The review, led by Qiaochun Lu and colleagues at Zhejiang University School of Medicine and partner institutions in China, systematically evaluates both the clinical and mechanistic evidence for beta-lactam–macrolide combination therapy. The authors apply a three-level grading framework to distinguish established findings from probable or merely hypothesized ones. Their central conclusion is nuanced: the combination shows its clearest benefit in adults with severe community-acquired pneumonia, while evidence in non-severe pneumonia and pediatric populations remains inconsistent. Biological synergy, they caution, does not automatically translate into clinical benefit for every patient.

The strongest clinical signal comes from severe community-acquired pneumonia. In the double-blind ACCESS trial, adjunctive clarithromycin added to a beta-lactam significantly improved a composite early endpoint combining symptom reduction and inflammatory markers, reduced new organ failure, and shortened time to discharge alive. A subsequent meta-analysis of randomized trials estimated higher clinical success with macrolide add-on therapy, and a network meta-analysis ranked beta-lactam plus macrolide favorably among empirical strategies for severe disease. Yet the mortality benefit remains suggestive rather than definitive, derived largely from observational data vulnerable to confounding by illness severity and treatment timing.

Outside severe pneumonia, the picture is far less favorable. The cluster-randomized CAP-START trial found beta-lactam monotherapy noninferior to combination strategies for 90-day mortality in non-ICU wards, and an open-label randomized trial in moderately severe pneumonia failed to establish monotherapy inferiority. Pediatric cohort data, including a study of more than 2,500 hospitalized children, showed no routine outcome benefit from empirical macrolide combination therapy. Guidelines reflect this unevenness: the 2019 ATS/IDSA recommendations support the combination for hospitalized and severe pneumonia, while the 2023 European guideline conditionally favors adding a macrolide over a fluoroquinolone in severe disease but rates the evidence as very low certainty.

What explains the apparent synergy at the mechanistic level? The review identifies several complementary pathways. The most established is target complementarity: beta-lactams inhibit peptidoglycan crosslinking while macrolides block translation, so the two drugs attack distinct essential processes simultaneously. A second, more speculative hypothesis holds that beta-lactam-induced cell-wall injury increases macrolide penetration into the bacterial cell. Evidence for this comes from indirect models, such as bacteriophage-derived endolysins that disrupt peptidoglycan and enhance macrolide activity, but direct demonstration with conventional clinical combinations is lacking.

Additional mechanisms operate at subinhibitory concentrations. In vitro studies show that azithromycin downregulates the MexAB-OprM efflux pump in Pseudomonas aeruginosa and suppresses quorum-sensing signals of the las and rhl systems, reducing production of virulence factors such as elastase, rhamnolipids, and pyocyanin. In serial-passage and animal models, azithromycin repressed translation of the stress-response regulator rpoS and delayed emergence of resistance to ceftazidime-avibactam. Macrolides also alter biofilm matrix composition and alginate production, potentially exposing proliferating bacteria to beta-lactam activity. These findings lend biological plausibility to the combination but remain largely preclinical.

Host-directed effects may be equally important. In the ACCESS trial, clarithromycin modulated tumor necrosis factor-alpha responses in stimulated immune cells and altered circulating interleukin-10 and the IL-8/IL-10 balance, suggesting correction of infection-related immune dysregulation. Preclinical work indicates macrolides can dampen pro-inflammatory macrophage activation, promote an M2-like phenotype with enhanced phagocytosis, and influence dendritic-cell and T-cell responses. The authors grade cytokine modulation as supported by patient-derived data, while broader immune effects remain probable based on animal and ex vivo evidence.

The review also emphasizes that the three macrolides are not interchangeable. Clarithromycin carries the only direct randomized evidence from the ACCESS trial, which cannot be extrapolated to azithromycin or erythromycin. Azithromycin’s combination evidence is essentially preclinical, and its use in pneumonia regimens rests primarily on atypical-pathogen coverage rather than proven synergy. Erythromycin has virtually no contemporary evidence for acute combination therapy and is limited by gastrointestinal intolerance and strong CYP3A4 inhibition. All macrolides can prolong the QT interval, and large pharmacoepidemiologic studies have linked macrolide therapy to elevated cardiovascular risk, although the ACCESS trial itself found no increase in adverse events.

Resistance considerations further complicate the picture. erm-mediated ribosomal methylation generally abolishes macrolide activity, and a beta-lactam partner cannot restore susceptibility, a critical point when atypical coverage is the goal. Macrolide exposure also selects for resistance in colonizing microbiota and environmental reservoirs. The authors advocate an antibiotic time-out at 48 to 72 hours, using clinical response and microbiological findings to de-escalate to beta-lactam monotherapy once atypical infection becomes unlikely. Pharmacokinetic differences matter too: beta-lactams require sustained concentrations above the minimum inhibitory concentration, while macrolides achieve high tissue levels with prolonged post-antibiotic effects, a complementarity that may support combination use in severe disease.

