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.

The Bråten (AIM) 2019 trial was not a superior trial to Albert 2013: why antibiotic exposure changes the interpretation

Abstract

The 2019 Bråten AIM trial is often considered superior to Albert 2013 because it was newer, multicentre, and larger overall. This interpretation overlooks differences in population and antibiotic exposure. AIM included 118 patients with Modic change type 1 (MC1; 58 amoxicillin, 60 placebo), whereas Albert randomised 162 MC1 patients (90 co-amoxiclav, 72 placebo). AIM administered 0.75 g amoxicillin every eight hours; Albert evaluated 0.5 g and 1.0 g regimens. A new study-arm-level analysis identified a strong exposure-response association between oral dose, modelled intradiscal probability of target attainment (PTA), and 12-month improvements in pain and disability. Estimated MIC₉₀ PTA was 36.4% for AIM's regimen and 56.4% for 1.0 g every eight hours, meaning AIM achieved approximately 65% of the higher-dose PTA. AIM should therefore be interpreted as an intermediate-exposure trial, not a definitive test of higher-dose oral amoxicillin. Meta-analyses should account for dose and target-site exposure.

Albert vs Bråten

The 2019 AIM trial by Bråten and colleagues is often treated as the definitive test of antibiotics for chronic low back pain associated with Modic changes.¹ That interpretation usually rests on three observations: AIM was newer, multicentre, and recruited 180 participants.

From this perspective, AIM appears methodologically superior to the 2013 Albert trial,² and its conclusion - that amoxicillin did not provide a clinically important benefit - is often presented as outweighing the earlier positive result.

But this comparison overlooks two important questions:

1. Were the directly comparable patient populations actually larger in AIM?

2. Did the trials test equivalent antibiotic exposures?

The answer to both is NO.

A new study-arm-level exposure-response analysis provides a pharmacological explanation for the apparently conflicting outcomes (Czaplewski et al., 2026).³ Rather than showing that Albert's result failed to replicate, the evidence suggests that the trials occupy different positions on an antibiotic exposure-response curve.

AIM was not the larger study for the directly comparable population

AIM randomised 180 participants overall: 118 with Modic change type 1 (MC1) and 62 with Modic change type 2 (MC2). The groups were analysed both together and separately.

The Albert trial enrolled only patients with MC1. It randomised 162 participants: 90 to co-amoxiclav and 72 to placebo.

For the directly comparable MC1 population, therefore, the relevant sample sizes were Albert 162 vs Bråten 118. 

AIM was larger only when its biologically distinct MC1 and MC2 groups were combined.

For the MC1 population studied by Albert, the Albert trial was larger.

Being newer and multicentre remains relevant to study appraisal, but these characteristics do not automatically make AIM the more informative trial for estimating the effect of oral amoxicillin in MC1 patients.

The trials did not test the same antibiotic exposure

Albert evaluated co-amoxiclav at two amoxicillin doses:

• 0.5 g every eight hours

• 1.0 g every eight hours

The Albert 2013 publication pooled the two active-dose groups for its principal treatment comparison, although it reported a trend towards greater efficacy with the double dose. The new exposure-response analysis separated the dose groups using dose-specific data.

AIM used an intermediate regimen:

• 0.75 g amoxicillin every eight hours

AIM therefore did not reproduce Albert's highest-exposure regimen. It tested a dose between Albert's low- and high-dose groups and used treatment for 90 rather than 100 days.

This distinction is crucial. A trial of 0.75 g three times daily cannot determine the clinical result achievable with 1.0 g three times daily if intradiscal exposure increases meaningfully with dose.

Probability of target attainment reveals a substantial exposure gap

Probability of target attainment (PTA) estimates the proportion of patients expected to achieve a predefined pharmacodynamic target against Cutibacterium acnes at the proposed infection site.

