Antimicrobial Therapy in Community-Acquired Pneumonia in Children

Purpose of Review

Empirical antibiotic therapy remains the cornerstone of treatment in community-acquired pneumonia (CAP). However, the best option for empirical antibiotics for treatment on an ambulatory basis, as well as in those requiring hospitalization, is still unclear. This review tries to answer the question regarding the most appropriate antibiotics in different settings in children with CAP as well as duration of therapy.

Recent Findings

Recent studies have provided insights regarding use of oral antibiotics in children with mild to moderate CAP, and severe CAP with lower chest retractions but no hypoxia. In view of rapidly emerging resistance among various causative pathogens, several new drugs have been currently approved, or are under trial for CAP in children.

Summary

Current knowledge suggests that the choice of antibiotics for ambulatory treatment of CAP is oral amoxicillin with a duration of 3–5 days. Children with CAP with lower chest retractions but no hypoxia can be treated with oral amoxicillin. Severe pneumonia can be treated with intravenous antibiotics consisting of penicillin/ampicillin with or without an aminoglycoside. Several new drugs have been developed and approved for use in CAP caused by multidrug-resistant organisms, but these should be used judiciously to avoid emergence of further resistance. Future research is needed regarding the safety and efficacy of newer drugs in children.

     

Efficacy and safety of telithromycin 800 mg once daily for 7 days in community-acquired pneumonia: an open-label, multicenter study

Background  

Community-acquired pneumonia (CAP) remains a major cause of morbidity and mortality throughout the world. Telithromycin (a new ketolide) has shown good in vitro activity against the key causative pathogens of CAP, including S pneumoniae resistant to penicillin and/or macrolides.     

Achieving bacterial eradication using pharmacokinetic/ pharmacodynamic principles

Evidence from studies in otitis media indicates that antimicrobials and dosing regimens that have equivalent bacteriologic efficacy against susceptible pathogens can have significantly different bacteriologic success rates against resistant strains of the same species. Unlike macrolide and fluoroquinolone resistance, penicillin resistance can be overcome in Streptococcus pneumoniae by increasing the dose, and hence increasing the time for which the serum concentrations are above the MIC. The new clinical formulation of extra-strength amoxicillin-clavulanate provides 90 mg/kg per day amoxicillin plus 6.4 mg/kg per day clavulanate (14:1) divided every 12 h, compared with 45/6.4 mg/kg per day b.i.d. with conventional dosing. The pharmacokinetic/pharmacodynamic (PK/PD) profiles of extra-strength amoxicillin-clavulanate predict that the new formulation will be more effective than the conventional formulation against S. pneumoniae with elevated amoxicillin MICs and against Haemophilus influenzae. In an open-label, non-comparative study in children with acute otitis media, the extra-strength formulation had high bacteriologic success rates against the major respiratory pathogens, including penicillin-resistant S. pneumoniae. The development of new antimicrobial agents and formulations should be aimed at meeting PK/PD parameters predictive of bacterial eradication of both susceptible and resistant strains.     

Ribosomal resistance: Emerging problems and potential solutions

Many systemic antibiotics use ribosomal inhibition to suppress the replication of bacteria. Current research suggests that resistance to macrolide, lincosamide, and streptogramin B (MLS_B) antibiotics is emerging among clinical isolates of Streptococcus pyogenes and Streptococcus pneumoniae. Erythromycin methylases, encoded by erm genes, modify an essential adenine residue in 23S rRNA and confer cross-resistance to MLS_B antibiotics. More recently, macrolide efflux (mef) genes were identified in isolates of S. pyogenes and S. pneumoniae that show resistance to 14- and 15-membered macrolides (M phenotype). Resistance to MLSB has been associated with the increased use of erythromycin, and the recent emergence of the M phenotype has coincided with the marketing of newer macrolides. However, despite increasing macrolide resistance among clinical isolates of S. pneumoniae, convincing data on treatment failures directly attributable to MLSB or M phenotypes are limited. Possible solutions to emerging MLS_B and M phenotype resistance include the introduction of alternative antibiotics, the more prudent use of antibiotics, combination therapy, molecular diagnostics, enhanced understanding of pharmacodynamic variables, and redefined resistance breakpoints.     

