Optimization of antimicrobial therapy for Streptococcus pneumoniae- infected community acquired pneumonia in children at Da Nang and Quang Nam in Vietnam.
by NGUYEN Thi Nam Phong
by NGUYEN Thi Nam Phong
Introduction Streptococcus pneumoniae is the most commonly identified pathogenic factor causing community-acquired pneumonia (CAP). Empirical treatment is recommended for good coverage of S. pneumoniae. However, pneumococcal resistance varied between geographical regions, and the emergence of Multidrug-resistant S. pneumoniae (MDRS) leads to treatment failure. This study aimed to define the susceptibility of the antibiotics and the synergy of combinations used in empirical treatment at three hospitals in central Vietnam. Studied results provide clinicians with updated data about the antimicrobial resistance of S. pneumoniae, enabling them to select appropriately and safely antibiotics for the CAP treatment. In addition, for MDRS, two potential antimicrobial agents, ceftriaxone (CRO) and levofloxacin (LVX), were selected to evaluate the in vitro bactericidal, synergistic effect and pharmacokinetic/pharmacodynamic (PK/PD) parameters for optimizing antibiotic use against MDRS.
Methods This cross-sectional observational study was conducted in the middle region of Vietnam at the pediatric departments of three hospitals; specifically, Da Nang Hospital for Woman and Children (DN), Quang Nam Children’s Hospital (QN1), Pediatrics Department of General Hospital at Northern Mountain of Quang Nam (QN2) from 2017 to 2018. Nasopharyngeal aspiration (NPA) samples from 360 CAP inpatients aged 2 months to 5 years were collected. The identification of pneumococcal strains underwent steps such as observation of colony morphology, gram staining, optochin susceptibility testing, bile salt solubility, and confirmed by mass spectrometry for suspected strains. The susceptibility of commonly-used antibiotics was investigated using disk diffusion testing and the E-test method. Multi-drug resistant (MDR) S. pneumoniae strains were also determined. S. pneumoniae strains with the highest penicillin MIC (Minimum Inhibitory Concentration) were used in the synergistic determination of antimicrobial combination by E- test. Two potential antimicrobial agents, ceftriaxone (CRO) and levofloxacin (LVX) and their combinations in different concentration ratios were evaluated for bactericidal effect using time-kill experiments. PK/PD indexes were calculated to estimate the effect of therapies. From these results, several combinations with different LVX/CRO ratios, of which therapeutic concentrations were expected to be achieved, were proposed for the treatment of MDRS.
Results The rate of CAP children carrying S. pneumoniae at three hospitals was 79/360 and accounted for 21.9%. In which DN, QN1, QN2 hospitals made up 36.7, 27.8 and 35.5%, respectively. The susceptibility testing demonstrated that all 56 tested pneumococcal strains (100%) were resistant to erythromycin and azithromycin, whereas none of the strains (0%) developed the resistance to levofloxacin, vancomycin, and linezolid. The rates of clindamycin- and cotrimoxazole-resistant pneumococci were 96.4 and 87.5%, respectively. For β-lactam antibiotics, the susceptible percentages of pneumococcal strains to penicillin G, co-amoxiclav, amoxicillin, cefotaxime, and ceftriaxone were 91.1%, 78.6%, 85.7%, 89.3%, and 51.8%, respectively. Percent of pneumococcal strains with antibiotic-corresponding MIC values were included penicillin MIC ≤ 2 µg/mL (91.1%); (amoxicillin + acid clavulanic) MIC ≤ 3 µg/mL (93%); amoxicillin MIC ≤ 3 µg/mL (93%); cefotaxime MIC ≤ 1 µg/mL (89.3%); ceftriaxone MIC ≤ 2 µg/mL (96.4%). A very high rate (83.9%) of the tested strains were MDR S. pneumoniae. This study showed that the presence of azithromycin and gentamicin slightly decreased the MIC value of cefotaxime or ceftriaxone in combination on the SP-3 strain. However, combinations of (macrolides and beta-lactams), (gentamicin and cephalosporins), (vancomycin and ceftriaxone) did not show synergistic effects in in-vitro tests. Both MDRS strains 