CASE
A 10-year-old male with a history of congenital heart disease and heart transplantation 3 years prior presented with the chief complaint of diarrhea. The patient reported having up to 4 to 5 episodes of watery, nonbloody stools daily for the last 3 weeks accompanied with fatigue and loss of appetite and oral intake. He had no recent travel history and no dietary risk factors, such as ingestion of unpasteurized foods. He was afebrile and denied significant abdominal pain during the exam but pain with urination. Laboratory work at presentation was significant for an elevated creatinine level of 4.49 mg/dL (baseline, 0.7 to 0.8 mg/mL), sodium level of 129 mmol/L, and bicarbonate level of 12 mmol/L. His peripheral white blood cell count was 2.7 × 103/μL with 60.4% neutrophils. Urine displayed 16 white blood cells per high-power field and grew >100,000 CFU of Escherichia coli. A BioFire gastrointestinal pathogen panel (bioMérieux, Salt Lake City, UT) ordered the day after presentation was positive for Salmonella and sapovirus. At the time of admission, the patient had been on an immunosuppression regimen of tacrolimus and mycophenolate. However, these medications were paused at admission given the presence of acute kidney injury from dehydration. The patient was started on oral ciprofloxacin at 10 mg/kg of body weight twice a day intravenously (i.v.) for his urinary tract infection and gastroenteritis. Blood cultures were collected at the time of presentation and incubated in a Bactec FX instrument (BD, Sparks, MD). Gram-negative rods were isolated from the Plus aerobic bottle after 16 h of incubation, and antimicrobials were broadened to ceftriaxone (50 mg/kg every 24 h i.v.). An ePlex BCID-GN panel (GenMark, Carlsbad, CA) was performed and was positive for Salmonella sp. and the CTX-M antimicrobial resistance gene. Antibiotic treatment was escalated to meropenem (20 mg/kg every 8 h i.v.). Stool cultures grew Salmonella.
MIC testing was performed on Salmonella isolated from blood and stool cultures by the Phoenix NM-306 panel (BD, Sparks MD). Both isolates were resistant to ampicillin (MIC, >16 μg/mL) and ceftriaxone (MIC, >32 μg/mL) but susceptible to trimethoprim-sulfamethoxazole (MIC, ≤0.5/9.5 μg/mL). Ciprofloxacin and levofloxacin MICs were off scale on the Phoenix panel and uninterpretable by Clinical and Laboratory Standards Institute (CLSI) guidelines (1). Etest (bioMérieux, Durham, NC) MICs were 0.12 μg/mL for ciprofloxacin and 0.25 μg/mL for levofloxacin, both intermediate. The patient’s clinical condition stabilized, and he was discharged after 2 days on ciprofloxacin (20 mg/kg twice a day orally) for a total course of 14 days. Serotyping at the Tennessee Department of Health revealed both blood and stool isolates were Salmonella enterica subsp. enterica serovar Infantis.
DISCUSSION
Nontyphoidal Salmonella (NTS) infections are a common cause of self-limiting enterocolitis and diarrhea with an estimated global incidence of 95.1 million cases annually in 2017 (2). NTS can invade normally sterile sites, resulting in bacteremia and focal infections. The global incidence of invasive NTS infections is estimated at 7.5 per 100,000 but is disproportionally high in sub-Saharan Africa, where incidence rates are 34.5 per 100,000 (2). Globally, children younger than 5 years are at highest risk for invasive salmonellosis (2). Immunocompromised patients and those with malnutrition, chronic liver disease, hemoglobinopathies, malaria, and schistosomiasis are also at increased risk of invasive infection (3). The primary risk factor for invasive disease in this case was the patient’s immunosuppression following the heart transplant. Certain serovars of NTS, including Dublin, Choleraesuis, Heidelberg, and Virchow, are more likely to cause invasive disease (4).
Antimicrobial therapy is not routinely recommended for NTS intestinal infection. Antimicrobial therapy prolongs the duration of fecal shedding and increases risk for relapse, likely due to loss of protective microbiota. Antimicrobials are recommended for patients younger than 3 months of age, as well as those with chronic gastrointestinal disease, HIV, cancer, immunosuppressive illnesses or therapies, or severe infection (5). These factors increase the risk for extraintestinal spread and documented extraintestinal infection (4). Management has become increasingly complex due to the development of resistance to first-line antimicrobials used to treat NTS, including ampicillin, fluoroquinolones, trimethoprim-sulfamethoxazole, and ceftriaxone, making antimicrobial susceptibility testing (AST) important. Over the last decade, changes to Salmonella AST standards (6) have been made (Table 1). Most clinical laboratories in high-income countries only occasionally recover Salmonella from extraintestinal sources, leading to lack of familiarity on how to best address AST for NTS.
