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95

J Gandhara Med Dent Sci

October - December 2026

ORIGINAL ARTICLE

How to cite this article

EMPIRICAL ANTIBACTERIAL THERAPY FOR CULTURE-NEGATIVE PYOGENIC

SPONDYLODISCITIS: FUNCTIONAL AND RADIOLOGICAL OUTCOMES AND THE ROLE OF

TISSUE DIAGNOSIS

Abdul Satar

1

, Muhammad Zahid Khan

2

, Samir Khan Kabir

2

Satar A, Khan MZ, Kabir SK.

Empirical Antibacterial Therapy for

Culture-Negative Pyogenic

Spondylodiscitis: Functional and

Radiological Outcomes and the Role

of Tissue Diagnosis. J Gandhara Med

Dent Sci. 2026;13(4): 95-102.

Date Submission:

21-08-2026

Date Revised:

04-09-2026

Date Acceptance:

05-09-2026

2

Assistant Professor, Department of

Orthopedics and Spine Surgery,

Hayatabad Medical Complex,

Peshawar

Correspondence

1

Abdul Satar,

Professor, Department of

:

Orthopedics and Spine Surgery,

Hayatabad Medical Complex,

Peshawar

+92-333-9396005

satardr@yahoo.com

ABSTRACT

OBJECTIVES

This study aimed to determine the ecacy of empirical antibacterial treatment

of

culture-negative

pyogenic

spondylodiscitis

in

terms

of

functional

and

radiological

outcomes,

with

secondary

assessment

of

pain,

inammatory

response, treatment failure, recurrence, and requirement for surgery.

METHODOLOGY

A

prospective

observational

cohort

design

was

used

at

the

Department

of

Orthopaedics

and

Spine

Surgery,

Hayatabad

Medical

Complex,

Peshawar.

Adults with clinical, biochemical, and magnetic resonance imaging ndings

compatible with native pyogenic spondylodiscitis, negative blood cultures, and

no immediate indication for surgery were included. Patients with suspected

tuberculosis, brucellosis, postoperative infection, malignancy, hemodynamic

instability, or progressive neurological compromise were excluded. Empirical

therapy was selected to cover staphylococci, streptococci, and aerobic Gram-

negative bacilli. Functional status was measured using the Oswestry Disability

Index (ODI), pain with the Visual Analogue Scale (VAS), and inammatory

response using C-reactive protein (CRP) and erythrocyte sedimentation rate

(ESR).

Assessments

were

performed

at

baseline,

6

weeks,

3 months,

and

6

months. Two readers independently classied the six-month MRI. Longitudinal

outcomes were analysed using linear mixed-eects models.

RESULTS

Sixty-four patients entered the empirical-treatment cohort, and 61 completed

6-month follow-up. Mean age was 50.3 ± 12.0 years, and 39 patients (60.9%)

were male. Mean ODI decreased from 62.7 ± 9.7 at baseline to 25.2 ± 13.4 at

6 months; the adjusted mean reduction was 37.38 points (95% CI 35.46–39.29;

p<0.001). Mean VAS decreased from 7.62 ± 0.62 to 2.23 ± 1.20, corresponding

to an adjusted reduction of 5.39 points (95% CI 5.17–5.61; p<0.001). Median

CRP declined from 70.4 mg/L to 5.7 mg/L, while mean ESR decreased from

75.8 ± 16.2 to 26.0 ± 17.2 mm/hour. Favorable MRI response was observed in

54/61 patients (88.5%; 95% CI 78.2–94.3), and overall treatment success was

achieved in 56/61 (91.8%; 95% CI 82.2–96.4).

CONCLUSION

A structured antibacterial

pathway improved patient outcome, supporting a

non-biopsy

approach

when diagnosis

is

clear,

blood

cultures

are

negative,

other

serious

conditions

are

excluded,

and

multidisciplinary

monitoring

is

present. However, tissue diagnosis remains crucial for diagnostic uncertainty

or empirical treatment failure.