See Czaplewski et al., 2026: Higher exposure to antibiotics is associated with greater clinical improvement of chronic low back pain with Modic changes

The exposure-response paper modelled free intradiscal amoxicillin exposure and estimated MIC₉₀ PTA as follows:

Oral regimen	Estimated MIC90 PTA
0.5 g every eight hours	12.95%
0.75 g every eight hours	36.42%
1.0 g every eight hours	56.35%

The AIM regimen achieved an estimated PTA of approximately 36.4%, compared with 56.4% for Albert's 1.0 g regimen. AIM's PTA was therefore only about 65% of the PTA achieved by the 1.0 g regimen.

Neither oral regimen reached the commonly used population benchmark of at least 90% PTA. This suggests that oral delivery itself may have difficulty producing reliable antibacterial exposure within a poorly vascularised disc.

Nevertheless, the difference between 36.4% and 56.4% is substantial. AIM tested a regimen expected to achieve the target in only a little over one-third of patients. It should therefore not be treated as an estimate of the maximum benefit potentially achievable with oral amoxicillin.

The missing variable was exposure

AIM reported a small treatment effect overall. At 12 months, the adjusted between-group difference in RMDQ was -1.6 points. In its MC1 subgroup, however, the difference was -2.3 points in favour of amoxicillin, with a 95% confidence interval of -4.2 to -0.4.

AIM regarded this as below its predefined threshold for clinical importance. Yet the direction and intermediate magnitude of the finding are consistent with what the exposure-response analysis would predict from an intermediate dose.

Findings of the new exposure-response study

Across oral study arms, higher nominal dose and higher modelled intradiscal PTA were both significantly associated with greater 12-month improvements in pain and disability. The associations were statistically significant in all four oral models.

Within the oral dataset:

• Nominal dose explained 99.9% of between-arm variation in pain improvement.

• Nominal dose explained 98.3% of between-arm variation in disability improvement.

• MIC₉₀ PTA explained 88.7% of variation in pain and 91.1% in disability.

This produces a coherent ordering:

placebo -> 0.5 g -> 0.75 g -> 1.0 g

Clinical improvement increased as estimated exposure increased. AIM did not sit outside this pattern. It occupied the intermediate exposure position and produced an intermediate clinical response.

That is not a failed replication of an equivalent intervention. It is a result consistent with a previously unrecognised exposure-response relationship.

The 1.0 g outcome was reproduced in a much larger cohort

The interpretation is strengthened by the 2017 open-label study, which treated 1,024 patients with co-amoxiclav at 1.0 g every eight hours for 100 days.⁴

Although an open-label cohort does not provide the same protection against bias as a randomised placebo-controlled trial, its outcome at the 1.0 g dose was highly consistent with the corresponding Albert 2013 dose group. The exposure-response pattern also remained directionally consistent when the large 2017 cohort was excluded from sensitivity analyses.

The 2017 study is not a substitute for randomisation. However, the reproducibility of the clinical change at the same dose is relevant evidence that should not be ignored when interpreting the oral literature.

What AIM can and cannot tell us

AIM remains an important, carefully conducted randomised trial. It provides valuable evidence about 750 mg amoxicillin three times daily in its selected population.

It does not, however, establish that:

• all oral amoxicillin regimens are clinically equivalent;

• 750 mg and 1,000 mg every eight hours produce equivalent intradiscal exposure;

• the 1.0 g regimen evaluated by Albert is ineffective;

• dose and target-site exposure can be disregarded when comparing trials.

A more precise conclusion is:

AIM found that 0.75 g amoxicillin every eight hours did not achieve its predefined clinically important benefit in the overall MC1/MC2 population. Its MC1 subgroup showed a smaller benefit than Albert 2013, consistent with its lower modelled intradiscal exposure.

This interpretation preserves AIM's findings without extending them beyond the regimen and population actually studied.

Why conventional meta-analyses can produce uncertain conclusions

Systematic reviews commonly pool antibiotic studies as though they were evaluating a single intervention.^5,6 But "antibiotics" is not an exposure level.

Combining trials that used different doses, schedules, treatment durations, drugs, routes, and patient populations can obscure a genuine exposure-response relationship. Averaging suboptimal regimens with higher-exposure regimens may underestimate the outcome associated with the latter.