TABLE 1.
Summary of AST considerations for Salmonella spp
| General | Specific |
|---|---|
| First-line antimicrobial agents for testing and reporting | Ampicillin |
| Ceftriaxone | |
| Fluoroquinolone (ciprofloxacin, levofloxacin, ofloxacin) | |
| Trimethoprim-sulfamethoxazole | |
| Additional antimicrobial agents to test and report in case of resistance to first-line agents or intolerance | Azithromycin |
| Meropenem or imipenem | |
| Special testing considerations | |
| Aminoglycosides, first- and second-generation cephalosporins | Inactive clinically, never report as susceptible, regardless of test results |
| Ceftriaxone | Ensure use of current CLSI/FDA or EUCAST breakpoints |
| Resistance often due to CMY-type AmpCs | |
| Consider confirmation of resistance if uncommon in region | |
| Fluoroquinolones | Preferred tests include ciprofloxacin MIC (CLSI) or pefloxacin disk (EUCAST) |
| Ensure use of Salmonella-specific breakpoints | |
| May require use of off-line testing (e.g., disk or gradient diffusion) if automated system does not have fluoroquinolone dilutions low enough | |
| Azithromycin | Testing may be difficult to interpret due to fuzzy/double zones of inhibition by disk and gradient diffusion methods |
| Read at 80% inhibition | |
| Confirm resistance by testing at a reference laboratory | |
| Do not report on urine isolates | |
| No CLSI or FDA breakpoint and no FDA-cleared tests are available for NTS | |
| Carbapenems | Few clinical data available, primarily for meropenem or imipenem |
| Discuss with infectious diseases physician before reporting results |
When to perform AST on Salmonella and what to test.
AST should not be conducted routinely on fecal isolates of NTS. Laboratories may develop protocols to test selected isolates for patients at increased risk of invasive disease, such as from children <3 months of age. Laboratories may also consider testing to rule out the most common typhoidal serovars, Salmonella enterica serovar Typhi and Salmonella enterica serovar Paratyphi A (4), on fecal isolates as these serovars warrant routine AST because of unique virulence potential and high incidence of resistance. AST is always indicated for extraintestinal isolates of Salmonella.
If AST is performed for a fecal isolate, ampicillin, a fluoroquinolone, and trimethoprim-sulfamethoxazole should be evaluated. In addition, an expanded-spectrum cephalosporin is tested for extraintestinal isolates (1). Chloramphenicol may be tested upon request but is rarely needed as it is almost never prescribed due to lack of availability and risk of toxicity (4). Aminoglycosides, first- and second-generation cephalosporins, and cephamycins should never be reported as susceptible, regardless of AST results, as they are not effective clinically (1).
Few data are available for treatment of NTS resistant to first-line agents, although azithromycin or a carbapenem may be considered (4). Susceptibility testing for these agents should be performed upon request or reflexively in cases of multidrug-resistant NTS (i.e., resistance to ≥3 of the first-line agents).
Antimicrobials with special AST considerations.