KEYWORDS:

Pyogenic

Spondylodiscitis;

Native

Vertebral

Osteomyelitis;

Culture-Negative Infection; Empirical Antibacterial Therapy; Tissue Biopsy;

Oswestry Disability Index; Magnetic Resonance Imaging

INTRODUCTION

Pyogenic

spondylodiscitis

is

an

infection

of

the

intervertebral disc and adjacent vertebral endplates that

is generally considered within the clinical spectrum of

native

vertebral

osteomyelitis.

Although

uncommon

relative

to

degenerative

spinal

disorders,

its

clinical

importance

is

disproportionate

because

delayed

diagnosis

may

result

in

persistent

pain,

vertebral

destruction,

epidural

extension,

neurological

impairment,

deformity,

prolonged

antimicrobial

exposure,

and

the

need

for

operative

treatment.

1,2

Population-based data demonstrate an increasing burden

of

vertebral

osteomyelitis,

particularly

among

older

adults and patients with diabetes, chronic kidney disease,

immunosuppression,

repeated

healthcare

exposure,

or

invasive

procedures.

3

Long-term

follow-up

studies

further show that residual pain and neurological decits

http://doi.org/10.37762/jgmds.13-4.984

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J Gandhara Med Dent Sci

October - December 2026

may persist even after infection control.

4

The diagnosis

is frequently challenging because clinical presentation is

nonspecific. Severe or progressive spinal pain is the most

consistent

symptom,

while

fever

may

be

absent

and

leukocytosis is neither suciently sensitive nor specic

to

exclude

disease.

1,2

ESR

and

CRP

are

more

useful

inammatory markers and provide practical information

during

both

diagnostic

evaluation

and

treatment

monitoring.

MRI

is

the

imaging

modality

of

choice

because it can identify vertebral marrow abnormalities,

intervertebral

disc

involvement,

endplate

destruction,

epidural extension, and paravertebral or psoas soft-tissue

disease.

1,5

Microbiological

identication

remains

a

central

principle

of

management.

The

Infectious

Diseases

Society

of

America

recommends

obtaining

appropriate

blood

cultures

and,

when

a

causative

organism has not been established, performing image-

guided aspiration or biopsy in

patients

with

suspected

native

vertebral osteomyelitis

whenever feasible.

1

In a

hemodynamically stable patient with stable neurological

findings,

empirical

antibacterial

therapy

is

generally

deferred while reasonable attempts are made to obtain

microbiological

conrmation.

This

strategy

permits

organism-directed

treatment,

facilitates

antimicrobial

stewardship, detects resistant

pathogens, and assists in

distinguishing

bacterial

infection

from

tuberculosis,

brucellosis,

fungal

infection,

malignancy,

and

inammatory

mimic.

1,5

The

practical

limitation

is

that

tissue

sampling

does

not

invariably

establish

an

organism. In a

10-year

study of image-guided biopsy,

Maamari

et

al.

demonstrated

that

diagnostic

yield

remains imperfect and is inuenced by factors such as

prior

antimicrobial

exposure

and

sampling

characteristics.

6

More recently, Winkler et al. evaluated

570

image-guided

core

biopsies

and

found

positive

microbiological

cultures

in

29.6%,

although

biopsy

osteomyelitis

and

emphasised

the

usefulness

of

pain,

ESR, and CRP trajectories in monitoring response.

10

Lee

et

al.

subsequently

reported

a

structured

treatment

protocol for 183 patients with culture-negative pyogenic

vertebral

osteomyelitis,

including

nonsurgical

and

surgical

pathways

selected

according

to

neurological

status,

abscess

burden,

and

mechanical

stability.

11

A

2026 cohort study likewise found that culture-negative

status

was

not

independently

associated

with

worse

recurrence or mortality when patients received adequate

treatment.

12

The

key

clinical

issue

is

therefore

not

whether microbiological diagnosis is valuable. It is clear,

however,

whether

an

initial

tissue

diagnosis

is

indispensable for successful treatment in every patient

with

a

convincing

culture-negative

pyogenic

presentation.