Comparative Efficacies and Tolerabilities of Intravenous Azithromycin Plus Ceftriaxone and Intravenous Levofloxacin with Step-Down Oral Therapy for Hospitalized Patients with Moderate to Severe Community-Acquired Pneumonia

Objective: To compare the efficacy and tolerability of ceftriaxone plus azithromycin with those of levofloxacin in the treatment of hospitalized patients with moderate to severe community-acquired pneumonia (CAP). Design: Randomized, open-label multicenter trial with 1 : 1 treatment allocation in an inpatient setting. Patients: 212 male or female inpatients with a clinical diagnosis of CAP were included in the study. In each treatment group >50% of patients had a pneumonia severity index of IV or V. Interventions: Open-label treatment with either intravenous (IV) ceftriaxone 1g and IV azithromycin 500mg daily or IV levofloxacin 500mg daily. Patients who improved clinically were switched to oral follow-on therapy with either azithromycin 500 mg/day or levofloxacin 500 mg/day. At the clinician’s discretion, oral cefuroxime axetil was added to the treatment regimen of patients who received oral azithromycin if a macrolide resistant pneumococcal isolate was documented. Results: Overall, both study treatments were well tolerated. Favorable clinical outcomes in clinically evaluable patients were demonstrated in 91.5% of patients treated with ceftriaxone plus azithromycin and 89.3% (95% CI ?7.1%, 11.4%) of patients treated with levofloxacin at the end of therapy visit and in 89.2% and 85.1% (95% CI ?6.7%, 14.8%) patients, respectively, at the end of study visit. Bacteriological eradication rates for both treatments were equivalent with the exception of Streptococcus pneumoniae; 44% of isolates were eradicated with levofloxacin compared with 100% of isolates with ceftriaxone plus azithromycin. Conclusions: As acknowledged by international CAP treatment guidelines, the combination of a third-generation cephalosporin and a macrolide is at least as efficacious as monotherapy with a fluoroquinolone with enhanced anti-pneumococcal activity, for hospitalized patients with moderate to severe CAP. Combined medication with a macrolide and third-generation cephalosporin may be preferred over fluoroquinolones as first-line therapy of hospitalized patients with CAP to minimize the development of multiresistant nosocomial Gram-negative bacilli.     

Severe pneumococcal pneumonia: impact of new quinolones on prognosis

Background  

Most guidelines have been proposing, for more than 15 years, a β-lactam combined with either a quinolone or a macrolide as empirical, first-line therapy of severe community acquired pneumonia (CAP) requiring ICU admission. Our goal was to evaluate the outcome of patients with severe CAP, focusing on the impact of new rather than old fluoroquinolones combined with β-lactam in the empirical antimicrobial treatments.     

Monotherapy versus Combination Therapy in Patients Hospitalized with Community-Acquired Pneumonia

Current international guidelines for the management of community acquired pneumonia (CAP) recommend therapy with a beta-lactam plus a macrolide or a 'respiratory' fluoroquinolone alone in patients hospitalized in a medical ward, and combination therapy with a beta-lactam plus a macrolide or a fluoroquinolone in patients hospitalized in the intensive care unit. However, which of the available options should be preferred remains a matter of debate, and there are surprisingly few prospective randomized trials strictly comparing mono- versus dual therapy strategies in CAP patients. Thus, the recommendation of combining a macrolide with a beta-lactam rather than using a beta-lactam alone in hospitalized patients is derived mainly from observational data, and the suggested combination of a beta-lactam with a fluoroquinolone in severe CAP has been rarely examined in a clinical trial.As there have been sound theoretical arguments for and against combination therapy regimens, the rationale for the different options is discussed and available clinical trial data are reviewed in this article. A final conclusion about the superiority of one antibacterial regimen over another in hospitalized patients with CAP cannot be drawn on the basis of the limited data available. So far, combination therapy probably should be preferred in all patients presenting with severe pneumonia, whereas in general, combination therapy is not necessary in patients in a medical ward, and combination therapy with a beta-lactam plus a macrolide or monotherapy with a respiratory fluoroquinolone should be considered equivalent in this latter patient group. On the other hand, the available data demonstrate that empirical coverage of atypical bacteria in all patients with mild-to-moderate CAP seems unnecessary, and beta-lactam monotherapy might perform equally well when compared with respiratory fluoroquinolones in patients with non-severe CAP. Thus, the alternative use of a beta-lactam alone at adequate dosage in clinically stable patients seems justified, if CAP due to Legionella pneumophila is unlikely.     

