. So other agents are now becoming more important with increasing fluoroquinolones resistance such as ceftriaxone, the third generation cephalosporins and azithromycin.


I included this slide just to illustrate the relative importance of these serotypes in terms of causing enteric fever. Paratyphi B, there is little that we know about Paratyphi B and Paratyphi C is really rare. 

As far as the paratyphoidal serotypes, Paratyphi A is the major serotype and of course, Typhi remains the major cause of enteric fever. But as you can see from this slide, this has changed over time. It is definitely predominantly Typhi causing enteric fever and it seems that Paratyphi A is slowly closing the gap. 

So we are seeing an increase in Paratyphi A and a decline in Typhi in terms of relative proportion as the agents causing enteric fever. This has implications in terms of prevention. We have a vaccine for typhoid fever and currently no licensed vaccine for Salmonella paratyphoid fever. 

Also in terms of resistance, we have to be aware of differences in resistance patterns in these serotypes.


NARMS began surveillance in 1996 and we started in 1996 with non-typhi Salmonella. NARMS has been receiving isolates from state laboratories and they were sending isolates, every tenth isolate of non-typhi Salmonella from 1996 to 2002. From 2002 to 2007, state labs were sending every twentieth. So we are receiving a representative sample of non-typhi Salmonella from state labs.

The Paratyphoidal serotypes were part of this sampling scheme until 2008 when we changed the scheme to enhance sampling. So beginning in 2008, we were receiving all Paratyphi A and C from state labs.

NARMS began surveillance with Salmonella Typhi in 1999 and ever since they have been receiving all Salmonella Typhi isolates from state laboratories.

So this is what we call out NARMS sampling scheme for routine submission.


If you have been to any of our posters, I am sure you have seen this slide. I take every opportunity to show this slide because this allows me to explain how we have evolved over time. 

We started in 1996 with 14 sites and we became nationwide in 2003. Currently we are in all 50 states represented by 50 state health departments and three local health departments. In 2009, last year, we added one more local health department, so we are now in 54 sites.


I have chosen to talk about important resistance patterns in the interest of time. So I will be focusing on these resistance patterns.


So what are we seeing in terms of multidrug resistance which again we typically define as resistance to the traditional first line agents. They are still high, they are still like 20 percent or lower, but with less use of these agents we are hoping that we will be seeing less of this. But this is kind of an illustration of how, you know, it is not easy to get rid of resistance once they are created. So we are still seeing it, they are not going away, although resistance to these agents has not increased.


Before I talk about some of our results in regard to quinolone resistance, please allow me to briefly review. Maria has given a very good explanation of these mechanisms of resistance. 

The major mechanism that we are aware is the chromosomal point mutations. This explains the correlation between nalidixic acid resistance and Ciprofloxacin resistance, one mutation for nalidixic acid and two or more point mutations for Cipro. Most literature would also report that one mutation also decreases susceptibility to Cipro. So this explains the correlation between nalidixic acid resistance and decreased susceptibility to Ciprofloxacin.

The other mechanisms which we usually refer to as emerging mechanisms are the plasmid-borne genes or the plasmid-borne mechanisms. I have listed a few examples. These confer decreased susceptibility to Ciprofloxacin which we define as MIC of 0.12 or higher.

These emerging mechanisms, plasmid-borne mechanisms, do confer decreased susceptibility but not necessarily resistance to nalidixic acid which could explain if we are going to start seeing more discrepancy discordance between nalidixic acid resistance and decreased susceptibility to Cipro.


I have included this slide to show the correlation between nalidixic acid resistance and decreased susceptibility. On the left side you have Typhi, on the right side you have Paratyphi A, B, and C. Is you can see, the blue bars, those are the ones -- the blue actually reflects nalidixic acid resistance and the red nalidixic acid susceptibility.

As you can see, the majority of Typhi isolates, the ones with decreased susceptibility with MIC of greater than or equal to 0.12, the majority of them have decreased susceptibility, and similar to Paratyphi A, B, and C, so almost a perfect correlation between nalidixic acid resistance and decreased susceptibility.


So over time this is what we are seeing in NARMS. Most of the time we use nalidixic acid resistance to represent decreased susceptibility because of the very close correlation between the two.

The dark blue bars represent decreased susceptibility and the light blue bars represent nalidixic acid resistance. You can see that over time they really are closely correlated. 

When we started in 1999, we were seeing 19 percent nalidixic acid resistance. That has increased to about 60 percent in 2009. Really, really compelling data.

We reached the halfway mark some time in 2005 and we have started seeing more and you see there was over 60 percent resistance to nalidixic acid in 2007. So it looks like we are going to stay there for quite a while.    Until 2008, we were seeing Ciprofloxacin resistance is rare and I would like to show the next slide.


