Discussion
Bacterial culture is the ‘gold standard' for the identification of pneumonia pathogens (17). In this study, the rate of isolation of bacterial agents of pneumonia was 67.1%, which is in agreement with others (18) and higher than others, with rates of 35% and 42% (19, 20). However, the rate reported here was lower than the one reported by Olwagen et al. (21) of 71%. Obviously, the rate of positive bacterial cultures varies widely by studies and countries and is dependent on sampling techniques, storage, culture, incubation, and temperature used, for which standardized techniques are required when working with such specimens (17). In addition, the present study was conducted with patients with severe pneumonia, which explains why the rate of isolated bacteria was so high.
The present study showed that severe CAP caused by S. pneumoniae (and other microorganisms) was common, mainly in children under 2 years of age, and followed by 2–5 years. This finding is consistent with what is in literature, with many studies recognizing that children under 5 years of age are more susceptible to pneumonia than older children, and tend to suffer a worse prognosis of the disease (18, 22). The proportion of boys with severe CAP due to pneumococci was higher than in girls, a finding which is in agreement with other studies (23, 24). Of the children with severe CAP, 93.3% did not have pneumococcal immunization status and only three (1.3%) were vaccinated. However, all these three were infected with pneumococci, which begs the question of which S. pneumoniae serotypes infected the children in the study group and that matched the serotypes of the vaccine used? This is also a limitation of this study, which is being implemented as a follow-up study in this area. A study in a northern province of Vietnam identified eight serotypes of S. pneumoniae isolated from unvaccinated children under 5 years of age with pneumonia, including 19F, 23F, 19A, 6A/B, 15A, 9V, 11A, and 14 (25).
The present study showed that most children with CAP caused by S. pneumoniae had peripheral blood oxygen saturation (SpO2) ≤ 96%. Some recent studies have shown that there are no signs or symptoms sufficient to confirm pneumonia in children, but diagnostic specificity can be improved when some clinical features, such as tachypnoea, fever, and hypoxia, are present (26, 27). A decline in SpO2 is also a valuable parameter for diagnosing pneumonia. According to Shah et al. (28), the presence of moderate hypoxaemia and increased breathing effort are the most relevant signs of pneumonia. In the present study, wheezing was less common in children infected with S. pneumoniae than in those infected by other microorganisms. A previous study demonstrated that wheezing was more common in atypical or viral pneumonia than in typical bacterial pneumonia (29).
The present study suggests that WBC is not a reliable indicator of the severity of the disease (Table 1), which is consistent with a previous study showing that WBC was a poor indicator of the etiology and severity of pneumonia (24). Esposito et al. (30) highlighted that WBC count had the lowest positive predictive value compared to procalcitonin and CRP. The present study found that up to 65.2% of children with severe CAP due to S. pneumoniae had an increase in CRP levels >10 mg/L. CRP is also considered an acute-phase reactant associated with disease severity in children with bacterial infection (31).
In this study, the majority of S. pneumoniae isolates were identified as MDR, with 98.9% of the isolates completely non-susceptible to penicillin and others. In recent years, the proportion of penicillin non-susceptible pneumococci has increased to over 60% (7–9). Consequently, penicillin is no longer the first-line antibiotic for children with severe CAP in many countries; clinicians are using cefotaxime and ceftriaxone, a third-generation cephalosporin, instead (32, 33). In this study, the rate of S. pneumoniae resistant to ceftriaxone was only 16.9%; however, the percentage of intermediate resistance was 46.0%. This result raises great concern about the likelihood of first-line antibiotic failure. When comparing the sensitivity of antibiotics between the two groups of ceftriaxone-susceptible and ceftriaxone-non-susceptible S. pneumoniae, ceftriaxone-non-susceptible strains were still sensitive to vancomycin (100%), linezolid (100%), and chloramphenicol (93.8%). A previous study on antimicrobial susceptibility testing for isolated S. pneumoniae also showed a low susceptibility rate to all antibiotics except vancomycin (100%), linezolid (100%), and levofloxacin (89.5%) (34). According to the results of a study conducted by Sweden et al., the proportion of MDR S. pneumoniae susceptible to vancomycin and levofloxacin was 100% (16). However, chloramphenicol is rarely used orally and intravenously in Vietnamese children due to its common side effects such as blood dyscrasias, aplastic anemia, and leukemia (35, 36). Therefore, vancomycin and linezoild may be suitable alternative antibiotics for severe MDR pneumococcal pneumonia.
Macrolide antibiotics have become less effective against S. pneumoniae, with high resistance rates reported in the present study for erythromycin (96.6%) and clarithromycin (88.8%). Other studies have found that S. pneumoniae is more resistant to macrolides and does not support the routine combination of β-lactam antibiotics with macrolides (16, 37). However, in contrast, other studies have suggested that macrolide combination therapy is more effective than β-lactam monotherapy, especially in children >5 years of age or in atypical bacterial co-infections with pathogens such as Mycoplasma pneumoniae (38, 39).
Analysis of the distribution of MIC, MIC50, and MIC90 among the studied S. pneumoniae isolates revealed that penicillin had an eight-fold increase in MIC90 (64 mg/L). This finding suggests that ceftriaxone is more suitable than penicillin for the initial treatment of severe CAP caused by S. pneumoniae. However, based on our study findings, an increase in the dose of ceftriaxone is needed, as evidenced by the 1.5-fold increase in MIC90 for this antibiotic in this study. Recommendations for how much to increase the dose depends on the pharmacokinetic/pharmacodynamic (pK/pD) breakpoint, which is another interesting follow-up to this study. In recent years, many recommendations have been made to increase the therapeutic dose of ceftriaxone to 100 mg/kg/day for severe infections or in places with insignificant penicillin resistance (≥25%) (33, 40).
In the present study, the fluoroquinolones, ciprofloxacin and levofloxacin, had a fairly wide MIC range of 0.18–128 and 0.18–24 mg/L, respectively. These results suggest that it may be difficult to choose a therapeutic dose of ciprofloxacin. Moreover, if a strain of S. pneumoniae was not susceptible to ceftriaxone, it was likely that it would not be susceptible to ciprofloxacin, although the rate of ciprofloxacin susceptibility to S. pneumoniae was 59.6%. Although there have been very few reports of treatment failure with ciprofloxacin, this antibiotic was not considered a “respiratory fluoroquinolone” in the United States (41). Indeed, the CLSI does not provide ciprofloxacin breakpoints for S. pneumoniae (14). Furthermore, ciprofloxacin is not recommended for the treatment of respiratory tract infections in most treatment guidelines (33, 42). In fact, the systemic use of fluoroquinolones in patients under 18 years is not recommended in many countries due to eventual adverse musculoskeletal effects (43). Therefore, extreme caution should be exercised when using ciprofloxacin to treat children with severe CAP.
Author contributions
Conceptualization, resources, and investigation: KT-Q, TN-T-D, HT-D, and VP-H. Software: HT-D, BT-X, ML, and SD-Q. Formal analysis: TN-T-D, SD-Q, HT-D, TN-V, BT-X, and ML. Manuscript writing, review, and editing: KT-Q, TN-T-D, HT-D, TN-V, BT-X, ML, and SD-Q. All authors have read, commented upon, and approved the final manuscript.