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

Vertebral osteomyelitis is an infectious disease that can develop 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 route of antibiotic administration. 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].

Identification of the causative bacteria and the use of appropriate antibiotics are necessary to achieve successful treatment and favorable outcomes 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 PVO often shows negative in the microbiological culture test [7, 8]. The guidelines for the choice and preferred route of antibiotic administration for culture-negative PVO have not been well established owing to insufficient relevant research result, 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 compare culture-negative PVO and culture-positive PVO in terms of clinical characteristics, use of antibiotics, assessment of therapeutic response, and outcomes.

The rate of causative bacterial identification varies as reported in the previous literatures [7, 11, 13], 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 CN group vs. 20/32 in CP group, p = 0.194). There are still debates on the influence of empirical antibiotics before tissue culture on the microbiological diagnostic yield [14‐17]. In addition, the rate of causative bacterial identification in PVO varies with 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 sufficient specimen quantity from the accurate area of the infectious lesion. In multivariate logistic regression analysis, the presence of epidural abscess was the most powerful statistically significant predictor of causative bacterial identification. PVOs with epidural abscess were more likely to present neurological deficits such as leg pain or weakness. These may require a surgical treatment for removing epidural abscess to relieve neurological symptoms, which also allows obtaining a sufficient quantity of proper specimen, thus leading to increased microbiological diagnostic yield despite the use of empirical antibiotics in advance.

In laboratory data, the initial CRP level 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 [11, 13, 18]. Kim et al. [18] showed that culture-positive PVO is more likely to be associated with body temperature ≥ 37.8 °C, higher initial ESR and CRP, and the presence of paraspinal abscess. In this study, similar results were presented with a larger extent of the affected lesion, presence of epidural abscess, worse back pain, and higher initial CRP level in the CP group. Among the regimens of antibiotics, more frequent use of quinolone as an effective antibiotic in the CN group also supports these results. We performed serial follow-up of ESR, CRP, and VAS score of back pain. By the 3rd month, the CRP level 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 of back pain at 3 months between the two groups. We assume that the mechanical stress on the injured intervertebral disc and endplates as well as the restoration process of the PVO lesion, which may result in the persistent elevated ESR and VAS score of back pain. The values of ESR, CRP, and VAS score of 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, CRP, and VAS score of back pain are meaningful and can help assess therapeutic response and decide regarding discontinuation of parenteral antibiotics or changing to oral antibiotics.

The recurrence rates reported in previous literatures have varied greatly. McHenry et al. [19] reported a recurrence rate of 14% in 253 patients, Park et al. [10] of 9.9% in 314 patients, and Kim et al. [18] 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, 20‐23]. Some studies reported that less than 6-8 weeks of antibiotic therapy may be associated with an increased risk of recurrence [18, 19, 24, 25]. Compared to the results of many previous literatures, our results showed relatively longer duration of antibiotics and lower recurrence rate of 6.8%. Kim et al. [18] 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 expect prolonged antibiotic therapy to be helpful in preventing recurrence. As mentioned above, culture-negative PVO shows fewer infectious signs and lower values of inflammatory markers, which may also be associated with a shorter duration of parenteral antibiotic therapy than in culture-positive PVO. However, as higher CRP level is usually associated with a higher risk of treatment failure in PVO, switching from parenteral antibiotics to oral antibiotics may be favorable in cases with lower CRP level [18, 26]. We think that the assessment of therapeutic response based on laboratory data allows for shortening the duration of parenteral antibiotics and hospital stay with favorable outcomes, particularly, under an environment with low rates of causative bacterial identification. 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 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 unnecessary use of antibiotics. To overcome these limitations, further studies with a larger number of participants under a prospective design are required.

Culture-negative PVO required a shorter duration of parenteral antibiotics and enabled changing to oral antibiotics compared to culture-positive PVO in terms of achieving 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. The presence of epidural abscess was the most significant factor for the identification of causative bacteria in PVO, which is associated with obtaining sufficient proper specimen via surgical culture.