Antimicrobial therapy and assessing therapeutic response in culture-negative pyogenic vertebral osteomyelitis: a retrospective comparative study with culture-positive pyogenic vertebral osteomyelitis

Abstract

Background

There are still controversies over the treatment and outcomes in culture-negative pyogenic vertebral osteomyelitis (PVO). The purpose of this study is to investigate the antimicrobial therapy, assessment of therapeutic response, and outcome of culture-negative PVO compared to culture-positive PVO.

Methods

Retrospective study was performed with non-surgical lumbar PVO. The patients were divided into two groups based on the causative bacterial identification (CN group with culture-negative and CP group with culture-positive). The clinical features, use of antibiotics, laboratory data, and outcomes were compared between the two groups.

Results

Seventy-three patients with 41 (56.2%) of the CN group and 32 (43.8%) of the CP group were enrolled. Group CN showed a shorter duration of parenteral antibiotics (45.88 ± 16.14 vs. 57.31 ± 24.39, p = 0.019) although a tendency of prolonged duration of total (parenteral + oral) antibiotics (101.17 ± 52.84 vs. 84.19 ± 50.29 days, p = 0.168). When parenteral antibiotics were discontinued or switched to oral antibiotics, erythrocyte segmentation rate (ESR, normal range: < 20 mm/h), C-reactive protein (CRP, normal range: < 0.5 mg/dL), and visual analogue scale (VAS) score for back pain were 42.86 ± 24.05 mm/h, 0.91 ± 1.18 mg/dL, and 4.05 ± 1.07, respectively, with no significant differences between the two groups. The recurrence rates of CN and CP groups were 7.3% (3/41) and 6.3% (2/32), respectively (p = 1.000).

Conclusions

CN group required a shorter duration of parenteral antibiotics than CP group. Discontinuation of parenteral antibiotics or changing administration route can be considered based on the values of ESR, CRP, and VAS score for back pain.

Background

Vertebral osteomyelitis is an infectious disease can be developed by pyogenic, tuberculous, or brucellar causes [1]. The annual incidence of hospitalization with pyogenic vertebral osteomyelitis (PVO) in the United States between 1998 and 2013 rose from 2.9 to 5.4 per 100,000 individuals [2]. There is still no clear guidance regarding the duration and administration route of antibiotics. Generally, an extended course of parenteral antibiotics followed by a maintenance course of oral antibiotics is required in the treatment of PVO [3–5]. Infectious Diseases Society of America (IDSA) recommends 6 weeks of parenteral or highly bioavailable oral antimicrobial therapy for bacterial native vertebral osteomyelitis [6].

The causative bacterial identification and the use of appropriate antibiotics are necessary to achieve successful treatment and favorable outcome in PVO. Despite a lot of effort, it is not always possible to identify the causative microorganism in clinical practice. About 50% of patients with PVO are treated with empirical antibiotics because it is negative in the microbiological culture test [7]. The guidelines for the choice and preferred administration route of antibiotics for culture-negative PVO have not been well established owing to insufficient relevant research results, which is originated in the variety of causative microorganisms and rate of antibiotic resistance depending on the regions. Herein, we conducted a retrospective study to investigate the clinical characteristics, use of antibiotics, assessment of therapeutic response, and outcome of culture-negative PVO compared to culture-positive PVO.

Methods

Patients and data collection

 This retrospective study was performed at a single tertiary-care university hospital from October 2014 to September 2018 and 118 patients diagnosed as lumbar PVO. Patients were excluded if they had tuberculous spondylitis, tumors, postoperative development, accompanying bone infection at another site, trauma, pregnancy, concomitant severe medical problems, less than six months of follow-up period, or age <19 years. All clinical and radiological data were obtained and reviewed retrospectively from electronic charts under the approval of the institutional review board.

Diagnosis of PVO

 PVO was diagnosed based on clinical symptoms, laboratory data, and radiological findings. The clinical symptoms included fever and back pain with or without radiating pain. Elevated erythrocyte segmentation rate (ESR, normal range: < 20 mm/h) or C-reactive protein (CRP, normal range: < 0.5 mg/dL) or both along with specific magnetic resonance (MR) findings of PVO as a contiguous single lesion was an important clue for diagnosis of PVO. The PVO lesion comprised the upper and lower vertebrae around the infected disc with or without epidural, psoas, and paraspinal abscesses, and was defined as one level (e.g., if there were two infected discs, three vertebrae were included centering on the two infected discs, which were defined as two levels).