This

question

is

especially

relevant

in

resource-constrained

settings,

when

biopsy

is

unavailable

or

delayed,

when

the

procedure

is

technically dicult,

when prior

treatment

may

reduce

yield, or when patients decline invasive sampling. At the

same time, a non-biopsy pathway is only defensible if

important

alternative

diagnoses

are

rigorously

considered

and

predened

triggers

exist

for

rescue

biopsy

or

surgery

when

treatment

response

is

inadequate. The study was undertaken to determine the

efcacy

of

empirical

antibacterial

therapy

for

culture-

negative

pyogenic

spondylodiscitis

in

terms

of

functional

and

radiological

outcomes.

Secondary

objectives were to quantify longitudinal changes in

pain

inuenced

clinical

management

in

37.5%.

7

These

findings demonstrate that tissue biopsy can be clinically

valuable even when culture yield is modest, but they also

explain why a substantial subgroup of patients remains

culture-negative

despite

appropriate

investigation.

Culture-negative

native

vertebral

osteomyelitis

is

therefore increasingly recognised as a distinct diagnostic

and

therapeutic

challenge.

A

2024

narrative

review

emphasised

prior

antimicrobial

therapy,

low

pathogen

burden,

fastidious

organisms,

technical

sampling

limitations,

and

noninfectious

mimics

as

major

contributors

to

culture-negative

disease.

5

More

recent

work has highlighted the potential role of 16S ribosomal

RNA

polymerase

chain

reaction,

next-generation

sequencing,

and

microbial

cell-free

DNA

testing

in

selected

culture-negative

cases,

although

accessibility,

cost,

interpretation,

and

specicity

remain

practical

limitations.

8

Clinical outcome data nevertheless suggest

that

culture

negativity

does

not

necessarily

imply

treatment

failure.

Kim

et

al.

found

that

clinically

diagnosed

culture-negative

pyogenic

vertebral

osteomyelitis

had

outcomes

broadly

comparable

with

microbiologically conrmed disease.

9

Yu et al. similarly

reported comparable recurrence rates between

culture-

negative and culture-positive lumbar pyogenic vertebral

and

inammatory

markers

and

to

determine

rates

of

treatment success, treatment failure, recurrence, rescue

tissue sampling, and unplanned surgery.

METHODOLOGY

This

prospective

observational

cohort

study

was

conducted in the Department of Orthopaedics and Spine

Surgery,

Hayatabad

Medical

Complex,

Peshawar,

Pakistan

(October

2025February

2026,

with

6-month

follow-up).

The

Institutional

Research

and

Ethical

Committee approved the study (Approval No. 2884, 30

September 2025). Sample size was based on an estimate

of

the

favorable

treatment-response

proportion.

Assuming

an

expected

response

of

90%,

a

95%

confidence

level,

and

absolute

precision

of

8%,

approximately 54 evaluable participants were required.

Allowing for attrition, recruitment of at least 60 patients

was

targeted.

Consecutive

adults

(≥18

years)

with

suspected

native

pyogenic

spondylodiscitis

were

enrolled if they had new/worsening spinal pain, elevated

ESR/CRP,

characteristic

MRI

ndings

(disc

and

Empirical Antibacterial Therapy for Culture

97

J Gandhara Med Dent Sci

October - December 2026

adjacent

endplate

involvement),

and

≥2

negative

aerobic/anaerobic

blood

culture

sets

before

empirical

therapy. Patients with suspected tuberculous, brucellar,

or

fungal

infection;

postoperative/implant-related

infection;

malignancy;

positive

blood

cultures;

hemodynamic

instability;

uncontrolled

sepsis;

severe/progressive

neurological

decit;

major

instability;

or

compressive

epidural

abscess

needing

urgent

decompression

were

excluded.

Demographics,

symptom

duration,

comorbidities,

prior

infection/antimicrobial exposure, and neurological status

were recorded, along with CBC, ESR, CRP, renal/liver

function, and blood cultures. TB/brucellosis testing was

added

when

clinically

indicated;

atypical

cases

were

excluded

from

the

pyogenic

pathway.

MRI

of

the

affected

region

was

obtained

in

all

patients,

with

epidural/paravertebral

involvement

documented

separately.