The reviewers conclude that beta-lactam–macrolide therapy is a biologically and clinically defensible option for selected severe infections, particularly severe community-acquired pneumonia, but not a universally synergistic strategy. Most proposed molecular pathways are pathogen- and exposure-specific, and several remain hypothetical. Future research should link defined drug exposures and pathogen-specific mechanisms to patient-centered outcomes, stratified by severity, macrolide agent, and resistance phenotype. Until then, the combination should be reserved for the right patients, at the right time, with the right drugs—rather than extrapolated indiscriminately across the infectious-disease spectrum.

Subject of Research: Mechanisms and clinical evidence for synergistic interactions between macrolide and beta-lactam antibiotics in bacterial infections

Article Title: Mechanistic insights into the synergistic interactions between macrolides and beta-lactams in bacterial infections

Article References: Lu, Q., Qian, X., Li, Y., Liu, Y., Chen, Z., He, L., Yu, Y., Jin, Z., & Shi, Y. (2026). Mechanistic insights into the synergistic interactions between macrolides and beta-lactams in bacterial infections. Frontiers in Cellular and Infection Microbiology, 16, Article 1894766. https://doi.org/10.3389/fcimb.2026.1894766

Image Credits: AI Generated

DOI: 10.3389/fcimb.2026.1894766

Keywords: macrolides, beta-lactams, antibiotic synergy, community-acquired pneumonia, clarithromycin, azithromycin, antimicrobial resistance, biofilms, quorum sensing, immunomodulation, pharmacokinetics, antibiotic stewardship

Researchers at the University of Tennessee College of Veterinary Medicine, working with the Gastrointestinal Laboratory at Texas A&M University, enrolled twelve healthy research colony Beagles with no history of gastrointestinal signs and no antimicrobial exposure for at least six months. One dog was excluded early after developing acute intervertebral disc disease unrelated to the trial, leaving eleven animals for analysis. Each dog received azithromycin at 2 mg/kg by mouth every eight hours for eight days, a regimen corresponding to roughly one-half to one-fifth of the dose used for antimicrobial purposes. Fecal samples were collected at baseline, during treatment, and at multiple points across a five-week recovery window, with daily fecal scoring throughout the 45-day study. All dogs acted as their own controls, a design considered appropriate given the well-established temporal stability of the canine fecal microbiome.

The analytical approach combined quantitative PCR measurement of sixteen core bacterial taxa with a validated Dysbiosis Index, the only analytically validated assay for fecal dysbiosis in dogs and cats. In parallel, twenty-nine conjugated, unconjugated, and oxo-isoforms of primary and secondary bile acids were quantified using liquid chromatography-tandem mass spectrometry. The choice of bile acids was not arbitrary. Bile acid metabolism is one of the most sensitive functional readouts of gut microbial health, because a single bacterial species, Peptacetobacter hiranonis, performs the critical conversion of primary bile acids into secondary forms through enzymes encoded by the bai operon. When that conversion falters, it signals more than a shift in microbial census: it signals a loss of metabolic function with potential consequences for the entire intestinal ecosystem.

The results confirmed the researchers’ hypothesis with striking clarity. Even at the reduced prokinetic dose, azithromycin triggered measurable dysbiosis. By day six, the abundances of seven of sixteen core taxa had fallen significantly, including P. hiranonis, Faecalibacterium, and Fusobacterium, three of the most functionally important members of the canine gut community. Faecalibacterium produces short-chain fatty acids that fuel the cells lining the intestine and modulate mucosal immunity, while Fusobacterium is a major butyrate producer that ferments amino acids rather than carbohydrates. P. hiranonis dropped dramatically, with median abundance falling from roughly 6.65 to 1.77 log DNA per gram of feces during treatment. Fecal scores also rose significantly during administration, though they remained within the normal range, suggesting at most a mild, transient loosening of stool.

The metabolic consequences followed directly from the microbial losses. By day eleven, the percentage of primary unconjugated bile acids had risen significantly, with a median of about 94 percent in the most affected animals, while secondary bile acids, lithocholic acid and deoxycholic acid, declined sharply. The strength of the relationship was remarkable: the increase in primary bile acids correlated negatively with P. hiranonis abundance at a coefficient of -0.936, a near-perfect inverse association. This tight coupling makes physiological sense. With the bacterium that performs 7-alpha-dehydroxylation suppressed, primary bile acids accumulated unconverted. Because elevated primary bile acids can stimulate colonic water secretion and alter mucosal permeability, the authors speculate that this metabolic shift may even have contributed to the mild increase in fecal scores observed during treatment.

The good news is that the damage was largely temporary. By day twenty-six, P. hiranonis had normalized in all but one dog, and every animal had recovered by day thirty-six. Fecal bile acid proportions returned to baseline by day forty-five. Of the nine taxa significantly altered by the drug, eight bounced back within the study window. This recovery pattern contrasts favorably with previously published work on tylosin and metronidazole, where sustained elevations in primary bile acids have been documented in individual dogs for up to eight weeks. The authors note, however, that their recovery measurements may have been flattered by the sampling schedule, since bile acids were only measured on days eleven and forty-five, leaving the exact timing of metabolic recovery unknown.

