What's Hot This Year in Infectious Diseases Clinical Science

Abstract

The field of infectious diseases saw numerous exciting advances in 2023. Trials of new antibiotics and treatment regimens sought to address rising rates of antimicrobial resistance. Other studies focused on the most appropriate use of currently available treatments, balancing the dual goals of providing effective treatment and impactful antimicrobial stewardship. Improvements in disease prevention were made through trials of both new vaccines and new chemoprophylaxis approaches. Concerning trends this year included increasing rates of invasive group A streptococcal infections, medical tourism-associated cases of fungal meningitis, and the return of locally acquired malaria to the United States. This review covers some of these notable trials and clinical developments in infectious diseases in the past year.

Each year, the IDWeek meeting marks a chance for the infectious diseases community to gather and reflect on the advances made in the field over the past year. In choosing the clinical studies to highlight for the “What's Hot in ID Clinical Science” session, we faced the difficult challenge of parsing through many outstanding clinical trials from the past year. With full acknowledgement to the dozens of excellent studies that we were not able to cover, the following topics represent those that we choose to highlight at IDWeek 2023.

COMBATING ANTIMICROBIAL RESISTANCE

New Drugs

One of the biggest threats facing humanity is the rising rates of antimicrobial resistance [1]. The infectious diseases field has recognized the need for new antimicrobials, particularly for the treatment of resistant gram-negative bacteria. Due to high rates of resistance and limited treatment options, carbapenem-resistant Acinetobacter baumannii (CRAB) is one of the most challenging bacterial pathogens to treat. A. baumannii earned the top spot on the World Health Organization's list of priority pathogens [2] and was the target of a recently published pathogen-specific phase III trial. The ATTACK trial tested the use of sulbactam-durlobactam, a new β-lactam/β-lactamase inhibitor combination, versus colistin (both given with imipenem) for treatment of bloodstream infections or pneumonia due to A. baumannii [3]. For laboratory confirmed CRAB infections, all-cause mortality was 19% in the group receiving sulbactam-durlobactam versus 32% in the group receiving colistin, meeting the study's predetermined non-inferior margin. Although the trial was not powered to show superiority, the results numerically strongly favored the sulbactam-durlobactam arm. Based on the results of this study, sulbactam-durlobactam received Food and Drug Administration (FDA) approval in 2023.

Another important gap in the antimicrobial armamentarium is the need for more oral antibiotics for the treatment of extended spectrum β-lactamase (ESBL)-producing gram-negative bacterial infections. Two such antibiotics, tebipenem and sulopenem, have notably failed to received FDA approval. Although both of these antibiotics are undergoing further phase III trials, the results of the initial trials using sulopenem, an oral thiopenem, for both uncomplicated and complicated urinary tract infections (UTIs) were published this year [4, 5]. Sulopenem did not meet its primary non-inferiority endpoints of microbiologic and clinical cure in complicated UTIs or ciprofloxacin-sensitive uncomplicated UTIs. However, this was driven by microbiological failure due to asymptomatic bacteriuria in both trials. Hopefully, the results of an ongoing third trial, REASSURE [6], will provide clarity on whether sulopenem warrants FDA approval.

New Approaches

In addition to studying new antimicrobials for the treatment of resistant pathogens, there is interest in improving the use of current antibiotics or combining currently approved antibiotics in new ways to improve outcomes. Unfortunately, approaches that are informed by in vitro studies and theoretical approaches do not always show benefit in clinical trials, as demonstrated by 2 recent studies focused on optimizing the use of carbapenems. The OVERCOME RCT looked at 467 patients with bloodstream infections or pneumonia due to XDR A. baumannii, XDR Pseudomonas aeruginosa, or carbapenem-resistant Enterobacterales (CRE) with documented susceptibility to colistin [7]. Patients were randomized to receive either colistin monotherapy (with a placebo) or colistin with a carbapenem. Despite in vitro data showing synergy between colistin and carbapenems in carbapenem-resistant bacteria, the study found no mortality benefit to combination therapy. Failure was driven mostly by the large number of A. baumannii isolates in the study. Although there was a trend toward a benefit when CRE and P. aeruginosa were present, the study lacked sufficient power to assess for a significant difference given the small number of patients in these subgroups.

