Medical Director, Infection Prevention, El Camino Hospital, Palo Alto Medical Foundation
SOURCE: Watkins LKF, Luna S, Bruce BB, et al. Clinical outcomes of patients with nontyphoidal Salmonella infections by isolate resistance—Foodborne Diseases Active Surveillance Network, 10 US sites, 2004-2018. Clin Infect Dis 2024;78:535-543.
These authors assessed the impact of antimicrobial resistance of nontyphoidal Salmonella infection on clinical outcomes in patients in the United States from 2004-2018. They matched epidemiological data from 5,549 clinical cases from the Foodborne Diseases Active Surveillance Network to susceptibility data from the National Antimicrobial Resistance Monitoring System (NARMS). All of the isolates were tested using broth microdilution method (Sensititre), which included 13-14 antimicrobial agents, although these changed slightly over the years. Resistance was defined as any resistance to one or more agents, while clinical resistance was defined as resistance to one or more of five commonly used therapeutic agents (ampicillin, azithromycin, ceftriaxone, ciprofloxacin, and trimethoprim-sulfamethoxazole) (for those isolates tested to all five agents). The breakpoint for azithromycin was based on the current breakpoint for S. typhi isolates (≥ 32 mcg/mL). Isolates with intermediate susceptibility to ciprofloxacin (≥ 0.12 mcg/mL to 0.5 mcg/mL) were included in the resistant group (since this has been reported to affect outcomes), whereas isolates with intermediate resistance to other agents were included in the susceptible group.
Resistance to one or more agents was observed in 20% of isolates (1,105/5,549), while clinical resistance was observed in 16% (469/2,969) (for those isolates tested to all five agents). Resistance, in declining order of frequency, was observed for tetracycline (12.8%), streptomycin (11.3%), sulfisoxazole (11.2%), ampicillin (10.6%), ceftriaxone (3.1%), amoxicillin-clavulanic acid (2.9%), trimethoprim-sulfamethoxazole (1.7%), azithromycin (0.3%), and ciprofloxacin (0.3%). An additional 3.9% of isolates demonstrated intermediate susceptibility to ciprofloxacin. Serotypes with the highest frequency of resistance included Hadar (73%), I4,[5],12.i (49%), Heidelberg (44%), Typhimurinum (34%), and Agona (31%). Hadar and Heidelberg also were more often associated with invasive infection. Of all isolates, 85% belonged to one of 20 serotypes.
Patients with resistance to any agent were clinically similar to those without resistant isolates, except they were more likely to have traveled internationally (16% vs. 8%). Among those with resistant infections with a recent history of international travel, travel to Asia was more common than travel to Mexico (33% vs. 12%).
In unadjusted binary analysis, patients with nontyphoidal Salmonella infections with any resistance were more likely to be hospitalized compared to those with nontyphoidal Salmonella infections with no resistance (31% vs. 28%, P = 0.01). Patients with nontyphoidal Salmonella infections with any resistance were more likely to have hospital stays of three days or longer compared to those with isolates with no resistance (20% vs. 16%, P = 0.01), or death (1.0% vs. 0.4%, P = 0.01). Patients with isolates with resistance to ciprofloxacin specifically had a greater chance of death (2% vs. 0.4%, P = 0.01). Patients with isolates with multidrug resistance were more likely to be hospitalized than those with no resistance (34% vs. 28%, P < 0.01).
Even after adjustment for demographic factors (i.e., age, sex, international travel, state, season, serotype, source), the observed increased risk for hospitalization remained for those with resistance to any agent (adjusted odds ratio, 1.23). However, for those patients with isolates with clinical resistance to one or more of the five commonly used antimicrobials, no increased risk of hospitalization or length of stay was observed in adjusted analysis. This suggests that other factors may be important, such as host factors and virulence. Clinical resistance was so low as to perhaps not greatly affect outcomes in this statistical analysis.
Clinicians should be aware that nontyphoidal Salmonella isolates are at increasing risk for resistance to one or more commonly used antimicrobials. About 3% to 4% of isolates demonstrate decreased susceptibility to ciprofloxacin, ceftriaxone, or amoxicillin-clavulanate, although susceptibility to azithromycin is largely preserved in nontyphoidal infections in U.S. patients. And clinical resistance was more common in patients with a recent travel history.
SOURCE: McChalicher CWJ, Lombardo MJ, Khanna S, et al. Manufacturing processes of a purified microbiome therapeutic reduce risk of transmission of potential bacterial pathogens in donor stool. J Infect Dis 2023;228:1452-1455.
Minimally processed fecal microbiota transplant (FMT) has been used to prevent recurrence of Clostridioides difficile infection (CDI). While FMT has a favorable safety profile, some low-level risk of transmission of pathogens and drug-resistant organisms persists. Two problems exist: Screening techniques generally have been developed in the setting of active infection, rather than in patients with colonization, where microbial colony counts may be so low as to escape detection. And, as seen with COVID, emerging pathogens require the development of new protocols for screening and safety, disrupting the availability of products.
While FMT remains Food and Drug Administration-approved, several events have led to safety alerts for the product, including the transmission of Shiga-toxin producing Escherichia coli to five people, with one death. Two clinical trials for the treatment of non-CDI-related conditions in immunocompromised hosts resulted in two patients who developed sepsis due to extended spectrum beta-lactamase (ESBL)-containing Escherichia coli, one of whom died. Another five patients became colonized.1,2 While stored FMT capsules used in the clinical trial and cultured on exclusion media failed to yield the ESBL organism, whole genome sequencing demonstrated a match between the clinical isolates and that from the donor stool.