One finding stood out as genuinely atypical. Streptococcus, a group of gram-positive commensals that usually flourishes during dysbiosis thanks to its tolerance of the acidic, substrate-rich conditions antibiotics create, instead declined significantly by day eleven and never recovered for the duration of the study. The pattern defies the standard ecological script. The authors ruled out simple pharmacokinetic explanations: azithromycin’s reported half-life in dogs ranges from 51 to 90 hours, meaning the drug should have been fully eliminated within about nineteen days, and post-antibiotic effects last only hours. The most plausible explanation, they argue, is a lasting ecological disruption within the fecal microbiome, one whose clinical significance in healthy dogs remains uncertain but which deserves attention in future work.

Equally unexpected was the absence of Escherichia coli overgrowth, a hallmark response to metronidazole, tylosin, and amoxicillin in dogs. The researchers attribute this to azithromycin’s distinctive macrolide structure, which confers higher basicity and greater intracellular uptake, enhancing its activity against Enterobacteriaceae. In human medicine, the drug demonstrates excellent activity against common enteropathogenic strains of E. coli. This pharmacological idiosyncrasy also helps explain why the Dysbiosis Index, which normally rises sharply after antibiotic exposure, increased only modestly in this study. Because the two taxa that typically drive the index upward, E. coli and Streptococcus, both decreased instead, the index understated the true extent of dysbiosis. The authors emphasize that the tool must always be interpreted alongside the abundances of all core bacteria, since clear functional change was evident even when the composite score appeared reassuring.

Clinically, the study offers a measured but important message. Short-term low-dose azithromycin was well tolerated in healthy dogs, with no gastrointestinal adverse effects, no changes in body weight or body condition, and normalization of nearly every disturbed parameter within five weeks. Yet the authors caution against extrapolating too readily to the clinic. Healthy research Beagles do not represent the dogs that would actually receive the drug as a prokinetic, and animals with pre-existing dysbiosis, altered bile acid metabolism, or chronic enteropathy could respond very differently. Antimicrobial resistance, which was not evaluated here, remains an additional consideration whenever an antibiotic is deployed for a non-antimicrobial purpose. The prokinetic efficacy of azithromycin in dogs, moreover, has never been rigorously proven, so future dosing strategies may differ from the one tested. What the study establishes is a proof of principle: even at doses one-fifth of those used against infection, azithromycin is not microbiologically silent. It remodels the gut ecosystem and disrupts one of its most essential metabolic functions, and it does so in a pattern that is mostly, though not entirely, reversible. For veterinarians weighing the drug against alternatives, and for researchers designing the next generation of prokinetic trials, that evidence now exists.

Subject of Research: Effects of low-dose azithromycin on the fecal microbiome and fecal bile acids in healthy dogs

Article Title: Effect of low dose azithromycin on the fecal microbiome and fecal bile acids in healthy dogs

Article References: Smith, C., Husnik, R., Gaschen, F., Kirk, C., Zhu, X., & Suchodolski, J. (2026). Effect of low dose azithromycin on the fecal microbiome and fecal bile acids in healthy dogs. Journal of Veterinary Internal Medicine, 40(5), Article aalag220. https://doi.org/10.1093/jvimsj/aalag220

Image Credits: AI Generated

DOI: 10.1093/jvimsj/aalag220

Keywords: azithromycin, dogs, microbiome, bile acids, dysbiosis, prokinetics, Peptacetobacter hiranonis, veterinary medicine, qPCR, gut health, macrolides, Streptococcus

The study, led by Masoumeh Beig and co-first author Sara Hajilari, with Khalil Azizian and Ebrahim Kouhsari as equally contributing corresponding authors, followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and included studies published up to 8 February 2026. The team used R software to compute pooled prevalence estimates with 95 percent confidence intervals, quantifying heterogeneity with Cochran’s Q and tau-squared statistics. Their focus was the minimum inhibitory concentration, or MIC, the lowest concentration of an antibiotic that prevents visible bacterial growth. When MICs rise above established breakpoints, an isolate is classified as non-susceptible, signaling that standard dosing may fail at the site of infection.

Macrolides work by binding to the 50S subunit of the bacterial ribosome, blocking the exit tunnel through which newly synthesized proteins must pass. Erythromycin, the prototype 14-membered macrolide, azithromycin, a 15-membered derivative prized for its tissue penetration, and clarithromycin and roxithromycin, both 14-membered agents, all share this target. Josamycin, a 16-membered macrolide, binds somewhat differently and has retained activity where its smaller relatives have faltered. Resistance in mycoplasmas typically arises through point mutations in the 23S ribosomal RNA gene, particularly in domain V, which alter the drug-binding pocket. Because these organisms lack a cell wall, beta-lactam antibiotics such as penicillins are useless against them, leaving macrolides, tetracyclines, and fluoroquinolones as the principal therapeutic options.