Antibacterial

therapy

(typically

IV

vancomycin

plus

ceftriaxone,

or

cefepime

for

broader

Gram-negative

coverage;

alternatives

are

available

for

allergy/renal

impairment/resistant

colonisation)

targets

S.

aureus

(including

MRSA),

streptococci,

and

Gram-

negative

bacilli,

as

per

IDSA

guidance.

Patients

responding clinically/biochemically were transitioned to

oral therapy; total duration was ~6 weeks, extended as

needed.

Evidence

for

very

early

oral

transition

specifically

in

native

vertebral

osteomyelitis

remains

limited,

and

route

changes

were

therefore

made

conservatively.

13

Failure

to

improve

prompted

CT-

guided

or

operative

tissue

sampling

for

microbiology/histopathology. Surgery was reserved for

neurological

deterioration,

instability,

deformity,

uncontrolled

infection,

or

intractable

pain.

Although

early

surgery

may

be

advantageous

in

appropriately

selected

patients,

the

cohort

was

restricted

to

those

suitable

for

initial

conservative

management.

Assessments occurred at

baseline, 6

weeks, 3 months,

and

6

months,

including

ODI

(0100),

VAS

(010),

ESR, and CRP.

14

The primary outcomes were change in

ODI and proportion with favorable MRI response at 6

months

(assessed

by

two

blinded

readers

as

marked

improvement/partial

improvement/stable/progression).

Secondary

outcomes

included

VAS/ESR/CRP

trends,

treatment

success/failure,

recurrence,

rescue

biopsy,

unplanned

surgery,

adverse

events,

and

mortality.

RESULTS

Eighty-six

patients

with

suspected

pyogenic

spondylodiscitis

were assessed

for

eligibility. Twenty-

two

were

excluded

before

entry

into

the

empirical-

treatment

cohort:

eight

because

tuberculosis

was

confirmed, three because brucellosis was identied, four

because

blood

cultures

established

an

organism

requiring

targeted

treatment,

two

because

of

postoperative

or

implant-associated

infection,

three

because an immediate surgical indication was present,

and

two

because

another

diagnosis,

including

malignancy,

was

considered

more

likely.

Sixty-four

patients

commenced

the

empirical-treatment

pathway.

All

were

available

at

the

6-week

and

3-month

assessments,

while

three

were

lost

before

nal

evaluation.

Consequently,

61

patients

(95.3%)

completed

the

6-month

clinical

and

radiological

assessment.

Figure

1:

Participant

Flow

Through

Screening,

Empirical

Treatment, and 6-Month Follow-Up.

Isolated

persistent

osseous

MRI

abnormalities

did

not

constitute

failure.

Treatment

success

required

completion

of

therapy

without

infection-related

death,

unplanned

surgery,

or

recurrence

at

6

months;

failure

was dened as progression requiring rescue diagnosis,

major

regimen

change,

unplanned

surgery,

or

recurrence. Analyses used SPSS v27. Signicance was

set at p<0.05.

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J Gandhara Med Dent Sci

October - December 2026

Table

1:

Baseline

Demographic,

Clinical,

Laboratory,

and

Radiological Characteristics of the Empirical-Treatment Cohort

(n=64).

Characteristic

Value

Age,

years,

50.3  12.0

Gender

Male

39 (60.9)

Female

25 (39.1)

Symptom

duration,

weeks, median (IQR)

4.4

(3.6 - 5.5)

Fever at presentation

14 (21.9)

Diabetes mellitus

19 (29.7)

Hypertension

28 (43.8)

Current smoking

11 (17.2)

Lumbar involvement

43 (67.2)

Thoracic involvement

16 (25.0)

Cervical involvement

05 (7.8)

Multilevel disease

12 (18.8)

Epidural

inammatory

component

26 (40.6)

Paravertebral/psoas

component

18 (28.1)

Baseline ODI, mean 

SD

Baseline

VAS,

mean

 SD

Baseline

ESR,

mm/hour, mean  SD

Baseline

CRP,

mg/L,

median (IQR)

70.4

Abbreviations:

SD,

standard

deviation;

IQR,

interquartile

range;

ODI,

Oswestry

Disability

Index;