11 and 43 were resistant to CRO but susceptible to LVX. CRO was bactericidal against the MDRS 11 (MIC, 4 mg/L) but not the MDRS 43 (MIC, 8 mg/L) at 30-h post-incubation at 2× and 4× MIC. LVX showed the bactericidal activity against both strains at 30-h and 6-h at 2× MIC and 4× MIC, respectively. The CRO/LVX combination demonstrated the synergism against MDRS or eradicated the bacteria. CRO doses of 50-80 mg/kg once or twice daily achieved PK/PD target against the MDRS 11, while doses of 50 mg/kg twice daily or 80 mg/kg once or twice daily achieved PK/PD target against the MDRS 43. LVX doses of 8-10 mg/kg twice daily achieved PK/PD target against the MDRS 43 (MIC, 1 mg/L) but not the MDRS 11 (MIC, 2 mg/L). LVX 500 mg once daily attained PK/PD target for both MDRS strains. Our study suggested that the combination of 1 x MIC of LVX with 2 x MIC of CRO was sufficient to reach bactericidal effect and PK/PD target against both MDRS strains at 24 h with the lowest concentration. Other combinations should be selected depending on the resistance of the strains to antibiotics, the degree of bacterial eradication required, and the patient’s physical condition and weight and immunity. In general, using the CRO/LVX combination might help increase the bactericidal effect, reduce doses of single agents, thus decreasing the risk of side effects.
Conclusions Our data support using penicillin G, amoxicillin, co-amoxiclav, or cefotaxime as the first-line therapy for uncomplicated-pneumococci-induced CAP in Quang Nam and Da Nang. In contrast, vancomycin, linezolid, and levofloxacin should be used with caution as an alternative to other antibiotics or in cases of multidrug resistance. Due to a high prevalence of macrolide-resistant S. pneumoniae, a macrolide empirical monotherapy is not recommended for the management of CAP unless atypical microorganisms are suspected. Otherwise, the prevalence of multidrug-resistant pneumococci in Da Nang and Quang Nam (83.9%) is an issue of concern, it is required to make a dramatic change in the antibiotic-prescribing habits of physicians, other health care workers, and the public about the proper and wise use of antibiotics. CRO/LVX combination showed a synergistic effect against MDRS. The calculation of PK/PD indexes and time-kill results could help to optimize the antibiotic therapies against MDRS and prevent the emergence of drug resistance. The data of this research would also be beneficial for further studies, particularly the in-vivo studies on (LVX+CRO) combination and the effectiveness of the Pneumococcal conjugate vaccine for Vietnamese children.
Methods This cross-sectional observational study was conducted in the middle region of Vietnam at the pediatric departments of three hospitals; specifically, Da Nang Hospital for Woman and Children (DN), Quang Nam Children’s Hospital (QN1), Pediatrics Department of General Hospital at Northern Mountain of Quang Nam (QN2) from 2017 to 2018. Nasopharyngeal aspiration (NPA) samples from 360 CAP inpatients aged 2 months to 5 years were collected. The identification of pneumococcal strains underwent steps such as observation of colony morphology, gram staining, optochin susceptibility testing, bile salt solubility, and confirmed by mass spectrometry for suspected strains. The susceptibility of commonly-used antibiotics was investigated using disk diffusion testing and the E-test method. Multi-drug resistant (MDR) S. pneumoniae strains were also determined. S. pneumoniae strains with the highest penicillin MIC (Minimum Inhibitory Concentration) were used in the synergistic determination of antimicrobial combination by E- test. Two potential antimicrobial agents, ceftriaxone (CRO) and levofloxacin (LVX) and their combinations in different concentration ratios were evaluated for bactericidal effect using time-kill experiments. PK/PD indexes were calculated to estimate the effect of therapies. From these results, several combinations with different LVX/CRO ratios, of which therapeutic concentrations were expected to be achieved, were proposed for the treatment of MDRS.
