Oral antibiotics for chronic low back pain with Modic changes: a proof of concept, but intradiscal therapy is the future
By Lloyd Czaplewski
Chronic low back pain with Modic changes has become a battleground for a blunt question: do oral antibiotics work or not? That is the wrong question. Taken together, the oral antibiotic trials provide strong clinical proof of concept for antibacterial efficacy in a defined MRI-positive subgroup of chronic low back pain. At the same time, they highlight the limitations of oral treatment, because antibiotic penetration into disc tissue is poor. The more useful conclusion is not that the antibacterial hypothesis failed, but that future treatment will need better delivery to the site of infection, most likely through intradiscal therapy such as PP353.
Key takeaways
Chronic low back pain with Modic changes, or vertebrogenic lumbar back pain (vLBP) is a defined MRI-positive subgroup, not chronic low back pain in general.
The oral antibiotic randomised controlled trials are better understood as Phase 1b or Phase 2 proof-of-concept studies than as pivotal tests of oral antibiotic efficacy.
Differences between oral RCTs may reflect differences in intradiscal antibiotic exposure, not a simple contradiction between "positive" and "negative" studies.
Poor penetration into disc tissue makes oral therapy a weak and potentially underdosed test of antibacterial efficacy.
Intradiscal therapy, including PP353, is designed to improve antibiotic exposure at the site of infection and provides the greatest change from baseline in pain and disability.
Do oral antibiotics work for chronic low back pain with Modic changes?
The literature is often framed as a simple contest between positive and negative antibiotic trials. Did Albert et al., (2013) show benefit?1 Did Bråten et al., (2019) disprove it?2
That framing is too crude to be scientifically useful.
Clinical trials are not interchangeable just because they all used an antibiotic. They differ in patient selection, dose, formulation, route of administration, and exposure at the infected site. If the relevant pathology is a bacterial infection within the disc, then the key question is not whether an antibiotic was prescribed. It is whether enough active drug reached the disc for long enough to matter.3
See “Intradiscal pharmacokinetics of oral antibiotics to treat Chronic Lower Back Pain.” https://doi.org/10.1038/s44259-023-00002-7
Once the literature is viewed through that lens, the results look less contradictory and more like an exposure-response. Some regimens appear to have delivered limited intradiscal exposure and limited clinical effect. Others appear to have delivered greater exposure and greater effect. Read this way, the oral antibiotic literature does not refute antibacterial efficacy. It supports it, while also showing the limitations of oral delivery.4
See “Higher exposure to antibiotics is associated with greater clinical improvement of chronic low back pain with Modic changes.” https://doi.org/10.21203/rs.3.rs-10748663/v1
See “Analysis of microbiology assay sensitivity and intradiscal antibiotic exposure in patients with chronic low back pain with Modic changes” https://persicapharmaceuticals.com/wp-content/uploads/2026/07/118.Gilligan-v3.pdf
Chronic low back pain with Modic changes is a distinct MRI-defined subgroup caused by a bacterial infection of the disc
The microbiology hypothesis in this population is frequently misunderstood. The proposed mechanism is not a high-burden infection resembling osteomyelitis or an abscess. It is a low-burden intradiscal infection, potentially involving only hundreds to low thousands of bacteria in a poorly vascularised niche. That has major implications for how disc microbiology studies should be interpreted.5,6
If bacterial burden is low, then negative culture studies cannot be read at face value without examining assay sensitivity. Culture methods that are insensitive can easily miss a sparse microbial signal. The disc microbiology literature shows substantial heterogeneity in tissue mass, disruption methods, dilution volume, plated fraction, anaerobic culture conditions, incubation duration, prophylactic antibiotic reporting, and interpretation of positive findings. These are not minor technical details. They directly affect the lower limit of detection and what can reasonably be concluded from an apparently negative study.7
See “Assay sensitivity and the interpretation of culture-based disc microbiology studies: a scoping review” https://doi.org/10.21203/rs.3.rs-10748711/v1
Why oral antibiotics may be a sub-optimal treatment for intevertebral disc infection
If the disc is the site of infection, oral therapy faces an obvious translational problem: the intervertebral disc is poorly vascularised and penetration of oral antibiotic into disc tissue is limited.3
That matters because oral treatment can only work if enough active drug reaches the target tissue. For a time-dependent antibiotic such as amoxicillin, limited penetration into disc tissue can turn an apparently reasonable oral regimen into a weak test of the antibacterial hypothesis.