Causative bacterial identification

Patients diagnosed as PVO were divided into two groups according to the results of causative bacterial identification. The microbiological diagnosis was confirmed through more than two sets of blood culture or tissue culture for the PVO lesion by computed tomography (CT)-guided needle biopsy or open surgical biopsy. Patients with clinical symptoms and radiological findings indicative of PVO but without confirmation of causative bacterial identification were defined as the culture-negative group (CN group), and other patients in whom the causative microorganism was identified were defined as the culture-positive group (CP group).

Cure and recurrence

Patients were considered cured when they had absence of fever, improved clinical symptoms, and a sustained trend of normalized CRP during the follow-up period of at least six months after discontinuation on antibiotic therapy. Recurrence was defined as re-elevation of ESR and/or CRP, and the development of new or aggravation of existing PVO lesion on MR imaging, and recurred back pain and/or neurological symptoms with/without fever [8].

Functional and laboratory evaluations

All patients underwent the evaluation of clinical status and laboratory tests for the initial three months after the diagnosis of PVO and starting antibiotic therapy. Visual analog scale (VAS) scores for back pain and laboratory data, including ESR and CRP at initial (at the time of diagnosis), 1-week, 1-month, and 3-month were compared between the two groups. VAS was used to estimate back pain, with 0 representing no pain to 10 representing maximum pain. The levels of ESR and CRP when parenteral antibiotics were discontinued or switched to oral antibiotics were measured and compared between the two groups.

Statistical analysis

The Student’s t-test and the Mann-Whitney U test were used to compare parametric and non-parametric continuous variables, respectively. One-way analysis of variance (ANOVA) for parametric continuous variables and the Kruskal-Wallis test for non-parametric continuous variables were used to compare three population means, respectively. For categorical variables, the chi-square test was performed. Logistic regression analysis was used to investigate the clinical variables related to the identification of causative microorganisms. All clinical variables identified as statistically significant in univariate analyses were included in a multivariate analysis. Statistical analysis was carried out using SPSS version 25.0 software (SPSS Inc., Chicago, Illinois), and p values of <0.05 were considered statistically significant.

Results

Demographic and clinical data

 Among the 118 patients, 45 were excluded due to surgical related development (n=25), tuberculosis (n=12), ankylosing spondylitis (n=2), and follow-up loss (n=6). The final analyses were performed on 73 patients (44 men and 29 women) with a mean age of 64.73 ± 11.61 (42-84) years. There were no statistically significant differences in age, gender, underlying diseases, and history of spinal procedures between the two groups. However, there were statistically significant differences in the extent of affected PVO lesion [1.49 ± 0.93 (1-5) vs. 2.09 ± 1.28 (1-5) levels, p = 0.022] and the presence of epidural abscess (43.9% [18/41] vs. 84.4% [27/32], p = 0.001), except the presence of psoas muscle and paraspinal abscess. The recurrence rates were 7.3% (3/42) and 6.3% (2/32), respectively (p = 1.000). Detailed data are mentioned in Table 1.

Microorganisms and antibiotics

The rate of causative bacterial identification was only 43.8% (32/73) with 8 (25%) from blood culture, 15 (46.9%) from tissue culture of CT-guided needle or open surgical biopsy of the PVO lesion, and 9 (28.1%) from both blood and tissue cultures. According to the each methods of culture, 17 of 73 patients (23.3%) with blood, 7 of 37 patients (18.9%) with CT-guided needle biopsy, and 17 of 36 patients (47.2%) with open surgical biopsy were identified. Microbiologic findings of the 32 patients in the CP group are presented in Table 2. The most common causative microorganism was Staphylococcus aureus (40.6%, 13/32). Five cases of recurrence were noted: one with methicillin-resistant Staphylococcus epidermidis, one with Enterobacter, and three with culture-negative cases. Detailed data are mentioned in Table 2.

The regimens of antibiotics for the treatment of PVO are summarized in Table 3. Antibiotics were used before tissue culture of the PVO lesion in 71.2% cases (52/73), and there was no significant difference between the two groups (78.0% [32/41] vs. 62.5% [20/32], p = 0.194). β-Lactam and glycopeptide were used mainly as the effective antibiotics in both groups. The use of glycopeptide did not significantly differ between the two groups. However, quinolones were used statistically significantly more in the CN group (22.0% [9/41] vs. 3.1% [1/41], p = 0.036).

There was no statistically significant difference in the duration of total antibiotics between the two groups (101.17 ± 52.84 vs. 84.19 ± 50.29 days, p = 0.168). However, there were statistically significant differences in the duration of parenteral antibiotics (45.88 ± 16.14 vs. 57.31 ± 24.39, p = 0.019), oral antibiotics (55.29 ± 47.40 vs. 26.84 ± 41.10, p = 0.009), and the incidence of using oral antibiotics (75.6% [31/41] vs. 43.8% [14/32], p = 0.001) between the two groups, respectively. Detailed data are provided in Table 4.