A separate study published last year, the MERCY RCT, investigated whether there was a benefit from continuous versus intermittent infusion of meropenem in critically ill patients with sepsis [8]. Given that the mechanism of killing by β-lactam antibiotics is dependent on time above the minimum inhibitory concentration (MIC), continuous infusion of β-lactams should theoretically have a benefit over intermittent infusion. However, in this study of over 600 patients randomized to one of the 2 infusion methods, there was no significant benefit from continuous infusion of meropenem either with regards to the primary outcome of mortality or the secondary outcome of prevention of the emergence of resistance. This contradicts other smaller RCTs and meta-analysis data comparing continuous versus intermittent infusion of β-lactams that suggested a benefit [9–11]. Further clarity on whether there is any role for continuous infusion will likely come from the BLING III trial, in which 7000 patients will be randomized to receive continuous versus intermittent infusions of piperacillin-tazobactam or meropenem [12]. As these trials demonstrate, treatment of carbapenem-resistant organisms continues to be a challenge.

The treatment of rifampin-resistant tuberculosis is one area in which major improvements were made with the publication of the results of the TB-PRACTECAL study [13]. This trial, which was terminated early due to efficacy, randomized patients to receive either local standard care for rifampin-resistant tuberculosis or 24 weeks of one of the following 3 regimens: bedaquiline, pretomanid, and linezolid (BPaL), BPaL + moxifloxacin (BPaLM), or BPaL + clofazimine (BPaLC). All 3 study groups had higher rates of favorable outcomes than the standard care, with the BPALM arm having the highest rate of favorable outcomes. This represents an exciting advance in the treatment of resistant tuberculosis as favorable outcomes were achieved with shorter durations and lower medication burdens than other treatment regimens currently being used.

IDENTIFYING THE BEST USES OF CURRENT THERAPIES

Balancing Antibiotic Stewardship With Efficacy

Identifying opportunities to shorten the duration of antibiotic courses has been an attractive approach for antibiotic stewardship; however, the results from the PROSTASHORT study published earlier this year highlight the importance of using RCTs to study antibiotic durations [14]. Despite the findings of a previous RCT that found 7 days non-inferior to 14 days for the treatment of afebrile UTI in men [15], the PROSTASHORT RCT found that for febrile UTIs in men 7 days of ofloxacin was inferior to 14 days. Not only was the primary endpoint not met, but there were significantly higher rates of clinical failure and prescriptions of new antibiotics, suggesting the outcome was not driven solely by microbiologic failure.

Another area where stewardship must be balanced with efficacy is in the selection of antibiotics for routine surgical prophylaxis. Antibiotic selection in these cases is typically protocolized and rarely revisited, even as antibiotic susceptibility patterns change over time. A recent RCT looking at antimicrobial prophylaxis for pancreatoduodenectomy surgeries (Whipple procedures) suggests that it is time to revisit some of these choices [16]. In this large RCT spanning 26 different sites, patients undergoing open pancreatoduodenectomies, procedures that are high risk for infectious complications, were randomized to receive either piperacillin-tazobactam or cefoxitin as surgical prophylaxis. The trial was terminated early as the group receiving piperacillin-tazobactam had surgical site infections in 19.8% of cases compared to 32.8% in the cefoxitin group. Multiple secondary outcomes and subgroup analyses in this study also favored piperacillin-tazobactam.

Adjunctive Therapy With Corticosteroids

The potential for adjunctive non-antimicrobial therapies to improve outcomes during the treatment of infections remains an attractive approach. Corticosteroids are frequently employed in infections where the host immune response is a major contributor to the associated mortality and morbidity. However, the data regarding the use of steroids are often mixed, especially in community acquired pneumonia (CAP) where many trials have suggested a benefit associated with steroid use, but have failed to show an improvement in mortality [17]. The CAPE COD RCT published earlier this year showed a clear benefit with a reduction in 28 day all-cause mortality (6.2% vs 11.9%) among patients with severe CAP who were treated with hydrocortisone [18]. Patients in the treatment arm received IV hydrocortisone for 8 or 14 days according to pre-specified clinical criteria. Although this may limit the generalizability of these results to other steroids or other dosing regimens, it offers a clear answer to the question of whether steroids can be beneficial in pneumonia if the right patient population and treatment plan are selected.