As a result, safer products are being sought. These authors describe a manufacturing process whereby whole stool is exposed to high levels of ethanol, which selectively kills and inactivates live and vegetative bacteria (including drug-resistant bacteria) but preserves Firmicutes spores. This process is called VOWST (formerly SER-109), and the product is called VOS for VOWST oral spores. Exposure to high concentrations of ethanol resulted in rapid reduction of bacterial colonies by 6-7 log10. And spiked assays using four common bacterial organisms (Salmonella enterica, Staphylococcus aureus, Enterococcus faecalis, and Listeria innocua) were lysed within 30 seconds. The minimum deactivation rate was
13.4 log10 per minute of exposure — substantially faster than provided by autoclave sterilization processing.
Purified Firmicutes spore product has several advantages over current FMT products:
• The process is fast — it provides rapid inactivation/killing of bacteria.
• It avoids the current risk of transmission of pathogens and drug resistance.
• The spores are initially dormant, allowing the removal of solids and fibers during stool processing, essentially removing 99% of the total mass of the stool. What is left provides a low pill burden.
• Germination of bacteria from spores in the guts also suggests a low pill burden would be possible.
• The spores are resistant to gastric juices, so they can be administered orally.
References
- DeFilipp Z, Bloom PP, Torres Soto M, et al. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. N Engl J Med 2019;381:2043-2050.
- Blaser MJ. Fecal microbiota transplantation for dysbiosis — predictable risks. N Engl J Med 2019;381:2064-2066
SOURCE: Cortes-Penfield N, Krsak M, Damioli L, et al. How we approach suppressive antibiotic therapy following debridement, antibiotics, and implant retention for prosthetic joint infection. Clin Infect Dis 2024;78:188-198.
The lifetime risk of prosthetic joint infection (PJI) occurs in about 4% of joints, some of which is related to the initial arthroplasty surgery, and some occurs later, often from hematogenous seeding. Preserving the joint with surgical debridement and antibiotics is one of the greatest challenges in infectious disease. While many infectious disease physicians provide a course of suppressive antibacterial therapy (SAT) following a primary course of antibiotics, the benefits of such therapy, and the optimal regimen and duration of treatment, remain undefined.
These authors examined the available literature for factors that contribute to the risk of failure of debridement and primary antibiotic treatment (DAT), and whether long-term suppressive antibiotic treatment is of benefit. A total of 33 publications were examined, including 31 retrospective studies, one prospective study, and one case-control study. There was considerable variability between the studies, and only 14 defined PJI as a new or relapsed infection. Acute post-operative infection (occurring < 28 days post primary arthroplasty) varied from 17% to 100% in these studies, and infections involving total knee joints ranged from 0% to 76%. The type of infection also varied, although Staphylococcus sp. caused more than half of the infections. It appears that 42% were due to methicillin-sensitive S. aureus, 15.7% were due to methicillin-resistant S. aureus, 10% were due to streptococci sp., 4.1% were due to gram negatives, 8.9% were polymicrobial, and 9.5% were culture-negative.
All of the studies defined treatment failure as requiring re-operation, but other information varied considerably, and only one study included signs of recurrent or ongoing infection. Even the use of suppressive therapy often was difficult to distinguish from primary antibacterial therapy, and the authors initially defined SAT as any therapy beyond six weeks of primary antibacterial therapy. Eventually they defined SAT as more than six months beyond DAT. The types of primary antibacterial treatment and the selection of SAT also varied considerably. Adverse events, or events that led to stopping suppressive therapy, were only sporadically provided, and these were not categorized by severity.
Across the studies, the median treatment failure rate following DAT was 34%, and the mean time to failure was 27.8 weeks. Predictors of failure were multiple. The presence of Staphylococcus aureus infection was a significant predictor of failure; one study found that culture-negative infection had better outcomes. Other predictors of treatment failure included cirrhosis, the presence of concurrent bacteremia, higher initial C-reactive protein, prolonged symptom duration prior to DAT, and late-onset infection (possibly hematogenous) vs. acute infection. A shorter initial course of antibiotic treatment also may increase the risk of antibiotic failure, although the authors cautioned there was so much variability in the regimens that this may be difficult to interpret. Factors related to the initial procedure itself that were associated with an increased risk of treatment failure included revision arthroplasty, more than one debridement was required, the surgical control was suboptimal, and failure to do a liner exchange. Primary treatment with fluoroquinolones for gram-negative infection and the use of rifampin in S. aureus infection both were protective of failure.
The median duration of SAT was 161 weeks (96.5 weeks to 276 weeks). Nearly half of the patients received oral beta-lactams (47%), while tetracyclines (40%) and trimethoprim-sulfamethoxazole (12%) were used less often. Of those studies providing information on adverse events, 8.3% reported side effects of the SAT, leading to termination of treatment in 3.1%. The emergence of resistance or the risk of C. difficile infection was not provided.
Failure post-DAT occurred in 21/128 patients (15.2%) receiving SAT vs. 111/173 (64.2%) of patients not receiving SAT. While the use of SAT was not randomized, and undoubtedly there was some bias toward providing suppression for the most difficult cases, SAT post-DAT demonstrated a clear benefit in patients with PJI. SAT should be considered in patients with PJI, especially those at the highest risk for antibiotic failure. Whether shorter durations of SAT than that observed in this study would provide a similar benefit remains unknown.
