Infectious Disease Updates
January 1, 2026
By Carol A. Kemper, MD, FIDSA
DoxyPEP and Antimicrobial Resistance
Source: Bercot B, Assoumou L, Camelena F, et al. Antimicrobial-resistant Neisseria gonorrhoeae infections in men using doxycycline postexposure prophylaxis: A substudy of the ANRS 174 DOXYVAC trial. Clin Infect Dis. 2025;Nov 10:ciaf591. doi: 10.1093/cid/ciaf591. [Online ahead of print].
In October 2023, new United States guidelines provided recommendations for the use of doxycycline for postexposure prophylaxis to prevent bacterial sexually transmitted infections (STI), known as doxyPEP. A single dose of doxycycline 200 mg orally within 72 hours of sexual activity (vaginal, oral, or anal) was recommended for gay or bisexual men or for transgender women with a history of STI within the past year, or for others participating in sexual activities at higher risk for STI. This intervention was shown in several clinical trials to significantly reduce the risk of chlamydia and syphilis infection. The benefit of doxyPEP in the reduction of gonorrhea (GC) was mixed, most likely because of the presence of baseline resistance to tetracycline in many areas. For example, in 2022 in France, tetracycline resistance was observed in 66% of GC isolates using the recommended Clinical and Laboratory Standards Institute (CLSI) breakpoint (minimum inhibitory concentration [MIC] > 1 mg/L); however, using the recommended European laboratory standard breakpoint (MIC > 0.5 mg/L), 92.3% were considered resistant.
Although the new doxyPEP strategy has been widely embraced, there is concern that the broader use of this agent will promote the selection of GC resistance to other antibacterial agents, as well as impact general antimicrobial resistance rates.
These authors examined resistance rates to other antibacterial agents in GC isolates obtained from individuals enrolled in the ANRS 174 DOXYVAC trial. From 2021-2023, men who have sex with men and who were receiving human immunodeficiency virus (HIV) preexposure prophylaxis were randomized to receive doxyPEP (n = 362) vs. no postexposure prophylaxis (n = 183). They were tested for GC at baseline and every three months by both culture and nucleic acid amplification testing (NAAT), and MICs of GC bacteria isolated were determined by Etest. Whole genome sequencing and/or polymerase chain reaction sequencing were performed on all GC isolates or NAAT-positive samples.
A total of 78 GC isolates were cultured from clinical specimens, including seven isolates obtained at baseline and 71 isolates obtained during follow-up (11 urine, 12 throat, and 55 anal samples). There also were a total of 450 NAAT-positive samples, including 233 that were NAAT-only positive. All of the isolates were resistant to tetracycline according to the European standard breakpoint, and all of the GC isolates with MICs > 8 mg/L, consistent with high-level resistance (HLR), contained the tetM gene. A significant rate of HLR was observed in 35.5% of the GC isolates from doxyPEP users compared with 12.5% of isolates obtained from the no-PEP arm (P = 0.043). In addition, the proportion of NAAT-positive samples harboring the tetM gene was significantly higher in the doxyPEP arm vs. the no-PEP arm (60.0% vs. 24.5%, P < .001). MICs to ceftriaxone, azithromycin, and fluoroquinolones were similarly distributed between the two arms, and all isolates remained fully susceptible to ceftriaxone. However, reduced susceptibility to cefixime was observed in the doxyPEP arm vs. no-PEP (32.3% vs. 10.0%, P = 0.033).
Using the 78 GC isolates, a phylogenetic tree was constructed, showing they were broadly distributed into 21 different clonal types.
Antimicrobial resistance is becoming a worldwide emergency. In this substudy of a doxyPEP trial, statistically significant more frequent high-level tetracycline resistance and more frequent genetic markers of that resistance (tetM gene) were observed in GC isolates obtained from doxyPEP users compared with those from no-PEP users. Reduced cefixime MICs also were observed significantly more often in doxyPEP users compared with the no-PEP arm. However, the use of doxyPEP did not appear to affect MICs to ceftriaxone, fluoroquinolones, or azithromycin — although the rate of baseline resistance to fluoroquinolones already was quite high (72% to 74%).
I worry that the broader use of doxyPEP eventually will affect our ability to treat syphilis, especially in non-pregnant women, where the use of penicillin currently is limited by a critical antibiotic shortage, but also eventually will promote tetracycline/doxycycline resistance in skin flora, such as Staphylococcus epidermidis and Staphylococcus aureus, which could affect our ability to treat other serious infections.
Emergence of Resistance to Cefepime-Zidebactam
Source: Dorazio AJ, Aitken SL, Pierce VM, et al. First report of treatment-emergent resistance to cefepime-zidebactam in Pseudomonas aeruginosa. Clin Infect Dis. 2025;Nov 18:ciaf638. doi: 10/1093/cid/ciaf638. [Online ahead of print].