Biomarkers of Thrombosis, Fibrinolysis, and Inflammation in Patients with Severe Sepsis due to Community-Acquired Pneumonia with and without Streptococcus pneumoniae

Background:   

Severe Streptococcus pneumoniae (S. pneum) pneumonia has historically been associated with an acute presentation and increased mortality. Using data from patients with community-acquired pneumonia (CAP) and severe sepsis, we investigated: (1) the baseline patient characteristics and biomarkers of thrombosis, fibrinolysis, and inflammation in patients with CAP due to S. pneum infection (S. pneum CAP) or CAP due to infection with other or unidentified organisms (non-S. pneum CAP); (2) the behavior of these biomarkers over time and during treatment with drotrecogin alfa (activated) (DrotAA, recombinant activated protein C).     

Management of Community-Acquired Pneumonia

Patients with community-acquired pneumonia (CAP) are treated in hospital or in the ambulatory care setting depending on the severity of illness. Despite numerous guidelines proposed, there is no agreement on specific criteria for hospitalization other than the clinicians’ experience. The purpose of this review is to discuss the importance of the appropriate choice and timely administration of antibacterial agents, either in the hospital or in the outpatient setting.Since a high proportion of CAP patients will not have an etiologic agent identified at the time of initiation of treatment, the choice of antibacterial therapy is usually empiric. Antibacterial agents with activity against pneumococci and atypical pathogens causing pneumonia are the preferred choices. Macrolides, doxycycline, or respiratory fluoroquinolones have been recommended by various guidelines committees in North America for the treatment of pneumonia in patients with or without underlying comorbidities. Because of the increasing resistance to β-lactams as well other antibacterial agents such as macrolides, doxycycline, and sulfamethoxazole/trimethoprim (cotrimoxazole), it is important that clinicians are aware of local statistics on resistance to Streptococcus pneumoniae, as infection with this bacterium is associated with high rates of morbidity and mortality. More recently, fluoroquinolone resistance has been reported, but the percentage of pneumococcal strains resistant to this agent is relatively low compared with the other antibacterial agents.Switch (intravenous to oral) therapy is recommended for hospitalized patients with CAP to facilitate early discharge, which has been shown to improve patient satisfaction and reduce hospital costs. Early conversion to oral therapy has not been shown to be associated with increased complications or higher mortality. Following prompt intravenous therapy and stabilization, patients with CAP should be treated with oral therapy in the ambulatory setting.     

Moving Past the Routine Use of Macrolides—Reviewing the Role of Combination Therapy in Community-Acquired Pneumonia

Purpose of Review

Despite advances in diagnostic microbiology and sepsis management, community-acquired pneumonia (CAP) remains a significant cause of morbidity and mortality. Current recommendations regarding the use of beta-lactams in combination with macrolides published in clinical practice guidelines are variable and based on low-quality evidence that is frequently retrospective, observational, and heterogeneous in nature. While population-based studies have historically suggested improved clinical outcomes with the routine use of macrolide combination therapy in hospitalized patients with CAP, emerging evidence from recent randomized controlled trials has challenged this practice. In this article, we discuss the historical rationale and current evidence for combination macrolide therapy in the management of CAP.

Recent Findings

Recent randomized controlled trials have assessed the non-inferiority of beta-lactam monotherapy compared to beta-lactam/macrolide combination therapy in adult patients hospitalized with CAP. Beta-lactam monotherapy was associated with equivalent clinical outcomes in patients with mild to moderate CAP. Patients with severe CAP managed with beta-lactam monotherapy have demonstrated worse clinical outcomes when compared to patients treated with combination therapy. In addition, previous beta-lactam exposure prior to hospitalization has not been shown to negatively impact outcomes in patients managed with beta-lactam monotherapy in the hospital.

Summary

Current evidence supports the use of beta-lactam monotherapy in adult patients hospitalized with mild to moderate CAP. While existing evidence supports the use of combination therapy in patients with severe pneumonia, further large-scale randomized controlled trials are urgently needed to clarify the role of combination therapy in this population.

     

Correlation between usage of macrolide antibiotic and resistance of Streptococcus pneumoniae clinic isolates from chongqing children's hospital

To investigate the reasons of growing resistance problem of Streptococcus pneumoniae against macrolide in Chongqing, a retrospective method was employed to measure the minimal inhibition concentrations (MIC) of macrolide antibiotic against 1,210 S. pneumoniae clinic isolates. The defined daily doses (DDDs) of macrolide antibiotic were calculated. Polymerase chain reaction (PCR) was used to determine the presence of the erythromycin‐resistant genes in 100 macrolide‐resistant S. pneumoniae isolates. A decrease in macrolide consumption, from 371,100 DDDs in 2002 to 182,500 DDDs in 2005 (51% reduction); however, the rate of erythromycin resistance in S. pneumoniae showed continued increase from 88.0% in 2002 to 96.0% in 2005. No linear correlation was observed between the decline in macrolide consumption and continued increase in resistant rate in S. pneumoniae. In 100 macrolide‐resistant S. pneumoniae isolates, 68 had both erm(B) and mef(A) genotypes, 10 only had the erm(B), 20 only had the mef(A). Co‐existences of ribosomal modification coded by erm(B) gene and efflux effects coded by mef(A) gene were the main resistance mechanism against macrolides and might be attributed to the high drug resistance of S. pneumoniae in Chongqing. Pediatr Pulmonol. 2009; 44:917–921. © 2009 Wiley‐Liss, Inc.     

