As one of the common community-acquired pneumonia pathogens, MP is one of the smallest microorganisms among bacteria and viruses. MPP accounts for 10–40% of community-acquired pneumonia cases [2]. Since MP lacks a cell wall, MP is resistant to cell wall targeting antibiotics [3]. Macrolides, tetracyclines, and quinolones are effective drugs for pediatric patients with MPP. In China, macrolide antibiotics are currently the first choice for the treatment of children with MPP. Fluoroquinolones, including levofloxacin, have not
been used extensively to treat children because of their safety concerns in the pediatric population. Therefore, levofloxacin is not approved for use in children.
Macrolide-resistant MPP was first reported by a Japanese scholar in 2001. The problem of macrolide resistance in MP is a global concern. The rate of MP resistance in macrolide antibiotics is 3.5%~13.2% in the US [4] [5] and 90% or more in china [6].
Macrolide antibiotics target MP mainly by binding to the central ring of the 23S rRNA V region of the ribosomal 50S large subunit and inhibiting protein synthesis. The mechanism underlying macrolide resistance in MP involves a single base mutation in the 23S rRNA gene, which changes the structure of the main binding site of the macrolide antibiotics and reduces the binding affinity resulting in resistance. For the 14 and 15 -membered ring macrolides, A-G point mutation of 2063 and A-G point mutations of 2064 cause high-level resistance. A-G point mutation of 2067 and C-G or A point mutation of 2617 cause a low-level resistance [7][8]. Cao B et al. [9] analyzed more than 20 reviews of MP resistance from 2000 to 2015 and summarized the order of point mutation frequency: A2063G, A2064G, A2063T, A2063C, A1290G, C2617A, and A2067G.Out of these mutations, A2063G and A2064G account for about 80%-90% of the cases.
As compared with patients infected with macrolide-sensitive MP, patients infected with macrolide-resistant MP are reported to have a longer duration of symptoms and longer course of antibiotic treatment.[10] But macrolide-resistant MP does not necessarily cause more severe illness as compared with macrolide-sensitive MP. Some children who were infected with macrolide-resistant MP also demonstrated satisfactory results when treated with conventional therapy. These observations may be due to the following factors: the anti-inflammatory effects of macrolides, the self-limiting nature of MP infection, and the different degrees of resistance to different macrolides. Zhuang Yuan [11] reported that due to immune, conditioning, phagocytosis, and other body functions, the minimum inhibitory concentration (MIC) value in the laboratory does not perfectly correlate with the MIC value in the body. The pH of body has a greater impact on macrolide drugs. So, the laboratory drug sensitivity results are not completely consistent with drug resistance results in clinical studies. The coincidence rate between the two is about 70%. This may also explain the curative effect of conventional azithromycin treatment in children with macrolide resistant MP.
Some children with positive macrolide resistance mutations show poor results in conventional macrolide treatment and their condition even progresses to refractory MPP or severe MPP. Refractory MPP manifests as long fever and rapid clinical progression. Some patients even have alveolar consolidation, atelectasis, and necrotizing pneumonia. Complications also occur in the extra pulmonary system, including skin and mucous membranes, blood system, and central nervous system. Therefore, it is very important to timely select appropriate drugs to treat children infected with macrolide-resistant MP.
Morozumi et al. [12] gave tetracycline and quinolones to children with MP infection who were not effective in prolonging the application of macrolide antibiotics and achieved satisfactory results. Diana et al. [13] suggested that quinolones should be used to treat MPP in children who are refractory to macrolide antibiotics.
The helicase and topoisomerase IV of MP DNA. Were the target enzymes of quinolones. The quinolones inhibit MP by targeting protein synthesis. Levofloxacin is the third generation of quinolones. As compared with the first and second generation of quinolones, levofloxacin has the advantage of being a wide spectrum antibiotic with strong antibacterial activity, good tissue permeability, low toxicity, and less adverse effects. However, levofloxacin is reported to cause articular cartilage abnormalities, leading to limb dysfunction in some juvenile animals [14]. These observations suggest that children might experience the same toxicity; therefore, quinolones are not recommended in the pediatric population. In China, systemic quinolones are not recommended for children under 18 years. Although animal and cell experiments have shown that a certain concentration of quinolones can cause chondrocyte damage, the cartilage toxicity of quinolones in animal experiments is largely related to the species of experimental animals. Besides, the degree of damage positively correlates with the dose of the drug. However, the doses of the drugs in animal experiments are 10 to 30 times higher than the conventional doses for children.