Results The rate of CAP children carrying S. pneumoniae at three hospitals was 79/360 and accounted for 21.9%. In which DN, QN1, QN2 hospitals made up 36.7, 27.8 and 35.5%, respectively. The susceptibility testing demonstrated that all 56 tested pneumococcal strains (100%) were resistant to erythromycin and azithromycin, whereas none of the strains (0%) developed the resistance to levofloxacin, vancomycin, and linezolid. The rates of clindamycin- and cotrimoxazole-resistant pneumococci were 96.4 and 87.5%, respectively. For β-lactam antibiotics, the susceptible percentages of pneumococcal strains to penicillin G, co-amoxiclav, amoxicillin, cefotaxime, and ceftriaxone were 91.1%, 78.6%, 85.7%, 89.3%, and 51.8%, respectively. Percent of pneumococcal strains with antibiotic-corresponding MIC values were included penicillin MIC ≤ 2 µg/mL (91.1%); (amoxicillin + acid clavulanic) MIC ≤ 3 µg/mL (93%); amoxicillin MIC ≤ 3 µg/mL (93%); cefotaxime MIC ≤ 1 µg/mL (89.3%); ceftriaxone MIC ≤ 2 µg/mL (96.4%). A very high rate (83.9%) of the tested strains were MDR S. pneumoniae. This study showed that the presence of azithromycin and gentamicin slightly decreased the MIC value of cefotaxime or ceftriaxone in combination on the SP-3 strain. However, combinations of (macrolides and beta-lactams), (gentamicin and cephalosporins), (vancomycin and ceftriaxone) did not show synergistic effects in in-vitro tests. Both MDRS strains 11 and 43 were resistant to CRO but susceptible to LVX. CRO was bactericidal against the MDRS 11 (MIC, 4 mg/L) but not the MDRS 43 (MIC, 8 mg/L) at 30-h post-incubation at 2× and 4× MIC. LVX showed the bactericidal activity against both strains at 30-h and 6-h at 2× MIC and 4× MIC, respectively. The CRO/LVX combination demonstrated the synergism against MDRS or eradicated the bacteria. CRO doses of 50-80 mg/kg once or twice daily achieved PK/PD target against the MDRS 11, while doses of 50 mg/kg twice daily or 80 mg/kg once or twice daily achieved PK/PD target against the MDRS 43. LVX doses of 8-10 mg/kg twice daily achieved PK/PD target against the MDRS 43 (MIC, 1 mg/L) but not the MDRS 11 (MIC, 2 mg/L). LVX 500 mg once daily attained PK/PD target for both MDRS strains. Our study suggested that the combination of 1 x MIC of LVX with 2 x MIC of CRO was sufficient to reach bactericidal effect and PK/PD target against both MDRS strains at 24 h with the lowest concentration. Other combinations should be selected depending on the resistance of the strains to antibiotics, the degree of bacterial eradication required, and the patient’s physical condition and weight and immunity. In general, using the CRO/LVX combination might help increase the bactericidal effect, reduce doses of single agents, thus decreasing the risk of side effects.
Conclusions Our data support using penicillin G, amoxicillin, co-amoxiclav, or cefotaxime as the first-line therapy for uncomplicated-pneumococci-induced CAP in Quang Nam and Da Nang. In contrast, vancomycin, linezolid, and levofloxacin should be used with caution as an alternative to other antibiotics or in cases of multidrug resistance. Due to a high prevalence of macrolide-resistant S. pneumoniae, a macrolide empirical monotherapy is not recommended for the management of CAP unless atypical microorganisms are suspected. Otherwise, the prevalence of multidrug-resistant pneumococci in Da Nang and Quang Nam (83.9%) is an issue of concern, it is required to make a dramatic change in the antibiotic-prescribing habits of physicians, other health care workers, and the public about the proper and wise use of antibiotics. CRO/LVX combination showed a synergistic effect against MDRS. The calculation of PK/PD indexes and time-kill results could help to optimize the antibiotic therapies against MDRS and prevent the emergence of drug resistance. The data of this research would also be beneficial for further studies, particularly the in-vivo studies on (LVX+CRO) combination and the effectiveness of the Pneumococcal conjugate vaccine for Vietnamese children.