(i) Fluoroquinolones. Fluoroquinolones are often used for invasive NTS, as they have excellent intracellular penetration and oral bioavailability (6). These drugs were once avoided in children due to cartilage abnormalities observed in developing animals, but more recent data suggest this risk is low (5). Fluoroquinolone resistance is a significant problem among both NTS and typhoidal Salmonella strains (Table 2). Wild-type Salmonella displays ciprofloxacin MICs of ≤0.06 μg/mL (6). Prior to 2012, all Enterobacterales (including Salmonella) with ciprofloxacin MICs of ≤1.0 μg/mL were classified as susceptible by CLSI. Substantial clinical data demonstrated that strains with decreased ciprofloxacin susceptibility (DCS) (i.e., ciprofloxacin MIC of 0.12 to 1.0 μg/mL) were associated with delayed ciprofloxacin treatment response, clinical failure, and increased mortality for Salmonella Typhi infections. To a lesser extent, poor treatment outcomes were also documented for NTS with DCS (6). DCS is caused by single mutations to gyrA or gyrB and/or the presence of a plasmid-mediated quinolone resistance gene such as qnr or aac(6′)-lb-cr (6). Mutation of gyrA can be detected by testing nalidixic acid but not resistance mediated by qnr or aac(6′)-lb-cr (6). In 2012, CLSI updated ciprofloxacin, levofloxacin, and ofloxacin MIC breakpoints for Salmonella. The Salmonella-specific susceptible breakpoint is now ≤0.06 μg/mL for ciprofloxacin and ≤0.12 μg/mL for levofloxacin and ofloxacin. The susceptible breakpoints for ciprofloxacin and levofloxacin for the other members of the Enterobacterales are ≤0.25 μg/mL and ≤0.5 μg/mL, respectively (1). The U.S. FDA recognizes the Salmonella breakpoints (https://www.fda.gov/drugs/development-resources/antibacterial-susceptibility-test-interpretive-criteria).
TABLE 2.
Antimicrobial resistance reported for human isolates of Salmonella by the U.S. NARMS for 2018 (9) using CLSI breakpoints
| Antimicrobial | % resistance |
|
|---|---|---|
| Nontyphoidal Salmonella (n = 2,968) | Typhoidal Salmonella (n = 598) | |
| Ampicillin | 8.4 | 10.0 |
| Ceftriaxone | 3.5 | 2.2 |
| Chloramphenicol | 4.7 | 7.9 |
| Ciprofloxacin (includes intermediate and resistant results) | 8.6 | 86.1 |
| Trimethoprim-sulfamethoxazole | 2.6 | 8.2 |
| Azithromycin | 0.7 | 0.0 |
| Meropenem | 0.0 | 0.0 |
No single test detects all fluoroquinolone resistance mechanisms identified in Salmonella. CLSI endorses ciprofloxacin MIC as the preferred method by which to assess fluoroquinolone AST, whereas the European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommends pefloxacin disk diffusion (www.eucast.org). Pefloxacin disks are not available in the United States, but ciprofloxacin disk diffusion is a reasonable alternative test for fluoroquinolone AST. Of note, poor performance of the ciprofloxacin disk diffusion test has been reported using reagents available in other countries, including difficult-to-read zones of inhibition (7). The lowest dilution of ciprofloxacin tested by most commercial MIC test systems is 0.25 or 1.0 μg/mL (i.e., the current and historical susceptible breakpoint for Enterobacterales). Salmonella isolates with a ciprofloxacin MIC of ≤1.0 μg/mL may be susceptible, intermediate, or resistant, and those with MICs of ≤0.25 μg/mL may be susceptible or intermediate. A good approach is to test isolates with such off-scale MICs by disk diffusion or gradient diffusion (e.g., Etest), as we did in this case; both test methods have excellent performance (8). Ciprofloxacin is the best-studied fluoroquinolone for Salmonella AST, but if levofloxacin or ofloxacin is prescribed, these agents can be tested by an MIC method and reported using Salmonella-specific breakpoints published by CLSI (1). Importantly, disk breakpoints are not available for any fluoroquinolone other than ciprofloxacin or pefloxacin, by any organization.
(ii) Expanded-spectrum cephalosporins. Resistance to expanded-spectrum cephalosporins first emerged for NTS in the mid-1980s and was reported in the United States by the mid-1990s (4). While rates remain low overall among U.S. isolates (Table 2), selected serovars have increased resistance, including Newport (40% resistance), Typhimurium (26%), and Heidelberg (12%) (9). Primary resistance mechanisms are the plasmid-encoded AmpC enzyme CMY or the extended-spectrum β-lactamase (ESBL) CTX-M. In the United States, CMY-2 predominates, present in 73.9% of ceftriaxone-resistant NTS isolates with whole-genome sequencing data in NARMS (National Antimicrobial Resistance Monitoring System) Now (9), although CTX-M is also seen. Of concern, recent cases of probable in vivo transfer of ESBL and AmpC-encoding plasmids from colonizing Enterobacterales to NTS during cephalosporin treatment have been reported (10). These data reinforce the need for repeat AST for cases of suspected treatment failure.