Mycoplasma pneumoniae pneumonia revisited within the German Competence Network for Community-acquired pneumonia (CAPNETZ)

Background  

Currently, broad empiric antimicrobial treatment including atypical coverage is recommended for patients with mild to moderate community-acquired pneumonia (CAP). Therefore, the relative impact of each atypical pathogen, particularly Mycoplasma pneumoniae deserves renewed attention.     

Effectiveness of combination therapy versus monotherapy with a third-generation cephalosporin in bacteraemic pneumococcal pneumonia: A propensity score analysis

Objective

Combining a macrolide or a fluoroquinolone to beta-lactam regimens in the treatment of patients with moderate to severe community-acquired pneumonia is recommended by the international guidelines. However, the information in patients with bacteraemic pneumococcal pneumonia is limited.

Epidemiology and clinical manifestations of children with macrolide‐resistant Mycoplasma pneumoniae pneumonia in Taiwan

Mycoplasma pneumoniae accounts for 10–30% of community‐acquired pneumonia (CAP) in children. This study reveals the epidemiology and clinical manifestations of children with macrolide‐resistant (ML^r) M. pneumoniae pneumonia in Taiwan. Respiratory tract specimens were collected from children hospitalized with CAP for evaluation via PCR followed by DNA sequencing for several point mutations related to the ML^r character. Of the 412 specimens collected during the study period, 60 (15%) were positive for M. pneumoniae, 14 (23%) of which presented point mutation (all A2063G) in 23S rRNA. Clinical symptoms and chest X‐ray findings between the ML^s and ML^r groups were not significantly different. However, the ML^r group had longer mean duration of fever after azithromycin treatment (3.2 days vs. 1.6 days, P = 0.02) and significantly higher percentage of changing antibiotics for suspected ML^r strain (42% vs. 13%, P = 0.04). Although 58% of children in the ML^r group did not receive effective antibiotics, all children were discharged without sequelae. In conclusion, 15% of CAP in children is caused by M. pneumoniae and the macrolide‐resistance rate is 23% in Taiwan. Despite ineffective antibiotics, children with ML^r M. pneumoniae pneumonia recover completely. Pediatr Pulmonol. 2013; 48:904–911. © 2012 Wiley Periodicals, Inc.     

Efficacy and Tolerability of Once-Daily Telithromycin Compared with High-Dose Amoxicillin for Treatment of Community-Acquired Pneumonia

Background: This randomized, double-blind study compared the efficacy and tolerability of the new ketolide antimicrobial telithromycin with that of high-dose amoxicillin in the treatment of community-acquired pneumonia (CAP). Patients and Methods: Adult patients (n = 404), with signs and symptoms of CAP and radiologic confirmation were randomized to receive telithromycin 800 mg once daily (n = 199) or amoxicillin 1,000 mg three times a day (n = 205) for 10 days. Clinical and bacteriologic outcomes were assessed at post-therapy test-of-cure (days 17–24) and late post therapy (days 31–36). Results: The clinical cure rate for telithromycin-treated patients (per protocol) pst therapy (days 17–24) was 141/149 (94.6%) and compared well with that for amoxicillin (137/152 (90.1%)). Subset analysis of patients (per protocol) showed high clinical cure rates for patients aged ≥ 65 years (telithromycin 21/24, 87.5%; amoxicillin 22/29, 75.9%); those with documented pneumococcal bacteremia (telithromycin 10/10, 100%; amoxicillin 7/9, 77.8%); and patients with a Fine score ≥ III (telithromycin 31/34, 91.2%; amoxicillin 38/47, 80.9%). Bacterial eradication rates were comparable between treatments (telithromycin 42/48, 87.5%; amoxicillin 39/45, 86.7%), with 22/23 vs 18/21 Streptococcus pneumoniae strains 9/12 vs 11/13 Haemophilus influenzae strains and all Moraxella catarrhalis isolates (five and three patients, respectively) eradicated at the test-of-cure ivsit. Both treatments were generally well tolerated. Conclusion: Telithromycin 800 mg once daily is a convenient, optimal-spectrum, first-line treatment for CAP in adults, at least as effective and well tolerated as high-dose amoxicillin. Received: August 24, 2001 · Revision accepted: July 5, 2002 L. Hagberg (corresponding author)     