The numbers assembled by the Iranian team paint a genus-specific picture. For Ureaplasma species, pooled non-susceptibility was 13.3 percent for erythromycin, 15.3 percent for roxithromycin, 9.9 percent for clarithromycin, 6.4 percent for azithromycin, and just 2.6 percent for josamycin. For Mycoplasma species, the corresponding estimates were dramatically higher: 63.4 percent for roxithromycin, 84.5 percent for clarithromycin, 78.8 percent for azithromycin, and 7.7 percent for josamycin. Erythromycin non-susceptibility in Mycoplasma reached 75.7 percent. The authors caution, however, that Mycoplasma hominis is intrinsically resistant to 14- and 15-membered macrolides, meaning pooled estimates for erythromycin, azithromycin, clarithromycin, and roxithromycin in that species reflect biology as much as acquired resistance. For M. hominis, the clinically meaningful figure is josamycin, where pooled non-susceptibility was only 6.1 percent.

Geography emerged as a significant modifier for four of the five drugs examined. The meta-analysis detected significant geographic variation in non-susceptibility for erythromycin, clarithromycin, azithromycin, and josamycin, all with P values below 0.05, while roxithromycin showed no significant regional difference, with a P value of 0.283. This pattern suggests that local prescribing habits, population structure, and transmission dynamics shape resistance profiles unevenly across the globe. In regions where azithromycin has been deployed widely, including mass drug administration campaigns and routine sexually transmitted infection management, elevated MICs appear more frequently, whereas areas with lighter macrolide pressure retain comparatively vulnerable bacterial populations.

Perhaps the most reassuring finding is what the analysis did not show. Across the entire dataset, no significant temporal trends were observed for any of the evaluated macrolides: the P value was 0.994 for erythromycin, 0.165 for roxithromycin, 0.615 for clarithromycin, 0.326 for azithromycin, and 0.467 for josamycin. In other words, resistance levels appear to have remained roughly stable over the period covered by the included studies rather than climbing year over year. The authors interpret this cautiously, noting that stability is not the same as safety. A plateau at 75 percent erythromycin non-susceptibility in Mycoplasma offers little therapeutic comfort, and the absence of a trend may simply reflect the coarse resolution of pooled cross-sectional data.

The clinical implications are direct. Urogenital mycoplasmas and ureaplasmas are associated with urethritis, cervicitis, pelvic inflammatory disease, adverse pregnancy outcomes, and complications in neonates, and they are among the most difficult sexually associated bacteria to culture, often requiring nucleic acid amplification tests for detection and specialized broth-based systems for susceptibility testing. When macrolides fail, clinicians typically turn to tetracyclines such as doxycycline or to fluoroquinolones, but resistance to those classes has also been documented in these organisms, narrowing the armamentarium further. The new pooled estimates give guideline committees a quantitative baseline for deciding when macrolide therapy remains defensible and when an alternative should be the default.

Josamycin stands out as the quiet winner of the analysis. With pooled non-susceptibility of 2.6 percent in Ureaplasma and 7.7 percent in Mycoplasma overall, and 6.1 percent in M. hominis specifically, the 16-membered macrolide demonstrated consistently low MICs across the included studies. The authors suggest it may represent a promising alternative, particularly where 14- and 15-membered agents have lost efficacy. Josamycin is not licensed in every country, and its availability varies widely, but the data provide an evidence-based argument for reconsidering its place in treatment algorithms for urogenital infections, especially in regions where azithromycin MICs have drifted upward.

For erythromycin and azithromycin, the message is restraint. The combination of high erythromycin resistance and moderate elevation of azithromycin MICs, the authors conclude, warrants cautious use of these agents, reserving them for cases where susceptibility has been confirmed or where no better option exists. Empirical macrolide monotherapy for suspected Mycoplasma-driven disease, once a reflexive choice, now carries a substantial probability of failure in many settings. The researchers emphasize that ongoing global surveillance remains essential to support evidence-based treatment guidelines, since resistance in organisms with rapid replication and frequent horizontal gene exchange can shift within years, and the fragmented geographic data they aggregated highlight how little standardized susceptibility testing exists in much of the world.

The study, published open access on 8 October 2026 and citable under DOI 10.1186/s12879-026-14585-9, was approved by the Ethics Committee of Golestan University of Medical Sciences and conducted in accordance with the Declaration of Helsinki. The authors declared no competing interests and no external funding, and they state that a language-model tool was used solely to polish the manuscript’s prose, not to collect or analyze data. As antimicrobial resistance continues to erode the utility of first-line antibiotics across the infectious disease spectrum, this meta-analysis offers both a warning and a waypoint: the macrolide era for urogenital Mycoplasma is largely over in much of the world, but for Ureaplasma, and for josamycin across both genera, carefully stewarded options remain.

Subject of Research: Global macrolide antibiotic resistance in urogenital Ureaplasma and Mycoplasma species

Article Title: Global macrolide non-susceptibility in urogenital Ureaplasma and Mycoplasma: a systematic review and meta-analysis

Article References: Beig, M., Azizian, K., Hajilari, S., Shakourzadeh, M. Z., & Kouhsari, E. (2026). Global macrolide non-susceptibility in urogenital Ureaplasma and Mycoplasma: a systematic review and meta-analysis. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14585-9

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14585-9

Keywords: antimicrobial resistance, macrolides, Ureaplasma, Mycoplasma, erythromycin, azithromycin, josamycin, minimum inhibitory concentration, systematic review, meta-analysis, sexually transmitted infections, BMC Infectious Diseases

The research, conducted by a team at Jilin Jianzhu University’s Key Laboratory of Songliao Aquatic Environment and published in Environmental Monitoring and Assessment, is one of the most seasonally resolved portraits yet of antibiotic pollution in a cold-region urban water system. Between July 2024 and April 2025, the investigators sampled three weekdays in each of the four seasons, collecting water from the influents and final effluents of two wastewater treatment plants as well as from sites upstream and downstream of their shared receiving river. The design allowed them to follow the same molecules from the sewer, through the treatment train, and into the aquatic environment across an entire annual cycle.