VAS,

Visual

Analogue

Scale;

ESR,

erythrocyte

sedimentation rate; CRP, C-reactive protein.

mean 

S

D

62.7  9.7

7.62  0.62

75.8  16.2

(49.4 - 88.7)

Figure 2: Longitudinal change in Oswestry Disability Index. Points

Represent

Observed

Means

and

Error

Bars

Represent

Approximate 95% Condence Intervals

Pain

severity

showed

a

consistent

decline,

with

mean

VAS

scores dropping

from

7.62



0.62

at

baseline

to

4.69  0.88 at 6 weeks, 3.45  1.08 at 3 months, and 2.23

 1.20 at 6 months. Mixed-eects analysis indicated a

significant reduction of 5.39 points (95% CI 5.175.61;

p<0.001)

over

6

months,

reecting

meaningful

improvements

in

function

and

symptoms.

Mean

ESR

decreased from 75.77 

16.22

mm/hour

at baseline

to

42.94  17.14 at 6 weeks, 32.37  18.56 at 3 months, and

26.03  17.18 at 6 months, yielding an adjusted reduction

of 49.46 mm/hour (95% CI 47.0351.89; p<0.001). CRP

levels dropped rapidly,

with median values decreasing

from 70.39 mg/L (IQR 49.3988.73) at baseline to 17.25

mg/L (IQR 13.1624.64) at 6 weeks, 9.03 mg/L (IQR

6.1812.06) at 3 months, and 5.65 mg/L (IQR 3.817.85)

at 6 months. Log-transformed mixed-eects modelling

indicated

a

6-month

geometric

mean

ratio

of

0.087

relative

to

baseline

(95%

CI

0.0810.093;

p<0.001),

signifying about a 91% relative reduction in CRP.

Table

2:

Longitudinal

Functional,

Pain,

and

Inammatory

Outcomes

Outcome

Baseline

6

weeks

3

months

6

months

Adjusted

6 - month

eect

(95% Cl)

p-value

VAS,

7.62

 0.62

4.69

 0.88

3.45

2.23

 1.08

 1.20

−

5.39

(−5.61

to −5.17)

<0.001

ESR,

mm/hour,

75.77

 16.22

42.94

32.37

26.03

−

49.46

 17.14

 18.56

 17.18

(−51.89

to

<0.001

CRP, mg/L,

median

(IQR)

70.39

(49.39

 88.73)

17.25

(13.16

24.64)

9.03

(6.18

 12.06)

5.65

(3.81

 7.85)

GMR

0.087

(0.081

 0.093)

<0.001

Mixed-eects

models

used

time

as

a

xed

eect

and

participant

as

a

random

intercept.

CRP

was

log-

transformed; its eect is reported as a geometric mean

ratio (GMR).

mean  SD

ODI,

mean  SD

62.67

 9.71

 11.86

 11.23

−

(−39.29

to −35.46)

43.13

32.53

 13.38

25.24

37.38

<0.001

− 47.03)

At

the

6-month

MRI

assessment,

37

of

61

patients

(60.7%) demonstrated marked

radiological improvement

and 17 (27.9%) demonstrated partial improvement. Four

patients

(6.6%)

had

stable

abnormalities

without

convincing evidence of active progression, while three

(4.9%)

demonstrated

radiological

progression.

The

combined

favorable

radiological

response

rate

was

therefore

54/61

patients

(88.5%;

95%

CI

78.294.3).

Interobserver

agreement

for

the

four-category

MRI

response

classication

was

substantial

to

excellent

(weighted

kappa=0.84).

Soft-tissue

inammatory

components

generally

resolved

more

clearly

than

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J Gandhara Med Dent Sci

October - December 2026

residual

disc-space

narrowing,

endplate

destruction,

sclerosis, or marrow-signal abnormality. This pattern is

clinically

relevant

because

persistent

osseous

abnormalities may remain visible after infection control

and

should

not

be

interpreted

as

treatment

failure

in

isolation.

15,16

-

Figure 3: Distribution of Radiological Response Categories on 6

Month MRI

Overall

treatment

success

was

achieved

in

56

of

61

evaluable

patients

(91.8%;

95%

CI

82.296.4).