Clinical and microbiological characteristics of <Emphasis Type="Italic">Klebsiella pneumoniae</Emphasis> isolates causing community-acquired urinary tract infections

Background  

Klebsiella pneumoniae is the second most common species causing urinary tract infections (UTI). However, the host factors and virulence genes of K. pneumoniae related to UTI are poorly understood. The aim of this study was to analyze the capsular phenotype and virulence genes of K. pneumoniae isolates and host factors potentially relevant to community-acquired UTI.     

Evaluation of the Japanese Respiratory Society guidelines for the identification of Mycoplasma pneumoniae pneumonia

Background and objective: Community‐acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. Mycoplasma pneumoniae is one of the major causative pathogens of CAP. Early diagnosis of M. pneumoniae pneumonia is crucial for initiating appropriate antibiotic therapy. The aim of this study was to determine whether the Japanese Respiratory Society (JRS) guidelines on CAP are effective for diagnosing M. pneumoniae pneumonia. Methods: Between August 2008 and July 2009, adult outpatients with CAP were consecutively enrolled. The aetiology of CAP was determined by culture and real‐time polymerase chain reaction (PCR) methods to detect M. pneumoniae, urine antigen tests to detect Streptococcus pneumoniae and Legionella pneumoniae, blood and sputum culture for bacteria and real‐time PCR for eight common respiratory viruses. The predictive value of the JRS guidelines for differentiating M. pneumoniae pneumonia from typical bacterial and viral pneumonias was determined. Results: Data from 215 adult CAP outpatients was analyzed. An aetiological diagnosis was made for 105 patients (48.8%), including 62 patients with M. pneumoniae pneumonia, 17 patients with typical bacterial pneumonia and 23 patients with viral pneumonia. According to the JRS criteria for differential diagnosis of atypical pneumonia, 55 of 62 patients were correctly diagnosed with M. pneumoniae pneumonia (sensitivity 88.7%), and 31 of 40 patients with bacterial and viral pneumonia were correctly excluded (specificity 77.5%). Conclusions: The JRS guidelines on CAP provide a useful tool for the identification of M. pneumoniae pneumonia cases and differentiating these from cases of typical bacterial or viral pneumonia.     

Decreased Streptococcus pneumoniae susceptibility to oral antibiotics among children in rural Vietnam: a community study

Background  

Streptococcus pneumoniae is the most significant bacterial cause of community-acquired pneumonia among children under five years worldwide. Updated resistance information of S. pneumoniae among children is essential to adjust the recommendations for empirical treatment of community-acquired pneumonia, which will have immense implications for local and global health. This study investigated the prevalence of antibiotic resistance in isolated strains of S. pneumoniae and relationship with antibiotic use and demographic factors of children under five in rural Vietnam in 2007.     

Resistance of Helicobacter pylori strains to antibiotics in Korea with a focus on fluoroquinolone resistance

Background and Aim: New regimens, including those with new fluoroquinolones, have been developed to overcome the antibiotic resistance of Helicobacter pylori. We aimed to assess the antibiotic resistance rates, as well as the molecular mechanisms of fluoroquinolone resistance, of the clinical isolates obtained in Korea. Methods: The minimal inhibitory concentration (MIC) values of ciprofloxacin, amoxicillin, clarithromycin, metronidazole and tetracycline were determined by the agar dilution method for 185 treatment‐naïve Helicobacter pylori isolates. The resistant strains were evaluated for the presence of point mutations in the quinolone resistance‐determining region (QRDR) of the gyrA and gyrB genes by direct nucleotide sequencing. Results: Twenty‐nine (29/185, 15.7%) of the strains were found to be resistant to ciprofloxacin. The resistance rates to amoxicillin, clarithromycin, metronidazole and tetracycline were 2.2% (four of 185), 10.8% (20 of 185), 30.3% (56 of 185) and 0.5% (one of 185), respectively. The most common mutations in the H. pylori gyrA gene were found at codons corresponding to Asp87 (16/29, 55.2%) and Asn91 (10/29, 34.5%). Conclusions: Primary H. pylori resistance to ciprofloxacin occurred at a high frequency. The fluoroquinolone resistance is most likely mediated through amino acid point mutation in the gyrA gene at Asn87 and Asp91.