The analytical workflow was deliberately rigorous. Antibiotics were extracted from water samples using solid-phase extraction, a technique that concentrates trace organic compounds onto a sorbent cartridge before they are eluted for analysis. Quantification was then performed by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry, an approach sensitive enough to detect individual pharmaceutical compounds at concentrations of nanograms per liter, equivalent to parts per trillion. This combination of concentration and detection methods is now the standard for pharmaceutical monitoring, because the environmental levels involved are far too low for conventional chemical assays yet high enough to exert biological effects on microorganisms.

What the measurements revealed was a steep concentration gradient across the urban water cycle. In the raw sewage entering the plants, antibiotic concentrations ranged from undetectable to a remarkable 2,873.03 nanograms per liter. After treatment, effluent concentrations fell to between not detected and 941.59 nanograms per liter, and in the receiving river itself the measured levels ranged from not detected up to 93.25 nanograms per liter. Two chemical families dominated the profile: the fluoroquinolones, a class of broad-spectrum synthetic antibiotics that includes drugs such as ciprofloxacin and norfloxacin, and the macrolides, which include azithromycin and roxithromycin. Both classes are heavily prescribed in China and are known to persist in aquatic environments because they resist both biodegradation and sunlight-driven photolysis.

The seasonal signal was unmistakable. Concentrations were generally higher in winter and lower in summer, a pattern the authors link to several interacting factors. In cold climates, winter brings higher rates of respiratory infection and correspondingly greater antibiotic consumption, which flushes more of these compounds into the sewer system. At the same time, the biological processes inside treatment plants slow down dramatically as temperatures drop, because the microbial communities that break down organic pollutants, including pharmaceuticals, become far less active in cold wastewater. Reduced dilution in frozen, low-flow rivers compounds the problem, since the same mass of discharged antibiotic ends up in a smaller volume of receiving water.

Treatment performance told the same seasonal story from the other direction. For the eight antibiotics that were consistently detected, the apparent overall removal efficiency across the plants ranged from 32.99 percent to complete elimination, but removal was generally lower in winter and spring. This matters because conventional activated-sludge treatment was never designed with pharmaceuticals in mind. Antibiotics leave wastewater plants through three main pathways: biodegradation by the microbial community, sorption onto sludge particles that are settled out of the water, and abiotic processes such as hydrolysis. When water temperatures fall, all three mechanisms weaken, and a larger fraction of the incoming drug load simply passes through the plant and into the river.

One of the most practically interesting findings concerns the comparison between treatment technologies. The two plants in the study operated three distinct treatment lines: a conventional anaerobic-anoxic-oxic configuration followed by clarification, filtration, and ozonation; a similar biological process followed by clarification, cloth-media filtration, and ultraviolet disinfection; and an integrated anaerobic-anoxic-oxic membrane bioreactor, in which fine membranes replace secondary clarifiers and allow a much higher concentration of slow-growing microorganisms to be maintained in the bioreactor. During winter, the membrane bioreactor line achieved comparatively higher apparent removal of the macrolides azithromycin and roxithromycin than the parallel conventional line. The likely explanation lies in the longer solids retention times and denser microbial populations that membrane systems sustain, giving cold-slowed bacteria more opportunity and more biomass to degrade or sorb these persistent compounds even when conditions are unfavorable.

Downstream of the outfalls, the river told a coherent spatial story as well. Antibiotic concentrations rose sharply near the discharge points and then generally declined with distance downstream, as dilution, sedimentation, photodegradation, and microbial breakdown gradually whittled away the effluent signal. In a cold-region river, however, this natural attenuation is weakened for much of the year. Ice cover reduces light penetration and suppresses photolysis, low winter flows reduce dilution capacity, and cold water slows biodegradation, so the plume of pharmaceuticals extends further and persists longer than it would in a warmer climate. This is why the study’s cold-region focus is significant: most antibiotic monitoring data come from temperate or tropical systems, and the winter dynamics of northern cities have been comparatively understudied.

The ecological risk assessment converted concentration data into a measure of biological concern using risk quotients, a screening approach that compares measured environmental concentrations with predicted no-effect concentrations derived from ecotoxicological studies. The verdict was pointed: azithromycin was the main contributor to ecological risk, reaching moderate to high risk levels in winter. This finding resonates with a growing body of international research showing that macrolides are among the most hazardous antibiotics in surface waters, partly because they are toxic to photosynthetic aquatic organisms such as algae and cyanobacteria, the foundation of aquatic food webs. Even more troubling is the resistance dimension. Laboratory studies have demonstrated that bacteria can be selected for antibiotic resistance at concentrations far below those that cause obvious toxicity, meaning that chronic exposure to even nanogram-per-liter levels in a river can act as a subtle evolutionary engine, enriching resistant strains and the genes that carry resistance.