 The clinical variables related to the causative bacterial identification are presented in Table 5. The clinical variables with statistical significance identified in a univariate logistic regression analysis were included in a multivariate logistic regression analysis. Epidural abscess and initial VAS score for back pain were statistically significant predictors.

Changes of ESR/CRP and VAS score for back pain

There were statistically significant improvements in ESR, CRP, and VAS score of both groups between initial and 3-month, respectively (p < 0.01). In ESR, there were no statistically significant differences at initial, 1-week, 1-month, and 3-month between the two groups. There were statistically significant differences in CRP (9.21 ± 7.43 vs. 15.17 ± 10.32 mg/dL, p = 0.005) and VAS score for back pain (7.41 ± 0.92 vs. 8.13 ± 1.13, p = 0.004) at initial between the two groups, respectively. However, there were no statistically significant differences in CRP and ESR at 1-week, 1-month, and 3-month between the two groups, respectively. When parenteral antibiotics discontinued or changed to oral antibiotics, there were no statistically significant differences in ESR, CRP, and VAS score for back pain between the two groups. The values of ESR, CRP, and VAS score for back pain in total patients were 44.85 ± 24.99 mm/h, 0.89 ± 1.02 mg/dL, and 3.98 ± 1.08, respectively. Detailed data are provided in Table 6 and Figure 1.

Discussion

The rate of causative bacterial identification varies as reported in the literatures [7–9], and this study showed lower rate with less than 50% compared to other reports. The result is expected to be the most relevant to the use of empirical antibiotics before tissue culture for the PVO lesion (52/73, 71.2%) due to poor general conditions, including high fever or sepsis, although blood cultures were performed in all patients before administering empirical antibiotics. However, there was no statistically significant relationship between the use of empirical antibiotics before tissue culture and the causative bacterial identification (32/41 in group CN vs. 20/32 in group CP, p = 0.194). There are still debates on the influence of empirical antibiotics before tissue culture for microbiological diagnostic yield [10–13]. In addition, the rate of causative bacterial identification in PVO varies depending on the method of culture. Generally, the rate of positive-culture is higher with an open surgical biopsy than with needle biopsy, which is related to the obtaining of sufficient specimen in the accurate area of the infectious lesion. In a multivariate logistic regression analysis, the presence of epidural abscess was the most powerful statistically significant predictor for causative bacterial identification. PVOs with epidural abscess are more likely to present neurological deficits such as leg pain or weakness. These may lead to surgical treatment for removing epidural abscess to relieve neurological symptoms, which also allows to obtaining sufficient proper specimen, thus increased microbiological diagnostic yield despite the use of empirical antibiotics in advance.

In laboratory data, the initial value of CRP was significantly lower in the CN group than in the CP group. Previous studies reported fewer infectious signs and lower values of inflammatory markers in patients with culture-negative PVO, which may have been due to small inocula of pathogens [8, 9, 14]. Kim et al. [14] showed that culture-positive PVO is more likely to be associated with body temperature ≥ 37.8ºC, higher initial ESR and CRP, and the presence of paraspinal abscess. In this study, similar results were presented as a larger extent of affected lesion, presence of epidural abscess, worse back pain, and higher initial CRP in the CP group. Among the regimens of antibiotics, more frequent use of quinolone as effective antibiotics in CN group also supports these results. We performed serial follow-up of ESR, CRP, and VAS score for back pain. By the 3rd month, the values of CRP had almost normalized and VAS scores had decreased by more than 50% of the initial scores. However, despite a tendency of continuous decline, the value of ESR remained consistently higher than normal. There were no statistically significant differences in ESR, CRP, and VAS score for back pain at 3-month between the two groups. We assume that the mechanical stress on the injured intervertebral disc and endplates in addition to the restoration process of PVO lesion, which may result in the sustaining elevated ESR and VAS score for back pain. The values of ESR, CRP, and VAS score for back pain at the time of discontinuation of parenteral antibiotics or switching to oral antibiotics were 42.86 ± 24.05 mm/h, 0.91 ± 1.18 mg/dL, and 4.05 ± 1.07, respectively. There were no statistically significant differences between the two groups. We think that the values of ESR, CPR, and VAS score for back pain are meaningful and can help assess therapeutic response and make a decision for discontinuation of parenteral antibiotics or changing to oral antibiotics.