Five

patients

met

the

prespecied

denition

of

treatment

failure.

Three

ultimately

underwent

operative

intervention

because

of

progressive

neurological,

structural, or infection-control concerns. Two underwent

rescue

tissue

sampling

because

of

inadequate

clinical

and

biochemical

response;

outcome

categories

may

overlap.

DISCUSSION

The principal nding of this

study is that a structured

empirical

antibacterial

pathway

was

associated

with

substantial

improvement

in

disability,

pain,

inammatory

activity,

and

MRI

ndings

among

carefully

selected

patients

with

culture-negative

pyogenic spondylodiscitis. More than 90% of evaluable

patients met the predened criteria for overall treatment

success,

and

88.5%

demonstrated

a

favorable

MRI

response

at

6

months.

Mean

ODI

improved

by

approximately 37 points and mean VAS by more than

five points, accompanied by marked declines in CRP and

ESR.

These

ndings

are

consistent

across

functional,

symptomatic,

biochemical,

and

radiological

domains.

Current IDSA guidance recommends blood cultures and

image-guided biopsy when the causative organism has

not

been

established,

particularly

in

patients

who

are

neurologically

and

hemodynamically

stable.

1

Tissue

diagnosis

can

identify

resistant

pathogens,

narrow

antibacterial therapy, distinguish pyogenic disease from

tuberculosis,

fungal

infection,

or

malignancy,

and

support

antimicrobial

stewardship.

The

present

study

addresses

a

narrower

question:

whether

successful

treatment

is

achievable

in

selected

culture-negative

Empirical Antibacterial Therapy for Culture

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J Gandhara Med Dent Sci

October - December 2026

patients

when

initial

tissue

diagnosis

is

unavailable,

deferred,

or

nondiagnostic.

This

distinction

matters

because

the

diagnostic

yield

of

biopsy

is

variable.

Winkler et al. reported positive cultures in 29.6% of 570

image-guided core biopsies, although the results altered

management in 37.5% of cases.

7

Maamari et al. similarly

documented incomplete diagnostic yield and identied

procedural

and

clinical

factors

inuencing

biopsy

success.

6

A negative or unobtained biopsy therefore does

not

eliminate

the

need

to

treat

a

convincing

pyogenic

infection, but imperfect culture yield likewise does not

diminish

the

diagnostic

value

of

sampling

when

it

is

feasible. The present ndings are broadly consistent with

prior

culture-negative

cohorts.

Kim

et

al.

reported

a

treatment-failure

rate

of

9.2%

among

clinically

diagnosed

culture-negative

pyogenic

vertebral

osteomyelitis,

compared

with

17.3%

among

microbiologically conrmed cases, a dierence that did

not

reach

statistical

signicance.

9

Yu

et

al.

reported

recurrence rates of 7.3% and 6.3% in culture-negative

and

culture-positive

patients,

respectively,

and

highlighted ESR, CRP, and VAS as informative markers

of treatment response.

10

In the present cohort, treatment

failure occurred in 8.2% of patients

and recurrence in

3.3%, gures that align closely with these earlier reports.

Research

by

Lee

et

al.

(2022)

supports

a

stratied

approach

to

culture-negative

pyogenic

vertebral

osteomyelitis,

successfully

managing

it

non-surgically

or surgically based on neurological decit, abscess size,

and

mechanical

stability.

11

Dogan

et

al.

also

found

empirical antibiotics eective, suggesting a non-biopsy

strategy

for

some

patients.

17

Sako

et

al.

observed

that

while

culture-negative

vertebral

osteomyelitis

had

milder

inammation,

its

recurrence

and

one-year

mortality

rates

were

similar

to

culture-positive

cases

when

adequately

treated;

culture

status

did

not

independently

predict

outcomes.

12

Collectively,

these

studies

indicate that prognosis hinges

more

on patient

factors,

anatomical

severity,

infection

control,

and

treatment eectiveness than on culture status alone. This

study's

focus

on

functional

recovery

is

critical.