The Changchun study arrives amid intensifying global concern about antimicrobial resistance, which the World Health Organization ranks among the top public health threats of the century. Wastewater treatment plants occupy a pivotal position in this problem: they concentrate antibiotics, resistant bacteria, and resistance genes from entire urban populations into a single discharge stream, and they are simultaneously one of the few practical points of intervention. The findings from Northeast China suggest that cold-climate cities may need seasonally adjusted strategies, from enhanced winter treatment capacity to technologies such as ozonation and membrane bioreactors that maintain performance when conventional biology falters. They also underscore the value of long-term, seasonally resolved monitoring, because a snapshot taken in summer would have dramatically underestimated both the concentrations and the risks that northern rivers actually face. As winters in many regions grow more variable and urban pharmaceutical use continues to rise, the frozen rivers of places like Changchun may offer an early warning of challenges that colder cities worldwide have only begun to confront.

Subject of Research: Seasonal occurrence, treatment removal, and ecological risk of antibiotics in municipal wastewater and a receiving river in a cold-region Chinese city

Article Title: Seasonal patterns and ecological risks of antibiotics in municipal wastewater treatment plants and a receiving river in Northeast China

Article References: Sun, K., Meng, Q., Zhang, C., Wen, Z., Zhu, X., Li, R., Wang, Y., & Wang, M. (2026). Seasonal patterns and ecological risks of antibiotics in municipal wastewater treatment plants and a receiving river in Northeast China. Environmental Monitoring and Assessment, 198(11), Article 1144. https://doi.org/10.1007/s10661-026-16003-8

Image Credits: AI Generated

DOI: 10.1007/s10661-026-16003-8

Keywords: antibiotics, wastewater treatment plants, receiving river, seasonal variation, azithromycin, macrolides, fluoroquinolones, membrane bioreactor, ecological risk, antimicrobial resistance, Northeast China, cold-region water quality

The rationale for the combination rests on the complementary profiles of the two drugs. Azvudine, known chemically as FNC, is a nucleoside reverse transcriptase inhibitor approved in China for HIV treatment and later authorized for COVID-19. As an analogue, it is incorporated by viral polymerases and terminates RNA synthesis, acting directly on the SARS-CoV-2 RNA-dependent RNA polymerase. Carrimycin, by contrast, is a macrolide derived from the engineered antibiotic compound 4″-O-isovalerylspiramycin. Macrolides are best known as antibacterials, but several members of the class display immunomodulatory and anti-inflammatory properties, and Carrimycin has previously shown antiviral activity against coronaviruses. Pairing a direct-acting polymerase inhibitor with an agent that modulates host responses is an appealing strategy precisely because evolving SARS-CoV-2 variants have begun to erode the effectiveness of replication-targeted monotherapy.

To test the concept, the team turned to rhesus macaques, which remain among the most faithful animal models of human COVID-19 because they develop viral pneumonia, radiographic abnormalities, and immune responses that closely mirror clinical disease. Animals were inoculated intratracheally with SARS-CoV-2 and then treated orally for seven days with Carrimycin at 9 milligrams per kilogram, Azvudine at 0.07 milligrams per kilogram, or the two drugs together. The researchers then tracked viral loads, lung pathology, immune responses, and gut microbiota across the treatment groups, conducting the work in an animal biosafety level 3 facility under protocols approved by the institutional animal care committee.

The antiviral results were clear-cut. Both monotherapies significantly inhibited SARS-CoV-2 replication, but the combination produced additive effects, driving viral loads down further in both throat swabs and lung tissue. That pattern matters because viral burden in the lower respiratory tract correlates with disease severity and onward transmission risk. Notably, the authors reported no significant side effects in the treated animals, an important consideration for a combination intended for clinical use, since drug-drug interactions and cumulative toxicity often limit real-world combination regimens.

Lung protection was assessed by chest imaging and histopathology, and here the combination again outperformed either drug alone. Monotherapy reduced ground-glass opacities, the hazy areas on chest scans that reflect fluid and inflammatory infiltration of lung tissue, and mitigated focal interstitial pneumonia, the inflammation of the tissue between air sacs that characterizes severe COVID-19. The combination treatment demonstrated superior efficacy on both measures, suggesting that blunting viral replication while simultaneously damping host inflammation preserves lung architecture more effectively than either intervention alone.

To understand how the combination reshaped the lung environment, the researchers performed transcriptomic profiling and immunofluorescence staining of lung tissue. Gene expression analysis revealed enhanced immunomodulation under combination therapy, including suppression of neutrophil degranulation, a process in which activated neutrophils release enzymes and antimicrobial proteins that, when excessive, damage surrounding tissue and contribute to acute lung injury. The combination also increased populations of CD19-positive B cells and CD3-positive T cells, the cornerstones of adaptive humoral and cellular immunity, while decreasing CD68-positive macrophages, whose accumulation in the lung is associated with sustained inflammation.