The recurrence rates reported in the previous literatures have varied greatly. McHenry et al. [15] reported a recurrence rate of 14% in 253 patients; Park et al. [16] of 9.9% in 314 patients; and Kim et al. [14] of 6.6% in 151 patients. Unfortunately, data to guide the optimal duration of antibiotic therapy related to the recurrence of PVO are insufficient [7, 17, 18]. Some studies reported that less than 6–8 weeks of antibiotic therapy may be associated with an increased risk of recurrence [14, 15, 19, 20]. Compared to the results of previous literatures, our results showed relatively longer duration of antibiotics and lower recurrence rate of 6.8%. Kim et al. [14] reported a similar recurrence rate of 6.6% with an average of more than 100 days of the total antibiotics. Based on these results, we can expect that prolonged antibiotic therapy may be helpful in preventing recurrence. As mentioned above, culture-negative PVO shows fewer infectious signs and lower values of inflammatory markers, which may be also associated with shorter duration of parenteral antibiotic therapy than in culture-positive PVO. However, as a higher value of CRP is usually associated with a higher risk of treatment failure in PVO, switching from parenteral antibiotics to oral antibiotics may be favorable in the lower value of CRP [14, 21]. We think that the assessment for therapeutic response based on laboratory data allows for shortening the duration of parenteral antibiotics and hospital stay with favorable outcomes. However, we could not clearly explain the reasons for the frequent use and longer duration of oral antibiotics in culture-negative PVO. Considering the similar recurrence rate between the two groups, oral antibiotics are expected to prevent the recurrence despite the relatively short period of parenteral antibiotics in culture-negative PVO.

There were several limitations in this study. First, it was a retrospective study with a relatively small number of participants, which may have resulted in an underpowered statistical analysis. Second, the sample size of patients who experienced recurrence was small, and thus the statistical analysis of several factors related to recurrence was impossible. Third, false positives in the assessment of the therapeutic response requiring additional antibiotic therapy could not be accurately identified, which could have led to the use of unnecessary antibiotics. To overcome these limitations, further studies with a larger number of participants under the prospective design are required.

Conclusion

Culture-negative PVO required a shorter duration of parenteral antibiotics although a tendency of prolonged duration of total antibiotics with oral antibiotics compared to culture-positive PVO in terms of obtaining similar outcomes. Discontinuation of parenteral antibiotics or switching to oral antibiotics can be considered based on the values of ESR, CRP, and VAS score for back pain.

Abbreviations

Declarations

Ethics approval and consent to participate

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the principles of the 1964 Declaration Helsinki and its later amendments or comparable ethical standards. Written informed consent was waived due to retrospective study design under the approval of the Institutional Review Board, Yeungnam University Hospital (No. 2020-06-091).

Availability of data and materials

The datasets during and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by the National Research Foundation (NRF) of Korea grant funded by the Korea government (MSIP; Ministry of Science, ICT & Future Plan (2019M3E5D1A02068142).

Authors’ contributions

Conceptualization, funding acquisition, and supervision: IJ

Data curation, methodology, and resources: IJ, SWK, DY

Writing - original draft: DY

Writing - review & editing: IJ

All authors have read and approved the manuscript.

Acknowledgements

Not applicable

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Tables

Table 1 Demographic and clinical data

Data are presented as the mean ± standard deviation or frequency (%), CN culture negative, CP culture positive, BMI body mass index, PVO pyogenic vertebral osteomyelitis, ^a p value between group CN and CP, p values of <0.05 were considered statistically significant

Table 2 Microbiologic findings

Data are presented as frequency (%), PVO pyogenic vertebral osteomyelitis, MSSA methicillin-sensitive Stapylococcus aureus, MRSA methicillin-resistant Stapylococcus aureus, ^a Streptococcus viridians, Streptococcus pneumonia, Streptococcus bovis

Table 3 Regimens of antibiotics

Data are presented as frequency (%), ^a β-lactamase inhibitor, aminoglycoside, ^b Gentamicin and tazime, ^c Carbapenem, prepenem, and linezoid, CN culture negative, CP culture positive, ^a p value between the CN and CP groups, p values of < 0.05 were considered statistically significant

Table 4 Comparison of antibiotic treatment between the CN and CP groups

Data are presented as the mean ± standard deviation or frequency (%), CN culture negative, CP culture positive, ^a p value between group CN and CP, p values of < 0.05 were considered statistically significant

Table 5 Logistic regression analysis in the correlation between the causative bacterial identification (culture positive) and variable clinical variables

OR, odds ratio, CI confidential interval, CRP C-reactive protein (mg/dL), VAS visual analog scale, p values of <0.05 were considered statistically significant

Table 6 Changes of ESR/CRP and VAS score for back pain

ESR erythrocyte segmentation rate (mm/h), CRP C-reactive protein (mg/dL), VAS visual analogue scale, ^a p value between the CN and CP groups, p values of < 0.05 were considered statistically significant, * There is statistical significant difference compared to initial value (p < 0.01)