This systematic review and meta-analysis of seven studies including 22655 patients compared clinical outcomes of culture-negative and culture-positive sepsis or septic shock patients. We found that only about 40.1% of patients with sepsis or septic shock had a culture-positive infection. Culture-negative and culture-positive patients with sepsis or septic shock demonstrated similar mortality. The all-cause mortality was about 29.2% and we did not identify there was statistically significant difference in the all-cause mortality between culture-negative and culture-positive groups. Clinical picture of laboratory values and vital signs had only fair discrimination between culture- negative and culture-positive patients and that culture-negative and culture-positive patients had mostly similar risk factors for death[20].
Why should patients presenting with a clinical syndrome of sepsis or septic shock have culture-negative infection? First, the patients may have been prescribed empirical antibiotics at local clinics before sepsis or septic shock developed [23]. The most important predictor of culture negativity was receipt of antibiotics within the preceding forty-eight hours[20]. Second, the proportion of sepsis or septic shock cases caused by atypical pathogens, including fungal and viral infections, might be increasing [24, 25]. Conventional microbiological methods frequently not succeed in identifying a microorganism due to various reasons related to technical issues or intrinsic to the microorganism. Promising researches using polymerase chain reaction (PCR) methods showed that microbial deoxyribonucleic acid (DNA)could be rapidly detected in blood of septic patients and could detect potentially significant fungi and bacteria not retrieved from blood culture [26, 27]. In addition, sputum cultures had a quite low positivity rate, but bronchial aspiration could enhance the possibility of identifying the causative pathogens [28].Third, many patients having culture-negative sepsis or septic shock might actually have noninfectious causes, such as metabolic disorders, tissue injuries, inflammatory diseases, adverse effects of drugs, malignancies and subarachnoid hemorrhage [29, 30].
Besides all-cause mortality, culture-negative and culture-positive patients with sepsis or septic shock demonstrated similar ICU length of stay, mechanical ventilation requirements and renal replacement requirements in our meta-analysis. However, The hospital length of stay and mechanical ventilation duration of culture-positive group were both longer than that of the culture-negative group. These differences are likely due to differences in patient populations, proportions of the sites of infection, and resistance of the bacteria to antibiotics. The longer mechanical ventilation duration and hospital length of stay that we observed in culture-positive patients are likely attributed to the greater occurrence of risk factors, such as older age, higher proportion of malignancies and higher Acute Physiology and Chronic Health Evaluation II(APACHE II) Score. Since sepsis and septic shock are heterogeneous syndromes, the sites of infection were also quite different between the two groups. Previous retrospective studies demonstrated that culture-positive patients with intra-abdominal and lung infections were associated with poor clinical outcomes[31, 32]. However, urinary tract infections were associated with better clinical outcomes than that of the others[33]. We consider that culture negativity might imply susceptibility to the initial antibiotic regimens prescribed, leading to a lesser severity of disease. In addition, the clinical outcomes may be associated with not only the infection sources but also the management of the sepsis and septic shock.
What are the implications of our meta-analysis’s results? The Surviving Sepsis Campaign guidelines recommended early administration of broad-spectrum antibiotics in an effort to improve outcomes in culture-negative or culture-positive sepsis[34]. Every hour of delay in the administration of effective antibiotics from the onset of septic shock will result in increased mortality [35].Since there is no difference in the mortality between culture-negative and culture-positive sepsis and septic shock, early antimicrobial therapy is deemed appropriate among culture-negative septic patients if they are consistent with national guidelines for the clinical syndrome. Multiplex PCR amplification techniques should be used for the quantification of fungi, viruses and bacteria to elucidate the true-negative and false-negative rates of cultures [36, 37].If pathogens are not detected interventional laboratory tests should be used to escalate, continue, narrow, or cease antibiotics coupled with a search for noninfectious causes [38].
There are several limitations in our meta-analysis. First, the number of included cohort studies is small. Further large-scale clinical studies should be conducted in order to confirm these results. Second, many of the secondary outcomes such as ICU length of stay, hospital length of stay, mechanical ventilation requirements, mechanical ventilation duration and renal replacement requirements were not included in all of the studies examined in this meta-analysis. Third, there was still substantial heterogeneity among the included cohort studies. Very heterogeneous populations were included in both retrospective and prospective cohort studies. Therefore, our results should be interpreted with caution.