The oral evidence base includes regimens with estimated PTA values far below the conventional 90% benchmark.

Meta-analyses that do not account for this may primarily answer:

What is the average outcome across several incompletely exposed regimens?

That is different from asking:

What outcome is associated with a regimen that achieves adequate antibacterial exposure in the disc?

The uncertain conclusions of previous reviews may therefore reflect pharmacological heterogeneity rather than irreconcilable clinical evidence.

A better hierarchy for interpreting the evidence

For questions about the effect of the higher oral amoxicillin dose in MC1 patients, Albert 2013 is the more directly relevant randomised study:

• It included 162 MC1 participants, compared with 118 in AIM's MC1 subgroup.

• It evaluated the 1.0 g every-eight-hours regimen.

• It identified a trend towards greater efficacy at the higher dose.

• Its 1.0 g outcome was reproduced in the large 2017 open-label cohort.

AIM should be interpreted as the principal randomised study of the intermediate 0.75 g regimen, not as a higher-quality replacement for every dose examined by Albert.

Important limitations

The exposure-response findings are compelling but not definitive proof of efficacy. The analysis used study arms rather than individual-patient data, included a small number of studies, and relied on modelled rather than directly measured intradiscal exposure. Shared study characteristics and other differences between trials could contribute to the observed pattern.

The findings should therefore be considered hypothesis-strengthening evidence. They support a pharmacologically coherent reinterpretation of the literature and identify dose and intradiscal target attainment as variables that future trials must address directly.

This analysis also does not justify routine or unsupervised antibiotic treatment for chronic low back pain. Prolonged antibiotic use carries individual risks and contributes to antimicrobial resistance. Clinical use requires appropriate evidence, patient selection, safety oversight, and antimicrobial stewardship.

The conclusion should change

The oral antibiotic literature should no longer be reduced to "Albert was positive, whereas the superior AIM trial was negative."

The more accurate interpretation is:

• Albert 2013 was the larger randomised study in the directly comparable MC1 population.

• AIM used a lower dose than Albert's 1.0 g regimen and achieved only about 65% of its modelled PTA.

• AIM's intermediate clinical outcome was consistent with its intermediate exposure.

• The 1.0 g outcome was reproducible in the 2017 open-label cohort.

• Differences in pain and disability outcomes were strongly associated with dose and modelled intradiscal exposure.

AIM remains valuable evidence, but it is not an adequate estimate of what can be achieved with the higher oral regimen. For oral amoxicillin in MC1 disease, Albert 2013 should remain the reference randomised study for the 1.0 g three-times-daily dose.

The next generation of studies should not ask merely whether an antibiotic was administered. They should establish whether the regimen can achieve an appropriate pharmacodynamic target within the disc.

1          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.

2          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.

3          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.

4          Albert HB. Antibiotic treatment of patients with chronic low back pain and Modic changes. Schmerzmed 2017; 33: 49–52.

5          Wong AYL, Mallow GM, Pinto SM, et al. The efficacy and safety of oral antibiotic treatment in patients with chronic low back pain and Modic changes: A systematic review and meta-analysis. JOR Spine 2024; 7: e1281.

6 Liu C, Abdel Shaheed C, Braten LC, et al. Antibiotic treatment for low back pain, radicular pain, or both. Cochrane Database Syst Rev 2026; 4: CD014221.

FAQs

Was the AIM trial larger than Albert 2013?

AIM was larger only when patients with Modic change types 1 and 2 were combined. In the directly comparable Modic type 1 population, AIM included 118 participants, whereas Albert 2013 included 162.

Did AIM replicate Albert's highest amoxicillin dose?

No. AIM used 0.75 g every eight hours. Albert evaluated 0.5 g and 1.0 g every eight hours.

What was the estimated PTA for each regimen?

The estimated MIC₉₀ PTA was 36.4% for 0.75 g every eight hours and 56.4% for 1.0 g every eight hours. AIM's PTA was therefore approximately 65% of that of the higher-dose regimen.