Laboratories should ensure use of the current Enterobacterales CLSI/FDA ceftriaxone breakpoints, which were updated in 2010. NTS with plasmid-borne AmpC and ESBLs may test susceptible by obsolete breakpoints (i.e., MICs of 2, 4, or 8 μg/mL). Phenotypic ESBL testing, such as that described by the CLSI in the M100 standard (1), is not validated for Salmonella and cannot detect the presence of CMY-2 or other plasmid-borne AmpC β-lactamases. Many laboratories utilize multiplexed molecular tests to rapidly identify the genus and resistance genes in positive blood cultures, including evaluation of CTX-M. The absence of this gene should not be indicative of probable ceftriaxone susceptibility for NTS, given many resistant isolates harbor a plasmid CMY.
(iii) Azithromycin. Azithromycin is an alternative agent for the treatment of NTS infection and is used widely for the treatment of typhoid fever in southeast Asia (4, 5). CLSI breakpoints are for Salmonella Typhi alone (1) due to limited microbiological and clinical data for serovars other than Typhi and Paratyphi A. The CDC NARMS applies a cutoff of ≤16 μg/mL to define susceptibility for non-Typhi Salmonella (9), which is a reasonable breakpoint for clinical laboratories that are performing testing, although the limitation of this should be explained to clinicians as it is not an official clinical breakpoint but rather a guideline for relative susceptibility.
Testing azithromycin susceptibility for Salmonella is not straightforward. The FDA does not recognize any Salmonella breakpoints, meaning no tests can achieve FDA clearance in the United States. Many laboratories utilize gradient diffusion strips, although testing errors have been reported compared to reference broth microdilution (BMD) for Salmonella Typhi (11, 12). Azithromycin is bacteriostatic, and hazy or double zones of inhibition may be observed on some lots of Mueller-Hinton agar. Reading endpoints at 80% inhibition should be done when determining MICs in order to avoid overestimation, although this is not stipulated specifically by CLSI for Salmonella (1, 12). Given the low incidence of resistance (Table 2) and risk of overcalling resistance due to difficult-to-interpret endpoints, laboratories should have azithromycin resistance results confirmed by a reference laboratory that utilizes reference methods (i.e., BMD). Azithromycin has poor penetration in the urinary tract and should not be reported on urine isolates.
(iv) Carbapenems. Carbapenem therapy has been used successfully to treat cases of ceftriaxone- and fluoroquinolone-resistant Salmonella, although clinical data remain limited (13), and poor outcomes have been reported for meropenem monotherapy for typhoid fever (14). Of concern, carbapenem resistance has been described, due to isolates that express carbapenemases, including KPC, NDM, and OXA-48 (15). In cases of resistance to other treatment options, a carbapenem may be an option, although this should be discussed with infectious diseases physicians prior to reporting test results.
SELF-ASSESSMENT QUESTIONS
-
When performing fluoroquinolone AST on Salmonella, what is the preferred method endorsed by CLSI?
-
a.
Ciprofloxacin disk diffusion, applying Salmonella-specific breakpoints
-
b.
Ciprofloxacin MIC, applying Salmonella-specific breakpoints
-
c.
Pefloxacin disk diffusion, applying Salmonella-specific breakpoints
-
d.
Nalidixic acid disk diffusion, applying Salmonella-specific breakpoints
-
a.
-
2.
Ceftriaxone resistance is emerging among Salmonella isolates. When evaluating Salmonella isolates for ceftriaxone susceptibility, what is the preferred method?
-
a.
Evaluation of ceftriaxone by MIC or disk, applying current Enterobacterales breakpoints
-
b.
Evaluation of ceftriaxone by MIC or disk, applying Salmonella-specific breakpoints
-
c.
A phenotypic extended-spectrum β-lactamase test
-
d.
Evaluation for the presence of blaCTX-M by a molecular method
-
a.
-
3.
Which of the following statements are incorrect with regard to azithromycin AST for Salmonella?
-
a.
Disk diffusion and MIC endpoints should be read at 100% inhibition
-
b.
Azithromycin results should not be reported on urine isolates due to poor concentration of this agent in the urine
-
c.
CLSI azithromycin breakpoints for Salmonella are applicable only to Salmonella serovar Typhi
-
d.
Azithromycin resistance is uncommon among NTS isolates in the United States
-
a.