The pharmacokinetic modelling supports that concern. Published data suggest that amoxicillin exposure in herniated disc tissue is only about 6.5% of serum concentration. On that basis, oral amoxicillin given every 12 hours, even at doses up to 1000 mg, is unlikely to achieve effective intradiscal exposure. Mean exposure with 500 mg or 750 mg every 8 hours may reach efficacy targets for only about half of Cutibacterium acnes isolates, whereas 1000 mg every 8 hours is more likely to be effective. In practical terms, many oral regimens may be underexposed at the site that matters most: inside the disc.3,4
This is why a negative oral antibiotic trial does not automatically invalidate the antibacterial hypothesis. It may instead reflect a drug-delivery problem. That is standard translational reasoning, not special pleading. If a regimen fails to achieve adequate concentrations at the site of infection, its negative result cannot be assumed to refute the underlying biology.
What the oral antibiotic trials suggest about dose response
The new exposure-response analysis brings this issue into sharper focus.
In the preprint Higher exposure to antibiotics is associated with greater clinical improvement of chronic low back pain with Modic changes, study-arm-level data from four clinical studies were analysed, including oral and intradiscal antibiotic treatment arms as well as placebo or sham controls. Across the oral study arms, higher antibiotic exposure was significantly associated with greater 12-month improvement in pain and disability. This held whether exposure was measured by nominal oral dose, modelled intradiscal probability of target attainment, or ordinal exposure rank.4
The association was unusually strong. Nominal oral amoxicillin/co-amoxiclav dose explained 99.9% of the variability in pain outcomes and 98.3% of the variability in disability outcomes between study arms. That suggests the apparent heterogeneity across oral RCTs may not be random inconsistency. It may reflect different levels of antibiotic exposure at the infected site.4
This has important implications for how the Albert and Bråten trials are discussed. If one trial used higher effective exposure and another used intermediate exposure, then treating one as "positive" and the other as "negative" misses the more informative interpretation. Both may sit on the same dose-response and exposure-response curve, with clinical outcome tracking how much active drug likely reached disc tissue.
That is the key narrative shift. The oral antibiotic literature should not be framed primarily as a referendum on whether oral antibiotics worked. It should be framed as clinical proof of concept that antibacterial efficacy is real, while showing that oral delivery is likely to be suboptimal.
Why intradiscal therapy may be the next step
If the bacterial infection is intradiscal and the limitation of oral therapy is intradiscal exposure, then the translational next step is straightforward: deliver the antibiotic directly into the disc.
That is the rationale for intradiscal antibiotic therapy. Direct administration offers the possibility of achieving higher local antibiotic concentrations at the site of infection while reducing prolonged systemic exposure. In principle, that could improve efficacy, reduce total antibiotic burden, improve tolerability, and support better antibiotic stewardship than long oral regimens. In practice, these advantages appear to be have been delivered in the Phase Ib RCT of intradiscal linezolid (PP353).8
This is the critical distinction. The oral trials may have been enough to demonstrate that antibacterial treatment can help in a selected subgroup of chronic low back pain with Modic changes. But they do not follow the infection pharmacology to its logical endpoint. Intradiscal therapy does.
What is PP353 and why does it matter?
PP353 is an intradiscal linezolid therapy developed to improve antibiotic exposure directly within disc tissue. It matters because it represents a next-generation translational response to the limitations seen with oral treatment, as the field moves from oral antibiotic clinical proof of concept to development of more effective therapies.
The first-in-human phase 1b trial of intradiscal linezolid (PP353) was an international, randomised, sham procedure-controlled, double-blind study in chronic low back pain associated with Modic change type 1. Its significance lies less in ending the debate than in advancing it. The study is built on the premise that oral antibiotic RCTs provided evidence consistent with a bacterial mechanism, but that oral administration produces only modest intradiscal exposure alongside high systemic exposure. Intradiscal administration is intended to solve that delivery problem.8–10
The exposure-response preprint strengthens that case. In the combined oral and intradiscal analysis, estimated MIC90 probability of target attainment ranged from0 in placebo or sham arms, to0.5635 for 1.0 g q8h oral amoxicillin/co-amoxiclav, to 0.9214 for intradiscal linezolid 0.15 g. The association between target attainment and clinical outcome remained significant when intradiscal arms were added, and the slope did not change from the oral-only model. That consistency supports a shared pharmacodynamic relationship across antibiotics and routes of administration.4
In practical terms, PP353 matters because it fits a coherent development pathway:
A defined MRI-positive subgroup with Modic changes.
A plausible low-burden intradiscal bacterial infection.
Oral antibiotic RCTs that provide proof of concept, but are constrained by poor disc penetration.
PK/PD modelling showing why exposure matters.