Cefepime-zidebactam (CZ) is a novel beta-lactam/beta-lactamase inhibitor combination agent with potent in vitro activity against multidrug-resistant Pseudomonas aeruginosa (PsA). Zidebactam is a novel bicyclo-acyl hydrazide derivative of the diazabicyclooctane (DBO) scaffold that functions both as a beta-lactamase inhibitor and an enhancer, which binds to PBP3. The enhancer effect is mediated through complementary penicillin-binding protein (PBP) binding. This agent is in late-stage clinical development and has been granted fast-track status by the U.S. Food and Drug Administration (FDA) effective Dec. 2, 2025. This is the first time in history an Indian pharmaceutical company has successfully filed and received acceptance for a New Drug Application (NDA) at the FDA. The drug presently is available in the United States on a compassionate use basis.
These authors describe a single human case of evolving PsA resistance to a series of beta-lactam agents, eventually culminating in treatment-emergent resistance to CZ associated with mutations in PsA efflux genes.
A 40-year-old man required hospitalization at the University of Pittsburgh for pneumococcal sepsis, requiring intubation and extracorporeal membrane oxygenation. He received ceftriaxone until hospital day (HD) 16, when a tracheal aspirate grew PsA, and he was switched to meropenem. On HD 25, the patient deteriorated, requiring pressor support, and imaging demonstrated a dense necrotizing pneumonia. Respiratory cultures yielded a PsA isolate with reduced susceptibility to the usual beta-lactams. He was switched to ceftolozane-tazobactam and clinically improved. Over the next 105 days, his clinical course fluctuated, and he was sequentially treated with a variety of agents, including imipenem-relebactam (HD 38-57), combination ciprofloxacin-cefiderocol (HD 57-83), tobramycin and imipenem-relebactam (HD 83-102), as subsequent respiratory and other clinical PsA isolates demonstrated progressive resistance. On HD 98, a bronchoalveolar lavage (BAL) grew PsA resistant to all novel beta-lactam/beta-lactamase inhibitor agents, and on HD 102 the patient was started on compassionate use CZ. The patient initially improved, and he was weaning from mechanical ventilation when, on HD 128 and while continuing to receive CZ, the patient deteriorated again, developed new septic shock, and died on HD 131. A BAL from HD 130 grew PsA.
A total of 15 PsA isolates were obtained from 10 cultures over the period of four months. An initial PsA isolate collected on HD 22 was susceptible to all novel beta-lactam agents tested, including CZ with a minimum inhibitory concentration (MIC) of 2 mg/L. This isolate was categorized as sequence type ST-2555 containing a Pseudomonoas-derived cephalosporinase (PDC)-36 gene. Between HD 22 and HD 85, new mutations were observed in the PDC gene and with disruption in AmpD. In addition, cefiderocol resistance was observed on HD 98 and was associated with new mutations in tonB iron-dependent receptors pirR and pirA. At that time (HD 98), MICs for cefepime, zidebactam, and CZ already were diminished at 32 mg/L, 32 mg/L, and 8 mg/L, respectively. Thus, at the time CZ was initiated, resistance to all clinically available agents, including all novel agents, already had occurred. From HD 102 to HD 130, a four-fold increase in MIC to CZ was observed (from 8 mg/L to 32 mg/L), and the corresponding MICs for cefepime and zidebactam increased to 64 mg/L and > 128 mg/L, respectively. Mutations were observed in mexB gene, which affects pump structure, and mexR gene, which leads to increased pump expression, as well as mutations in the porin gene OprD. Across all of the PsA isolates, no mutations were identified in PBP2 or PBP3 genes.
As the authors admitted, they were amazed at the “remarkable capacity of PsA to evade antibacterial therapy.” This is the first report of emergent resistance to CZ, defined as an elevation in MIC more than four-fold, occurring during treatment. Whole genome sequencing of serial isolates compared with MICs showed that while ceftolozane-tazobactam selected for a point PDC mutation that conferred cross-resistance to ceftazidime-avibactam, it conversely increased susceptibility to imipenem-relebactam. In contrast, treatment with CZ selected for mutations in the mexAB-OprM operon that conferred broader cross-resistance to all beta-lactam diazabicyclooctane (DBO) combinations via antibiotic efflux, and conceivably could result in broader resistance to other classes of drugs. This worrisome resistance was observed following extensive treatment with a variety of beta-lactams and novel beta-lactam/beta-lactamase inhibitor combination agents, followed by prolonged exposure to CZ for 28 days.
Carol A. Kemper, MD, FIDSA, is Medical Director, Infection Prevention, El Camino Hospital, Palo Alto Medical Foundation.