ANSWERS TO SELF-ASSESSMENT QUESTIONS
-
When performing fluoroquinolone AST on Salmonella, what is the preferred method endorsed by CLSI?
-
a.
Ciprofloxacin disk diffusion, applying Salmonella-specific breakpoints
-
b.
Ciprofloxacin MIC, applying Salmonella-specific breakpoints
-
c.
Pefloxacin disk diffusion, applying Salmonella-specific breakpoints
-
d.
Nalidixic acid disk diffusion, applying Salmonella-specific breakpoints
-
a.
Answer: b. The M100, 32nd edition, Table 2A, comment 62, indicates that the preferred test for assessing fluoroquinolone susceptibility or resistance in Salmonella spp. is a ciprofloxacin MIC test. If a ciprofloxacin MIC test is not available, or levofloxacin or ofloxacin is used clinically, these may be tested by MIC. If MIC testing is not available (e.g., in developing countries where disk diffusion is the preferred test method), a ciprofloxacin or pefloxacin disk diffusion test may be used. Ciprofloxacin MIC is preferred over ciprofloxacin disk diffusion as some regions of the world have documented reagent issues that lead to difficult-to-interpret ciprofloxacin disk diffusion zones, although these are not seen in the United States. In this case, and if disk diffusion is the only AST method available, pefloxacin disk is an alternative test, if available. Nalidixic acid testing was discontinued by CLSI in 2012, when Salmonella-specific fluoroquinolone breakpoints were first introduced. The nalidixic acid screen detects some, but not all, fluoroquinolone resistance mechanisms found in Salmonella.
-
2.
Ceftriaxone resistance is emerging among Salmonella isolates. When evaluating Salmonella isolates for ceftriaxone susceptibility, what is the preferred method?
-
a.
Evaluation of ceftriaxone by MIC or disk, applying current Enterobacterales breakpoints
-
b.
Evaluation of ceftriaxone by MIC or disk, applying Salmonella-specific breakpoints
-
c.
A phenotypic extended-spectrum β-lactamase test
-
d.
Evaluation for the presence of blaCTX-M by a molecular method
-
a.
Answer: a. Ceftriaxone testing should be performed using any test method in-house (e.g., automated MIC or disk diffusion methods) and interpretation using current (2022) CLSI breakpoints. There is no Salmonella-specific guidance for testing ceftriaxone. ESBL tests (such as the CLSI double disk test) are validated for use only with Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis. Importantly, the majority of resistance is due to plasmid-mediated AmpC genes such as CMY-2, not ESBLs, so neither answer c nor answer d is sufficient to rule out resistance or to confirm susceptibility.
-
3.
Which of the following statements are incorrect with regard to azithromycin AST for Salmonella?
-
a.
Disk diffusion and MIC endpoints should be read at 100% inhibition
-
b.
Azithromycin results should not be reported on urine isolates due to poor concentration of this agent in the urine
-
c.
CLSI azithromycin breakpoints for Salmonella are applicable only to Salmonella serovar Typhi
-
d.
Azithromycin resistance is uncommon among NTS isolates in the United States
-
a.
Answer: a. Azithromycin endpoints are difficult to interpret, and guidance indicates use of an 80% cutoff may be appropriate when double zones of inhibition are noted by disk diffusion or gradient diffusion tests. Laboratories may, however, use these as a guidance point when testing NTS, but this limitation should be discussed with treating clinicians. CLSI breakpoints are validated against Salmonella serovar Typhi alone, due to the lack of data for other species. Azithromycin resistance remains low among NTS isolates in the United States.
TAKE-HOME POINTS
Fecal isolates of Salmonella do not warrant routine susceptibility testing.
When testing extraintestinal isolates of Salmonella, ampicillin, a fluoroquinolone, trimethoprim-sulfamethoxazole, and ceftriaxone should be reported.
Ciprofloxacin MIC is the preferred method for testing Salmonella for fluoroquinolone susceptibility, with interpretation using Salmonella-specific breakpoints, according to CLSI.
In instances of resistance to first-line agents, azithromycin and/or a carbapenem may be considered for testing and reporting.
Azithromycin should not be reported on urinary isolates of Salmonella.
Contributor Information
Romney M. Humphries, Email: romney.humphries@vumc.org.
Carey-Ann D. Burnham, Pattern Bioscience
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