A next-generation intradiscal therapy designed to improve exposure at the site of infection.
That is how translational drug development should progress: not by endlessly relitigating the limitations of first-generation oral proof of concept regimens, but by improving delivery to the target tissue.
Conclusion: oral antibiotics proved the concept, but better delivery is needed
The oral antibiotic literature in chronic low back pain with Modic changes should not be reduced to a binary verdict.
Taken together, the evidence supports a more precise conclusion. Oral antibiotics provide strong clinical proof of concept for antibacterial efficacy in a defined MRI-positive subgroup of chronic low back pain with Modic changes. At the same time, poor penetration into disc tissue makes oral therapy an inherently limited and likely suboptimal treatment approach.
That is not a contradiction. It is a familiar pattern in translational medicine. First-generation studies show that the mechanism is worth pursuing. Next-generation development improves how the mechanism is engaged.
On that reading, the future is not more debate about whether oral antibiotics worked "enough." The future is targeted intradiscal antibacterial therapy designed to achieve optimal exposure at the site of infection. PP353 is an example of that next-generation strategy.
Lloyd Czaplewski is CSO at Persica Pharmaceuticals Limited.
References
1 Albert HB, Sorensen JS, Christensen BS, Manniche C. Antibiotic treatment in patients with chronic low back pain and vertebral bone edema (Modic type 1 changes): a double-blind randomized clinical controlled trial of efficacy. Eur Spine J 2013; 22: 697–707.
2 Bråten LCH, Rolfsen MP, Espeland A, et al. Efficacy of antibiotic treatment in patients with chronic low back pain and Modic changes (the AIM study): double blind, randomised, placebo controlled, multicentre trial. BMJ 2019; 367: l5654.
3 Czaplewski LG, Zeitlinger M, Standing JF. Intradiscal pharmacokinetics of oral antibiotics to treat Chronic Lower Back Pain. npj Antimicrob Resist 2023; 1: 1–9.
4 Czaplewski L, Gilligan C, McHale D. Higher exposure to antibiotics is associated with greater clinical improvement of chronic low back pain with Modic changes. 2026; published online Sept 1. DOI:https://doi.org/10.21203/rs.3.rs-10748663/v1.
5 Capoor MN, Ruzicka F, Machackova T, et al. Prevalence of Propionibacterium acnes in Intervertebral Discs of Patients Undergoing Lumbar Microdiscectomy: A Prospective Cross-Sectional Study. PLoS ONE 2016; 11: e0161676.
6 Capoor MN, Ruzicka F, Schmitz JE, et al. Propionibacterium acnes biofilm is present in intervertebral discs of patients undergoing microdiscectomy. PLoS ONE 2017; 12: e0174518.
7 Czaplewski LG, Fischetti VA, Brüggemann H, Gilligan CJ, McHale D. Assay sensitivity and the interpretation of culture-based disc microbiology studies: a scoping review. 2026; published online Sept 10. DOI:10.21203/rs.3.rs-10748711/v1.
8 Lassen M, Scarborough M, Gilchrist N, Tripathi S, Price C. Intradiscal linezolid (PP353) treatment for chronic Low Back Pain associated with Modic Change type 1: a first-in-human, randomised, sham procedure-controlled, double-blinded, international phase 1b clinical trial. eClinicalMedicine 2026; published online Feb 2. DOI:10.1016/j.eclinm.2026.103764.
9 Tripathi S, Sneath R, Golash A, et al. Pharmacokinetics of PP353, a formulation of linezolid for intervertebral disc administration, in patients with chronic low back pain and Modic change Type 1: A first-in-human, Phase 1b, open-label, single-dose study. JOR SPINE 2024; 7: e70009.
10 Hagger G, Guest S, Birchall S, et al. Preclinical development and characterisation of PP353, a formulation of linezolid for intradiscal administration. JOR SPINE 2024; 7: e70010.
FAQs
Do oral antibiotics work for chronic low back pain with Modic changes?
The better interpretation is that oral antibiotic trials provide proof of concept for antibacterial efficacy in chronic low back pain with Modic changes, but oral treatment may be limited by poor penetration into disc tissue.
Czaplewski LG, Zeitlinger M, Standing JF. Intradiscal pharmacokinetics of oral antibiotics to treat Chronic Lower Back Pain. npj Antimicrob Resist 2023; 1: 1–9. https://doi.org/10.1038/s44259-023-00002-7
Czaplewski L, Gilligan C, McHale D. Higher exposure to antibiotics is associated with greater clinical improvement of chronic low back pain with Modic changes. 2026; published online Sept 1. https://doi.org/10.21203/rs.3.rs-10748663/v1.