Does the exposure-response analysis prove antibiotics are effective?

No. It is a study-arm-level analysis based partly on modelled exposure and cannot establish causality. It provides a pharmacologically coherent explanation for heterogeneity and supports further adequately exposed trials.

Why might previous meta-analyses be inconclusive?

Pooling regimens with substantially different doses and target-site exposure can dilute the apparent outcome of higher-exposure treatment. Future evidence syntheses should account for dose, schedule, route, and PTA.

Why negative disc cultures do not always exclude low-burden infection

Abstract

Studies of bacteria in intervertebral discs often appear contradictory, but variation in assay sensitivity may explain much of this inconsistency. Our scoping review examined methodological factors affecting the detection of low-burden bacteria, including tissue mass, homogenisation, dilution, plated fraction, anaerobic conditions, incubation time, quantitative methods, and prophylactic antibiotics. Protocols varied markedly, while reporting was often insufficient to estimate detection limits, restricting the interpretation of negative cultures and contamination claims. Two large studies using comparatively sensitive methods found viable Cutibacterium acnes in approximately 36% of 658 surgically excised discs, with around 10-11% of all specimens exceeding 1,000 CFU. Their findings were supported by quantitative culture, PCR, and direct microscopic visualisation of intratissue biofilms. Together, the evidence suggests that C. acnes in some discs cannot be dismissed solely as contamination. Future studies should explicitly report assay sensitivity and sufficient methodological detail to establish what negative results can reliably exclude.

Assay sensitivity:

Studies examining bacteria in intervertebral disc tissue have often been presented as contradictory (Gilligan et al., 2021). Some report finding bacteria in disc samples, while others report sterile cultures or interpret positive findings as contamination. It is easy to read this as a simple disagreement about whether bacteria are really present.

But that may be the wrong level at which to interpret the literature.

Our latest paper looks at a more basic question: how sensitive were the microbiology methods used in these studies?

Assay sensitivity and the interpretation of culture-based disc microbiology studies: a scoping review by Lloyd G Czaplewski, Vincent A. Fischetti, Holger Brüggemann, Chris Gilligan, Duncan McHale^.

In a low-bioburden setting, that question matters a great deal. If bacterial populations are small, then whether a study detects them may depend heavily on assay design rather than biology alone.

We reviewed published culture-based disc microbiology studies and examined methodological features known to affect analytical sensitivity, including tissue sample mass, tissue disruption, dilution volume, plated fraction, anaerobic culture conditions, incubation duration, use of quantitative methods and use of prophylactic antibiotics. Where enough detail was reported, we estimated approximate lower limits of detection and quantitation to compare the likely sensitivity of different protocols.

The main finding was that published methods varied markedly in their expected ability to detect low-burden bacterial populations. Only a minority of studies reported enough methodological detail for sensitivity to be estimated with any confidence, and formal lower limits of detection or quantitation were generally absent.

That matters because negative culture results are only as informative as the assay's ability to detect low-burden infection.

A sterile culture does not automatically exclude bacteria if the method used was not sensitive enough to recover them reliably. The same applies to contamination-based interpretations: in low-burden settings, those conclusions should also be considered in the context of assay design and detection capability.

This does not mean every positive culture is genuine infection, or that contamination is never a concern. It does mean that both positive and negative findings need to be interpreted with more methodological caution than is sometimes applied.

The broader message is simple. Some of the apparent disagreement in the disc microbiology literature may reflect differences in analytical sensitivity, not just differences in biology. Studies that use larger tissue samples, lower homogenization volumes, sufficient plated material, appropriate anaerobic conditions, longer incubation, and quantitative reporting would be expected to be more sensitive than those that do not. Furthermore, the use of prophylactic antibiotics that penetrate the disc prior to tissue harvest may reduce the apparent bioburden.

For that reason, future disc microbiology studies should report assay sensitivity clearly and explicitly. Authors, reviewers, and editors should expect the methodological detail needed to judge what a negative result can actually exclude.