Treating the Right Patients With the Right Drug

As equally important as identifying the right drug to use is identifying the right patients who would benefit from treatment with a drug. This can be challenging, especially in infectious syndromes such as sinusitis where the etiology can be multifactorial, and the offending pathogen is often unknown. This makes the results of an RCT published earlier this year looking at which children derive a benefit from antibiotics for acute sinusitis all the more interesting [19]. In this study of over 500 children ages 2–11 years who had persistent or worsening acute sinusitis, there was no difference in symptom improvement in response to antibiotics based on the presence or absence of colored nasal discharge. Nasal swabs were collected and cultured from 493 of the patients, and it was found that those who had a typical respiratory pathogen cultured (Streptococcus pneumoniae, Hemophilus influenzae, or Moraxella catarrhalis) were most likely to derive a benefit from antibiotic treatment. Although testing for these pathogens is not routinely done in sinusitis, it raises the question of whether more testing can help reduce unnecessary antibiotic prescriptions. According to estimates from the study's authors, cultures or molecular testing for just 2 pathogens, S. pneumoniae and H. influenzae, could have reduced the number of antibiotic prescriptions by 53% in their study population.

Identifying the appropriate treatment for patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections has been a hot topic as the coronavirus disease 2019 (COVID-19) pandemic continues to evolve. Much of the early research focused on patients who were either unvaccinated or previously unexposed to COVID-19, but those studies are no longer representative of the population. This makes the results of the EPIC-SR study, which have not yet been published but were released on ClinicalTrials.gov in August 2023 all the more important [20]. In this study, over 1400 patients who were either unvaccinated or were vaccinated and had at least one risk factor for severe COVID-19 disease were enrolled within 5 days of symptomatic onset of confirmed COVID-19 infection. Patients were randomized to receive either 5 days of nirmatrelvir-ritonavir or placebo. Despite the benefits that were seen in the EPIC-HR study [21], this study found no significant benefit from nirmatrelvir-ritonavir. There was no significant difference in time to sustained alleviation of overall COVID-19 signs and symptoms. The secondary analyses of the difference in hospitalizations (5 in the nirmatrelvir-ritonavir arm vs 10 in the placebo arm) and deaths (0 vs 1) were not statistically significant. Protection due to vaccination and prior COVID-19 exposures likely contributed to the low rates of hospitalization and death in this study and may explain why the trial was unable to show a benefit from nirmatrelvir-ritonavir in this low-risk patient population.

Navigating antibiotic allergies is another component to ensuring that patients receive the right treatment. Inaccurate listing of penicillin allergy can lead to suboptimal or overly broad antibiotic usage. Importantly, the majority of patients with a reported history of a penicillin allergy are not in fact allergic [22]. The feasibility of routine penicillin allergy testing and delabeling saw a major advance this year with the publication of the results of the PALACE RCT [23]. This study looked at penicillin testing in patients identified as having a low-risk penicillin allergy according to the previously validated PEN-FAST scoring system [24]. Patients with a score of <3 on this 0–5 scale were randomized to undergo either an oral penicillin challenge directly or penicillin skin prick testing first followed by oral penicillin challenge. There was no significant difference in the 2 groups with only 1 patient (0.5%) in each group having a positive oral penicillin challenge. This study is encouraging as it supports direct oral penicillin testing as an easier, quicker, and more cost-effective option to delabel low-risk patients.

PREVENTING INFECTIONS

Respiratory Syncytial Virus (RSV)

Some of the greatest successes in the field of infectious diseases have come through efforts to prevent infections. This past year saw the publication of data from several major RSV studies and subsequent FDA approval of vaccines to prevent RSV infections. In May 2023, the FDA approved RSV vaccines from 2 manufacturers for use in adults over the age of 60. This came on the heels of the publication of 2 separate phase III RCTs, the AReSVi-006 study and the RENOIR study [25, 26]. Both trials used vaccines containing the RSV Fusion or “F” glycoprotein stabilized in its prefusion form to elicit neutralizing antibodies. These studies, which were both large, multi-national trials with tens of thousands of participants, met their primary endpoints of reducing RSV associated lower respiratory tract infection (LRTI) with a vaccine efficacy of 82.6% in the AReSVi-006 trial and a vaccine efficacy of 66.7% in the RENOIR trial. A potentially important subgroup analysis in the AReSVi-006 study, however, showed that the vaccine was only 33.8% effective in patients over the age of 80. Both vaccines had favorable safety profiles, making them exciting options for the prevention of RSV in older adults.