Binz [15] reviewed and analyzed the clinical studies and concluded that there is no clear correlation between the application of fluoroquinolones and musculoskeletal adverse events. The latest five-year follow-up data showed that the incidence of musculoskeletal adverse events is low, and the events reverse after discontinuing the drug. Rosavonaet al. [16] conducted a systematic review and meta-analysis that involved eight studies and 23166 patients. The findings demonstrated that fluoroquinolones do not cause musculoskeletal diseases in minors, and these drugs should not be banned for children suffering from specific infections. LIU et al. [17] analyzed five randomized controlled trials (RCTs) involving1968 patients in the levofloxacin group and 1640 patients in the control group. Out of these five studies, two studies showed that osteoarticular event rates were not statistically significant between the levofloxacin group and the control group. As per the other three studies, adverse events of bones and joints were not observed in both the groups during treatment and follow-up. These observations suggest that the incidence of levofloxacin-induced adverse events in bones and joints in children is low, and most of these adverse events can be attended during follow-up.
Pharmaceutical experts created the "Expert consensus on the application of fluoroquinolone antibacterial drugs in children" [18] to standardize the application of these drugs in pediatrics. The "Expert consensus on diagnosis and treatment of mycoplasma pneumoniae pneumonia in children (2015)" recommends that children infected with macrolide-sensitive MP should be treated with macrolide antibiotics, and other antibiotics should be considered for MP resistant to macrolide antibiotics. The 6 cases in the present study were diagnosed with refractory MPP, and the mutations associated with drug resistance were present. After the conventional course of azithromycin treatment, the patients were still febrile. The course of treatment was extended to seven days. Three children were assisted by fiberoptic bronchoscopy. Although methylprednisolone and immunoglobulin were also administered simultaneously, the six children still had a recurrent fever and/or progressed imaging. Among them, one child was complicated with pulmonary embolism, and five cases had massive consolidation hydrothorax of the lung. The clinicians adjusted the therapy to levofloxacin, and comprehensively evaluated the condition of the children. After treating the children with levofloxacin, the body temperature returned to normal, and the imaging also improved to varying degrees. The follow-up time of the patients after levofloxacin treatment ranged from one week to five months. There were no drug-related adverse reactions during the course of treatment or follow-up. This study is limited in terms of the small number of included cases and short follow-up time.
The pharmacokinetic analysis of azithromycin by Zheng et al. [19] [20]highlighted that the first 24–48 hours are crucial for the success of antimicrobial treatment and that the effective drug concentration is critical since it can lead to treatment failure or increased toxicity. The reduction in C-reactive protein (CRP) and neutrophil count in children with an azithromycin trough concentration of > 0.25 mg/L was significantly higher than that in children with an azithromycin trough concentration of < 0.25 mg/L. The azithromycin loading dose of 15 mg/kg reaches the effective target concentration within 24–48 hours. If this dose is followed by a maintenance dose of 10 mg/kg, the area under concentration-time curve over 24 h (fAUC) to the MIC90 (fAUC/MIC) can be maintained above 50%. In this study, the mean clearance of azithromycin in children aged two to twelve years was 1.288 liters/h/kg. This value is in accordance with a previous pharmacokinetic study of intravenous azithromycin that reported average clearance (CL) values of 1.062 liters/h/kg in 7 children aged 2 to 6 years and 0.960 liters/h/kg in 8 children aged 6 to 12 years. The related risks of overdose for the proposed dosing regimens were 5.8% and 3.8%, respectively, for pediatric patients with normal and impaired liver function. In case the 15% dose reduction is not performed in children with ALT of 40, the probability of overdose increases from 3.8–6.3%. At present, the conventional dose of azithromycin is 10 mg/kg. The hypothesis that whether some children suffer from insufficient effective drug concentration that leads to poor therapeutic effect still needs further confirmatory studies.