A more accurate reading of the literature is not simply that some studies find bacteria and others do not. It is that the ability to detect low-burden infection may differ substantially between studies, and that this should shape how both sterile results and contamination-based interpretations are understood.

Considering microbiological methodology, we found that the two studies published by Capoor et al., "Prevalence of Propionibacterium acnes in Intervertebral Discs of Patients Undergoing Lumbar Microdiscectomy: A Prospective Cross-Sectional Study (2016)" and "Propionibacterium acnes biofilm is present in intervertebral discs of patients undergoing microdiscectomy" (2017) most likely to provide the best current estimates for low burden bacterial presence in disc tissue beacuse they provide the most detailed quantitative data available on this question.

Importantly, these studies did not rely on a single detection method. Instead, they combined quantitative culture, molecular detection of bacterial DNA, and direct microscopic visualization of bacteria within disc tissue, allowing the same hypothesis to be tested using independent approaches. 

How often was C. acnes found in disc tissue?

The 2016 study analysed disc tissue from 290 patients undergoing lumbar microdiscectomy and cultured C. acnes from 115 specimens, representing 39.7% of patients. 

The subsequent 2017 study analysed 368 additional patients and identified C. acnes in 119 specimens, representing 32.3% of patients. 

Combined, the two studies examined 658 surgically excised disc specimens, of which 234 were positive for C. acnes, corresponding to an overall prevalence of approximately 36%. 

In other words, across two of the largest studies ever performed in this field, roughly one in three herniated discs contained viable C. acnes.

How many bacteria were present?

An important strength of these studies is that they did not simply record whether cultures were positive or negative. They quantified bacterial burden.

In the 2016 study, C. acnes counts ranged from 100 to 9,000 CFU/ml, with a median value of 400 CFU/ml. Thirty-nine patients, representing 11% of the entire cohort, had bacterial burdens of at least 1,000 CFU/ml, which the investigators classified as abundant growth. 

In the 2017 study, bacterial counts ranged from 12 to 20,952 CFU/g, with a median burden of 350 CFU/g. Thirty-eight patients, corresponding to 10.3% of the study population, had counts exceeding 1,000 CFU/g. 

Across both studies, positive specimens therefore showed bacterial burdens spanning almost four orders of magnitude, from a few dozen organisms to more than twenty thousand colony-forming units. Median burdens were remarkably consistent at approximately 350-400 CFU, while around 10-11% of all surgical specimens contained relatively high bacterial burdens exceeding 1,000 CFU. 

Evidence from three independent methods

Perhaps the most compelling aspect of these studies is the convergence of findings from three independent methodologies.

1. Quantitative culture demonstrated viable bacteria

Both studies used anaerobic culture protocols specifically designed to improve recovery of biofilm-associated organisms. Disc tissues were homogenised before culture to disrupt bacterial aggregates and release viable organisms. Using these methods, C. acnes was repeatedly identified as the dominant bacterial species present within disc tissue. 

2. PCR confirmed bacterial DNA within the same tissues

The 2016 study independently quantified C. acnes genomes using real-time PCR. The investigators demonstrated a statistically significant correlation between culture-based bacterial counts and bacterial genome counts measured by PCR (r = 0.4363, p < 0.0001). Discs with higher culture burdens also contained significantly greater numbers of bacterial genomes. 

This is important because it shows agreement between two fundamentally different measurement techniques. The culture results were not occurring in isolation but were mirrored by independent molecular evidence of bacterial presence. 

3. Histology and fluorescence microscopy visualised biofilms in situ

The 2017 study extended these findings further by directly visualising bacteria within disc tissue.

Using confocal laser scanning microscopy, fluorescence staining, and fluorescence in situ hybridisation (FISH) with C. acnes-specific probes, the investigators examined disc samples with high bacterial burdens. Bacterial biofilms were visualised in seven of eight culture-positive specimens, while FISH confirmed that the organisms within these structures were C. acnes. 

Crucially, the bacteria were observed within the interior of disc tissue rather than being confined to tissue surfaces. The authors argued that this distribution was inconsistent with simple perioperative contamination and more consistent with bacteria residing within the disc itself. 