In addition to older adults, infants are also at high risk of complications related to RSV infections. Protection of infants can be accomplished through antibody transfer, either given shortly after birth with the monoclonal antibody nirsevimab, or via immunizing pregnant people. A smaller trial of 7000 pregnant people, the MATISSE phase III RCT, tested the use of the same vaccine studied in the RENOIR trial to prevent RSV in infants [27]. In this study, participants received either vaccine or placebo at 24–36 weeks gestation. Receipt of the vaccine by the mother had an 81.8% vaccine efficacy for preventing severe RSV-related LRTI requiring medical attention in the first 90 days after birth in the newborn, with a decrease in the efficacy to 69.4% at 180 days. Based on the results of this trial, this RSV vaccine was approved by the FDA for use in pregnancy in August 2023.

Cytomegalovirus

Prevention of cytomegalovirus (CMV) infection among transplant recipients is crucial to protecting graft survival as well as preventing morbidity and mortality in the transplant recipient [28]. Letermovir, an antiviral medication previously approved for use in hematopoietic stem cell recipients as prophylaxis against CMV was studied in high risk (CMV negative recipient, CMV positive donor) kidney transplant recipients [29]. The results of this study, published in June 2023, found that letermovir (plus acyclovir for herpes simplex virus prophylaxis) was noninferior to valganciclovir for the prevention of CMV disease with 10% of patients developing CMV disease in the letermovir group versus 11.8% in the valganciclovir group. In addition, there were fewer drug-related adverse events in the letermovir (plus acyclovir) group with significantly less leukopenia and neutropenia, making this an exciting alternative to valganciclovir.

FOLLOWING EMERGING TRENDS IN INFECTIONS

The field of infectious diseases remains ever changing as new pathogens emerge and old pathogens transform. The past year was no exception as highlighted by the US Centers for Disease Control and Prevention (CDC) Health Alert Network. One concerning trend has been an increase in the incidence of invasive cases of group A Streptococcus. This has been noted in many different countries, including the United States [30–32]. The reason for this increase remains unclear, with multiple hypotheses at the moment including increased clonal expansion of specific lineages, changes in immunity at the population level due to disruptions caused by the COVID-19 pandemic, and even a possible association between COVID-19 infections and group A Streptococcus [32–34].

Another concerning development for infectious diseases specialists to be aware of is an increase in infections related to growing rates of medical tourism [35]. This danger was highlighted by a recent outbreak of fungal meningitis associated with receiving epidural anesthesia at 2 clinics in Mexico [36]. Two patients in Texas were found to have meningitis after receiving anesthesia for cosmetic procedures at the same surgical center in Matamoros, Mexico, which led to a CDC health advisory in May 2023 [37]. Investigation into this outbreak led to the identification of Fusarium solani as the causative agent. Almost 200 US residents in at least 25 states are at risk based on their exposure history, highlighting the potential for medical tourism to lead to unusual and unexpected infections all across the United States.

Along with alterations in the distribution of infections due to the movement of people, climate change is also impacting the distribution of pathogens and their vectors. Decades of increasing ocean temperatures have shifted the range of Vibrio vulnificus, a gram-negative bacterium that thrives in warmer, brackish, or salt water. Examination of 30 years of V. vulnificus cases along with modeling using oceanographic and climate data showed a northward shift in cases of approximately 30 miles a year with an 8-fold increase in the number of infections over that time [38]. As noted in a September 2023 CDC health advisory, healthcare providers in areas as far north as New York and Connecticut are seeing fatal infections from this pathogen that was once limited mainly to the Gulf Coast [39].

Also of great concern this year, 2023 has brought the return of locally acquired malaria cases to the United States. After 20 years without a confirmed case of locally acquired mosquito-transmitted malaria, 10 cases in 4 states were reported between May and August 2023. Seven cases of Plasmodium vivax were identified in a 4-mile radius in Florida, whereas isolated cases of P. vivax were identified in Texas and Arkansas and a case of Plasmodium falciparum was identified in Maryland [40]. None of these patients had histories of recent travel to malaria-endemic regions. Although the risk of locally acquired malaria is still very low, it remains to be seen if these were just isolated incidents this year or the start of a larger trend.

CONCLUSION

Infectious diseases remains a dynamic field of study with many “hot topics” still waiting to be explored. We look forward to the array of ID clinical science discoveries that our colleagues will enlighten us to in 2024 and beyond.

Notes

Financial support. J. A. F. is supported by funding from the National Institute of Allergy and Infectious Diseases at the National Institutes of Health under grant number F32AI169905 and from the VUMC Faculty Research Scholars program.

References

Author notes