So this is actually showing the proportion -- the MICs of isolates with decreased susceptibility to Cipro. In the red -- I don’t know if you can see the red part, that represents the MICs that correlate with Cipro resistance. So these are isolates with decreased susceptibility to Cipro meaning MIC of more than or equal to 0.12 and the resistance breakpoint is 4. So isolates with more than equal to 4 are considered resistant.

So okay, from 1999 to 2005, we were not able to get Ciprofloxacin resistance -- I’m sorry, up to 2004, and then in 2005 we found one isolate resistant to Cipro, another isolate in 2000-- 2003 sorry. And then 2005, so one isolate in 2003, one isolate in 2005, three in 2006, four in 2007, and yeah, okay, we got a break in 2008. We did not see any. So what is going on? Then this year, this is just really fresh data. We just got this. We have about 12, although this is preliminary data. We don’t know yet when we start looking at these 12, they are coming from six sites, if we are going to be able to duplicate that. Maybe we will know exactly how many patients are represented by 12.

There are distinct isolates submitted by sites, but sometimes the duplication can be coming from different sites. So there are already unduplicated in terms of submission from sites. 

So 12 isolates in 2009.  So this is really of concern. I mean, not just -- you know, decreased susceptibility by itself is of concern. I know you are aware of findings from Crump et al saying that with decreased susceptibility you may have poor clinical outcomes, but we are really also much more concerned about Cipro resistance.


So this is what we are finding in Salmonella Paratyphi A. It is even higher. 83 percent quinolone resistance in Paratyphi A, although in Paratyphi B we hardly  -- the resistance is low and as far as multidrug resistance, it is rare.

For our routine submissions, these are the routine submissions from up to 2009, from 1996 to 2009. We were not able to detect isolates with Cipro resistance.  This is from our routine submissions.


So what do we know about those isolates with Cipro resistance? Of the nine patients up to 2008, eight have known travel history and all eight cases reported travel to India. We are just finding our more information about the 2009 cases. Of these 12 isolates, we have information as far as travel for six cases and six of them reported travel to South Asia. Five of the six reported travel to India and one traveled to Bangladesh. So we are seeing a pattern here.


These are just some of the findings that have been published using typhoid fever surveillance and NARMS data. Patients with resistant infections were more likely to report travel to Indian subcontinent and this is for Typhi. We are finding similar data as far as Paratyphi A. 


This is an enhanced surveillance for paratyphoid fever which we did in 2005-2006 when we collected all isolates from sites. 87 percent were resistant to nalidixic acid, one isolate was resistant to Cipro, and again we are seeing the correlation as far as travel to South Asia.


So there is some good news here. Resistance to ceftriaxone is rare, it is still rare Typhi. Two Typhi isolates resistant to ceftriaxone, one Paratyphi A, and so far no isolates resistant to both have been detected. Our lab is currently performing testing for azithromycin.


So to summarize our key findings, multidrug resistance has not increased in Typhi and it is still rare in Paratyphoidal Salmonella

As far as quinolone resistance, in typhi we have seen an increase in nalidixic acid resistance. Ciprofloxacin resistance using current breakpoints appears to be increasing.  In Paratyphi A, nalidixic acid resistance is high, although Cipro resistance is still rare. In Paratyphi B, quinolone resistance is low.


Ceftriaxone resistance is rare and co-resistance has not been detected. We documented the association between travel and quinolone resistance. Yesterday we talked about epidemiologic and clinical breakpoints and I think we can learn from the Typhi experience. We do need to look at both clinical breakpoints and epidemiologic breakpoints which in Typhi is represented by decreased susceptibility.


I would like to acknowledge our partnership with the state and local health departments and, of course, our NARMS partners at the FDA and USDA. Thank you.


DR. Fedorka-Cray: Our next speaker will be Dr. Brandi Limbago from CDC who is also the co-moderator. She will talk to us about Methicillin-resistant Staphylococcus aureus and food. Lest all of you think that we totally lost it up here, I am going to take one for the team so we can keep on schedule and get out of here. I will not be giving the presentation on Enterococcus and we will just direct you to the slides in your packet. Thank you.

DR. McDERMOTT: As long as you are on the subject Paula, I also wanted to suggest, because I know people have flights to catch and I would rather have more of a discussion than rush things, so I was going to propose we just soldier on through maybe until after Dr. Apley’s presentation, take a break then, and then maybe before the public comment period, we will watch the clock. If we have time we can do a short break then and then finish with the public comment period. So obviously you are free to take breaks when you wish and there are refreshments out there, but just in the interest of time so everyone can be sure and make their flights, I would like to propose that we do that.