The

signicant drop in average ODI from around 63 to 25,

mirrored

by

VAS

score

improvements,

demonstrates

substantial

disability

reduction.

This

highlights

that

successful treatment in spinal infection extends beyond

just

eradicating

the

infection.

Gupta

et

al.

reported

persistent back pain and neurological decits in many

patients

long-term,

underscoring

the

value

of

patient-

reported

outcomes

like

ODI,

which

capture

crucial

clinical

information

beyond

laboratory

results.

4

Inflammatory markers followed expected patterns, with

CRP

rapidly

decreasing

and

ESR

declining

more

gradually, consistent with previous ndings supporting

their

use

in

monitoring.

1,10

However,

these

markers

should not be interpreted in isolation: a rising CRP with

worsening

symptoms

demands

reassessment,

while

mild,

persistent

ESR

elevation

in

an

otherwise

improving patient does not necessarily signal treatment

failure.

The

empirical

antibacterial

regimen

was

designed to reect the most probable bacterial spectrum.

Park et al. identied

methicillin-susceptible

S.

aureus,

MRSA,

Enterobacteriaceae,

and

streptococci

as

the

predominant organisms in microbiologically conrmed

hematogenous vertebral osteomyelitis and demonstrated

substantial

theoretical

coverage

with

vancomycin

combined with ceftriaxone, ceftazidime, or cefepime.

18

This

provides

a

rational

basis

for

broad

empirical

coverage where clinically necessary, although regimens

should

always

be

adapted

to

local

resistance

patterns,

renal function, prior healthcare exposure, allergy history,

and

individual

risk

of

resistant

organisms.

The

treatment-duration

framework

used

in

this

study

also

warrants contextualisation. Bernard et al. demonstrated

that 6 weeks of antibacterial therapy was noninferior to

12

weeks

for

clinical

cure

in

microbiologically

confirmed pyogenic vertebral osteomyelitis.

19

Although

this trial does not directly establish 6 weeks as optimal

in culture-negative disease, it supports this duration as a

reasonable

initial

framework

when

clinical

and

biochemical response

is

satisfactory.

Longer durations

have

been

used

in

other

culture-negative

cohorts,

and

extension remains appropriate when disease is extensive,

drainage is inadequate, response is delayed, or diagnostic

uncertainty

persists.

9,10,11

The

radiological

ndings

require

careful

interpretation.

Although

88.5%

of

patients

demonstrated

a

favorable

MRI

response,

residual structural abnormalities were common. Ahn et

al. showed that CRP correlates more closely with soft-

tissue

change

and

ESR

with

bony

change

during

recovery,

while

Hecquet

et

al.

similarly

demonstrated

discordance

between

radiological

and

clinical-

biochemical

recovery.

15,16

Persistent

endplate

destruction,

sclerosis,

or

disc-space

narrowing

should

therefore

not,

in

isolation,

be

classied

as

treatment

failure in a patient who is otherwise improving clinically

and biochemically. The 6-month MRI in this study was

employed as a research outcome measure rather than as

a recommendation for routine imaging in all responding

patients.

These

ndings

indicate

that

tissue

diagnosis,

while

important,

is

not

indispensable

for

successful

outcomes

in every carefully selected patient, since a high

proportion

of

patients

achieved

favorable

outcomes

without

initial

microbiological

conrmation.

Tissue

diagnosis

nonetheless

remains

essential

whenever

presentation

is

atypical,

an

alternative

infectious

or

neoplastic process is plausible, resistant pathogens are a

concern,

or

empirical

therapy

fails.

The

appropriate

interpretation is therefore that an empirical pathway may

be suitable for a dened subgroup of patients, not that

biopsy

should

be

routinely

omitted.

This

position

is

Empirical Antibacterial Therapy for Culture

101

J Gandhara Med Dent Sci

October - December 2026

increasingly

relevant

given

advances

in

molecular

diagnostics.

Pourghazi

et

al.

(2026)

described

the

potential

of

16S

rRNA

PCR,

next-generation

sequencing,

and

microbial

cell-free

DNA

assays

to

supplement

conventional

culture

in

native

vertebral

osteomyelitis.