At the molecular level, combination therapy downregulated pro-inflammatory and apoptotic markers, pointing to reduced inflammatory signaling and less programmed cell death in infected lung tissue. Taken together, these findings suggest the combination does more than lower viral numbers; it shifts the lung immune landscape away from the maladaptive innate hyperinflammation seen in severe COVID-19 and toward a more effective adaptive response. That distinction is clinically significant, because mortality in severe COVID-19 is driven as much by immunopathology as by the virus itself, and therapies that address both axes have been sought since the beginning of the pandemic.

The study also uncovered a difference between the two drugs that monotherapy comparisons alone would have missed. Carrimycin, but not Azvudine, increased gut bacteria that produce short-chain fatty acids, metabolites with well-documented anti-inflammatory and immune-regulatory effects, and decreased harmful pathogens previously associated with COVID-19 progression. The gut-lung axis, the bidirectional communication between intestinal microbes and respiratory immunity, has emerged as a contributor to COVID-19 outcomes, and dysbiosis has been linked to worse disease. A drug that simultaneously acts on the lung and restores a favorable microbiome composition could therefore offer benefits beyond direct antiviral activity, potentially supporting recovery and reducing secondary complications.

The authors conclude that the Carrimycin-Azvudine combination showed superior efficacy in suppressing viral replication, alleviating lung injury, and correcting immune and inflammatory dysregulation, with Carrimycin providing additional gut microbiota benefits. They position the pairing as a promising therapeutic strategy against COVID-19 and its complications, particularly in a landscape where ongoing viral mutation, emerging resistance mutations, inadequate immunomodulation, and suboptimal organ protection limit existing antiviral options. The work was supported by the National Natural Science Foundation of China, the National Key Research and Development Program of China, and the CAMS Innovation Fund for Medical Sciences.

As with any preclinical animal study, the path from macaques to patients requires clinical validation, including pharmacokinetic confirmation of the doses used, human safety data for the combination, and efficacy trials in infected populations. Nevertheless, the study offers a mechanistically grounded template for next-generation COVID-19 therapy: a direct-acting antiviral paired with an immunomodulatory and microbiome-friendly partner, evaluated with the full toolkit of modern virology, imaging, transcriptomics, and metagenomics. If the additive antiviral and lung-protective effects observed here translate to humans, the combination could address precisely the shortcomings, resistance, inflammation, and organ damage, that have constrained single-drug approaches throughout the pandemic.

Subject of Research: Combination antiviral therapy with Carrimycin and Azvudine against SARS-CoV-2 infection in rhesus macaques

Article Title: Better antiviral and lung-protective effects of Carrimycin in combination with Azvudine in rhesus macaques infected with SARS-CoV-2

Article References: Li, H., Liu, Y., Xue, J., Li, J., Xu, J., Dong, B., Wang, T., Peng, X., Che, Y., Jiang, J., & Peng, Z. (2026). Better antiviral and lung-protective effects of Carrimycin in combination with Azvudine in rhesus macaques infected with SARS-CoV-2. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08933-1

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08933-1

Keywords: SARS-CoV-2, Carrimycin, Azvudine, combination therapy, rhesus macaques, lung injury, immunoinflammatory regulation, gut microbiota, antivirals, macrolides, COVID-19, translational medicine

The ubiquity of the contamination was striking. Three compounds in particular, trimethoprim, chlortetracycline, and sulfamethoxazole, were detected in 100 percent of the samples analyzed, meaning that no single site in the entire river system was free of antibiotic residues. Concentrations of individual antibiotics ranged widely, from as little as 2.8 nanograms per liter for lomefloxacin to a maximum of 1235.8 nanograms per liter for erythromycin, a macrolide antibiotic commonly used in both human medicine and livestock production. While such concentrations are measured in parts per trillion and are far below therapeutic doses, chronic exposure at these levels is precisely the condition that scientists worry can drive the evolution and spread of antibiotic resistance genes in aquatic microbial communities.

Spatial patterns in the data told a clear story about how the pollution moves through the watershed. Antibiotic concentrations followed the order of midstream greater than downstream greater than upstream, suggesting that the middle reaches of the river system, where urban development and population density are highest, act as a major loading zone. Equally telling was the comparison between the main river channel and its tributaries: levels in the tributaries were generally higher than in the mainstream, indicating that the main stem of the Beiyun River is strongly influenced by inflows from the smaller streams draining its sub-catchments. In effect, the tributaries function as conveyor belts, collecting antibiotic residues from neighborhoods, hospitals, livestock facilities, and industrial sites, and delivering them into the larger river.

To move beyond simple detection and identify where the antibiotics actually come from, the research team employed a quantitative source-apportionment method known as principal component analysis with multiple linear regression, or PCA-MLR. This technique, originally developed for tracing air pollution sources, works by reducing a large dataset of measured pollutant concentrations into a small number of underlying statistical factors, each of which corresponds to a characteristic pollution signature. Regression analysis then estimates how much each factor contributes to the observed concentrations of individual compounds. In this study, the model resolved the antibiotic load in the Beiyun River system into six identifiable pollution sources plus one unknown source, providing a quantitative breakdown that single-source monitoring cannot achieve.