Why triangulation matters

Every microbiological method has limitations when considered in isolation.

Culture can miss biofilm-associated organisms. PCR can detect DNA from non-viable bacteria. Histological techniques may identify organisms but not always determine their viability.

However, when multiple independent methods point to the same conclusion, confidence in that conclusion increases substantially.

In these studies:

• Viable C. acnes organisms were cultured from disc tissue. 

• C. acnes DNA was detected and quantified using PCR. 

• C. acnes biofilms were directly visualised inside disc tissue using microscopy and species-specific FISH probes. 

The convergence of culture, molecular and microscopic evidence provides a stronger case for genuine intradiscal colonisation or infection than any single technique could provide alone.

Take-home message

A review of these two landmark studies shows that approximately 36% of surgically excised lumbar disc specimens contained cultured C. acnes. Bacterial burdens ranged from roughly 12 to more than 20,000 colony-forming units, with median counts around 350-400 CFU, and approximately 10-11% of discs contained high bacterial burdens exceeding 1,000 CFU. 

Most importantly, these findings were supported by three independent lines of evidence: quantitative culture, quantitative PCR, and direct microscopic visualisation of C. acnes biofilms within disc tissue.

Taken together, these studies suggest that the presence of C. acnes in at least a subset of herniated discs cannot be dismissed solely as contamination and warrants continued investigation as a biologically relevant phenomenon.

Gilligan CJ, Cohen SP, Fischetti VA, Hirsch JA, Czaplewski LG. Chronic low back pain, bacterial infection and treatment with antibiotics. The Spine Journal 2021; 21: 903–14.

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.

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.

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.

Assay sensitivity and disc microbiology FAQs:

What did the assay-sensitivity analysis examine?

This analysis reviewed culture-based disc microbiology studies and looked at methodological features that affect analytical sensitivity.

The goal was to assess whether differences in microbiological methods could help explain why some studies detect bacteria while others report sterile findings or dismiss positive findings as contamination.

Which methodological factors were considered?

The analysis looked at factors such as:

• tissue sample mass

• tissue disruption methods

• dilution volume

• the fraction of material plated

• anaerobic culture conditions

• incubation duration

• use of quantitative methods

• use of prophylactic antibiotics

• 
  

Where enough information was available, approximate lower limits of detection and lower limits of quantitation were also estimated.

What did the analysis find?

It found that published microbiology protocols varied markedly in their expected ability to detect low-burden bacterial populations.

Only a minority of studies reported enough methodological detail for assay sensitivity to be estimated with confidence, and formal limits of detection or quantitation were generally absent.

What does that mean in simple terms?

A sterile culture does not automatically prove that bacteria were absent.

In a low-burden setting, a negative result may mean either:

• no bacteria were present, or

• the assay was not sensitive enough to detect a small bacterial population

Does this mean every positive culture proves infection?

No.

This analysis does not say that every positive result proves infection or that contamination is never a concern.

It says that both negative cultures and contamination-based interpretations should be judged in light of what the assay was actually capable of detecting.

Why have microbiology findings appeared inconsistent?

One likely explanation is differences in detection capability.

If one protocol is much more sensitive than another, one study may detect low-burden bacteria while another reports sterile cultures, even if the underlying biology is not fundamentally contradictory.

What is the fairest summary of this microbiology literature?

A fair summary may be:

Negative disc cultures do not automatically exclude low-burden infection, and contamination-based interpretations should be assessed in the context of assay sensitivity and study design.

Why does this matter for future microbiology research?

Future studies should report enough detail for analytical sensitivity to be judged, including:

• tissue mass analysed

• disruption and homogenization methods

• dilution volume

• plated fraction

• anaerobic conditions

• incubation duration

• quantitative methods

• estimated assay sensitivity, including limits of detection where possible

• use of prophylactic antibiotics

Without that information, it is difficult to know what a negative result can confidently exclude.

Lloyd Czaplewski is Chief Scientific Officer at Persica Pharmaceuticals Ltd