8

Techniques

aimed

at

reducing

culture-

negative

cases

may

improve

targeted

therapy

after

conventional

diagnostic

failures.

Until

they

become

standard,

well-defined

clinical

pathways

are

essential

when

a

causative

organism

remains

unidentied.

Treatment failures in ve patients highlight the need for

close

monitoring;

this

pathway

should

not

rely

on

a

passive

"treat

and

wait"

approach.

Symptoms

like

persistent severe pain, rising CRP, or new neurological

findings

should

trigger

swift

tissue

diagnosis

and

surgical intervention. In this group, biopsy and operative

management

were

crucial

to

the

treatment

algorithm.

These insights are particularly relevant in

tertiary-care

settings

with

limited

access

to

image-guided

biopsy,

given

that

conditions

like

tuberculosis

and

brucellosis

are

signicant

dierential

diagnoses.

Empirical

antibacterial treatment

should

proceed

with

caution

to

avoid

misclassifying

tuberculous

spondylodiscitis

as

culture-negative pyogenic disease, which could lead to

delayed

diagnosis

and

preventable

complications.

A

risk-stratified

approach

is

advisable:

clinically

stable

patients with MRI-confirmed pyogenic spondylodiscitis

and

negative

blood

cultures

may

be

considered

for

empirical therapy without immediate tissue diagnosis if

closely monitored. Lack of clinical improvement should

prompt tissue sampling and surgical consultation instead

of continuing broad-spectrum therapy.

LIMITATIONS

This

study

has

several

limitations:

its

single-center,

observational

design

limits

generalizability

and

causal

inference.

The

absence

of

a

contemporaneous

comparator group with systematic pretreatment biopsy

means it cannot prove noninferiority of omitting tissue

diagnosis.

Without

pretreatment

tissue

conrmation,

diagnostic misclassication is possible, especially where

atypical infections like tuberculous spondylodiscitis are

common. The cohort was limited to patients suitable for

initial conservative treatment, so findings may not apply

to

those

with

septic

shock,

neurological

compromise,

instability, or urgent surgical needs. The small number

of

treatment

failures

prevented

reliable

multivariable

modeling.

Finally,

6

months

of

follow-up

may

be

insucient

to

capture

late

recurrences

or

long-term

functional issues.

CONCLUSIONS

Empirical

antibacterial

treatment

eectively

improved

outcomes

in

select

patients

with

culture-negative

pyogenic

spondylodiscitis,

leading

to

signicant

reductions in disability, pain, and inammation, along

with

improved

MRI

ndings.

After

six

months,

approximately

90%

of

patients

demonstrated

overall

treatment success and favorable radiological responses.

This indicates

that

successful

treatment

without

initial

tissue diagnosis is feasible for clinically stable patients

exhibiting

characteristic

imaging,

negative

blood

cultures, carefully considered alternative diagnoses, and

multidisciplinary

monitoring.

Nevertheless,

tissue

diagnosis remains vital when the diagnosis is uncertain,

atypical infection or malignancy is suspected, resistant

pathogens are a

concern, or empirical treatment proves

unsuccessful. Thus, while not always necessary, initial

tissue conrmation remains a crucial diagnostic tool.

CONFLICT OF INTEREST:

None

FUNDING SOURCES:

None

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CC-BY-NC-SA 4.0

).

COPYRIGHTS:

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AUTHORS CONTRIBUTION

The authors accept responsibility for all aspects of the work

and will ensure that any concerns regarding the accuracy or

integrity of any part are properly investigated and resolved.

Abdul

Satar

-

Concept

&

Design;

Data

Acquisition;

Data

Analysis/Interpretation; Drafting Manuscript;

Critical Revision;

Supervision; Final Approval

Muhammad Zahid Khan -

Concept & Design; Data Acquisition;

Data

Analysis/Interpretation;

Drafting

Manuscript;

Critical

Revision; Supervision; Final Approval

Samir Khan Kabir -

Concept & Design; Data Acquisition; Data

Analysis/Interpretation; Drafting Manuscript;

Critical Revision;

Supervision; Final Approval

Empirical Antibacterial Therapy for Culture