The results of the apportionment pointed to two dominant contributors. Mixed pollution source inputs, a category that aggregates diffuse urban runoff, agricultural activity, and other combined pathways, explained 35.4 percent of the variance in the data, making it the single largest source. Wastewater treatment plant discharges ranked a close second, accounting for 31.1 percent of the variance. The chemical fingerprints of these two sources were distinct. The mixed source contributed most heavily to the quinolone antibiotics difloxacin and ciprofloxacin, accounting for 72.1 percent and 71.4 percent of their respective loads. The wastewater treatment plant source, by contrast, dominated the sulfonamide class, contributing 74.8 percent of sulfacetamide, 73.9 percent of sulfachloropyridazine, 73.3 percent of sulfadimethoxine, and 70.9 percent of sulfadiazine.

The prominence of wastewater treatment plants as a source is a recurring theme in urban water pollution research, and the Beiyun findings add Beijing to a long list of cities where conventional treatment infrastructure falls short of removing pharmaceutical micropollutants. Standard activated-sludge treatment processes are designed to strip out organic matter, nitrogen, and phosphorus, but many antibiotics are either poorly biodegraded or are re-released back into the water column as parent compounds or metabolites during sludge handling. Sulfonamides in particular are known to pass through treatment barriers with relatively high efficiency, which is consistent with the strong association between these compounds and treatment plant discharges found in the new study. Upgrading plants with advanced oxidation processes, ozonation, or activated carbon polishing has been shown elsewhere to substantially reduce pharmaceutical loads, and the source apportionment here suggests such upgrades would deliver measurable benefits in this watershed.

On the question of ecological risk, the study’s multi-level assessment delivered a nuanced verdict. Overall, the ecological risks posed by antibiotics across the Beiyun River system remained at acceptable levels, a conclusion that may surprise readers given the universal detection of the compounds. Risk quotients, calculated by comparing measured environmental concentrations with predicted no-effect concentrations for sensitive aquatic species, stayed within thresholds regarded as tolerable for the system as a whole. However, the assessment flagged specific exceptions. Tetracyclines showed relatively high risk quotients, reflecting the combination of their persistent detection and the known sensitivity of algae and other primary producers to this drug class. Clarithromycin, a macrolide, exhibited low but non-negligible risks to certain aquatic species, consistent with prior toxicological work showing that macrolides can affect photosynthesis and growth in freshwater organisms at environmentally relevant concentrations.

The significance of these findings extends well beyond the boundaries of a single watershed. Antibiotic residues in surface water are widely recognized as a key driver of antimicrobial resistance, one of the most serious public health threats of the coming decades. When bacteria in rivers are exposed to sub-inhibitory concentrations of antibiotics over long periods, strains carrying resistance genes gain a selective advantage, and those genes can then move between species and environments through horizontal gene transfer. Urban rivers like the Beiyun, which flow through neighborhoods where millions of people live, work, and recreate, represent critical nodes in this process, linking clinical and agricultural antibiotic use to the broader environmental resistome. Understanding exactly which sources contribute which compounds is therefore a prerequisite for designing effective interventions.

The study also highlights the value of source apportionment as a policy tool. Knowing that mixed diffuse inputs and treatment plant effluents together account for roughly two-thirds of the antibiotic burden allows regulators to prioritize interventions, whether through upgrading treatment technology, controlling runoff from livestock and aquaculture operations, tightening prescription and disposal practices, or managing the hydrological connections between tributaries and the main stem. The finding that tributaries consistently carry higher concentrations than the mainstream suggests that targeted action on sub-catchment scale pollution could yield disproportionate benefits for the entire river system.

For Beijing, a megacity of more than twenty million people whose rivers have undergone decades of engineering and restoration, the new data provide a baseline against which future management efforts can be measured. The research was funded by the Natural Science Foundation of Jiangxi Province, the Jiangxi Provincial Department of Science and Technology, and the National Natural Science Foundation of China, and was conducted by a team led from Jiangxi Agricultural University together with collaborators in Beijing. As antibiotic use continues to grow worldwide and urbanization intensifies across Asia, Africa, and Latin America, the Beiyun River system offers a case study in what complete pharmaceutical contamination of an urban watershed looks like, and a demonstration that with careful chemical detective work, the sources of that contamination can be named, ranked, and ultimately addressed.

Subject of Research: Antibiotic contamination, sources, and ecological risks in an urbanized Beijing watershed

Article Title: Occurrence, source apportionment, and risk assessment of antibiotics in the Beiyun River system: a highly urbanized watershed in Beijing, China

Article References: Lou, Q., Zhao, X., Zhang, X., Liang, L., Han, L., Tu, W., & Chen, M. (2026). Occurrence, source apportionment, and risk assessment of antibiotics in the Beiyun River system: a highly urbanized watershed in Beijing, China. Environmental Monitoring and Assessment, 198(10), Article 1125. https://doi.org/10.1007/s10661-026-15933-7

Image Credits: AI Generated

DOI: 10.1007/s10661-026-15933-7

Keywords: antibiotics, Beiyun River, Beijing, water pollution, source apportionment, PCA-MLR, ecological risk, wastewater treatment, sulfonamides, tetracyclines, macrolides, quinolones