Did the Bråten trial disprove the Albert trial?
Not necessarily. A more informative interpretation is that differences between trials may reflect differences in antibiotic exposure at the site of infection as a consequence of using different doses, rather than a simple contradiction between one "positive" and one "negative" study.
Czaplewski L, Gilligan C, McHale D. Higher exposure to antibiotics is associated with greater clinical improvement of chronic low back pain with Modic changes. 2026; published online Sept 1. https://doi.org/10.21203/rs.3.rs-10748663/v1.
Why might oral antibiotics fail in disc infection?
Oral antibiotics may fail because the intervertebral disc is poorly vascularised, which limits how much active drug reaches the infected tissue.
Czaplewski LG, Zeitlinger M, Standing JF. Intradiscal pharmacokinetics of oral antibiotics to treat Chronic Lower Back Pain. npj Antimicrob Resist 2023; 1: 1–9. https://doi.org/10.1038/s44259-023-00002-7
Czaplewski L, Gilligan C, McHale D. Higher exposure to antibiotics is associated with greater clinical improvement of chronic low back pain with Modic changes. 2026; published online Sept 1. https://doi.org/10.21203/rs.3.rs-10748663/v1.
Why does assay sensitivity matter in disc microbiology studies?
If bacterial burden is low, then insensitive or poorly reported culture methods may miss real microbial signals. That makes assay sensitivity central to interpreting negative disc culture studies.
Czaplewski LG, Fischetti VA, Brüggemann H, Gilligan CJ, McHale D. Assay sensitivity and the interpretation of culture-based disc microbiology studies: a scoping review. 2026; published online Sept 10. DOI:10.21203/rs.3.rs-10748711/v1.
Gilligan et al., Analysis of microbiology assay sensitivity and intradiscal antibiotic exposure in patients with chronic low back pain with Modic changes” https://persicapharmaceuticals.com/wp-content/uploads/2026/07/118.Gilligan-v3.pdf
What is the evidence for a dose-response effect in antibiotic trials for Modic changes?
Study-arm-level analysis found that higher antibiotic exposure was associated with greater improvement in pain and disability, and nominal oral dose explained most of the variability between observed oral trial outcomes.
Czaplewski L, Gilligan C, McHale D. Higher exposure to antibiotics is associated with greater clinical improvement of chronic low back pain with Modic changes. 2026; published online Sept 1. https://doi.org/10.21203/rs.3.rs-10748663/v1.
Why might intradiscal antibiotics work better than oral antibiotics?
Intradiscal therapy is designed to deliver higher antibacterial exposure directly to disc tissue while reducing prolonged systemic exposure.
Hagger G, Guest S, Birchall S, et al. Preclinical development and characterisation of PP353,a formulation of linezolid for intradiscal administration. JOR SPINE 2024; 7: e70010.
Tripathi S, Sneath R, Golash A, et al. Pharmacokinetics of PP353, a formulation of linezolid for intervertebral disc administration, in patients with chronic low back pain and Modic change Type 1: A first-in-human, Phase 1b, open-label, single-dose study. JOR SPINE 2024; 7: e70009.
Lassen M, Scarborough M, Gilchrist N, Tripathi S, Price C. Intradiscal linezolid (PP353) treatment for chronic Low Back Pain associated with Modic Change type 1: a first-in-human, randomised, sham procedure-controlled, double-blinded, international phase 1b clinical trial. eClinicalMedicine 2026; published online Feb 2. DOI:10.1016/j.eclinm.2026.103764.
What is PP353?
PP353 is an intradiscal linezolid therapy being developed as a next-generation approach for chronic low back pain associated with Modic changes.
Hagger G, Guest S, Birchall S, et al. Preclinical development and characterisation of PP353,a formulation of linezolid for intradiscal administration. JOR SPINE 2024; 7: e70010.
Tripathi S, Sneath R, Golash A, et al. Pharmacokinetics of PP353, a formulation of linezolid for intervertebral disc administration, in patients with chronic low back pain and Modic change Type 1: A first-in-human, Phase 1b, open-label, single-dose study. JOR SPINE 2024; 7: e70009.
Lassen M, Scarborough M, Gilchrist N, Tripathi S, Price C. Intradiscal linezolid (PP353) treatment for chronic Low Back Pain associated with Modic Change type 1: a first-in-human, randomised, sham procedure-controlled, double-blinded, international phase 1b clinical trial. eClinicalMedicine 2026; published online Feb 2. DOI:10.1016/j.eclinm.2026.103764.
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