LETTER
Mycoplasma pneumoniae is a common cause of various respiratory tract infections, including community-acquired pneumonia (CAP) (1). Macrolides are the drugs of choice for children, because although other antibiotics such as tetracyclines and fluoroquinolones are active in vitro against M. pneumoniae, they are not recommended because of the risk of severe adverse events when administered to younger patients. Over the last few years, the emergence of macrolide-resistant M. pneumoniae has been reported worldwide in epidemic, country-wide, or large community settings (2–5). However, the clinical relevance of resistant strains is largely debated, because it is not clarified whether resistant strains can cause more severe or prolonged disease, because no prospective, randomized, double-blinded, controlled studies comparing clinical outcomes in macrolide-resistant patients treated with and without macrolides have been carried out (6, 7).
During an outbreak of M. pneumoniae infection in Southern Italy (8), we observed eight children hospitalized because of CAP associated with macrolide-resistant M. pneumoniae infection, and 38 were hospitalized because of CAP associated with macrolide-sensitive M. pneumoniae infection. In all cases, M. pneumoniae DNA was detected by means of previously described real-time PCR (8) in nasopharyngeal swabs obtained upon admission. All of the patients were treated with oral clarithromycin (15 mg/kg/day in two doses). Comparison was made between children with macrolide-resistant M. pneumoniae and those with macrolide-sensitive M. pneumoniae. The continuous variables were analyzed using a two-sided Student test if they were normally distributed (on the basis of the Shapiro-Wilk statistic), or a two-sided Wilcoxon rank-sum test if they were not. The categorical variables were analyzed using contingency table analysis and the chi-squared or Fisher's test, as appropriate. All of the analyses were two-tailed, and P values of ≤0.05 were considered significant.
Table 1 summarizes the demographic, clinical, laboratory, and radiographic findings and outcomes in the macrolide-resistant and macrolide-sensitive patients. The data show that the presence of macrolide-resistant M. pneumoniae does not change the presentation of CAP, because the signs and symptoms, laboratory results, and radiographic findings were similar in the two groups, regardless of the M. pneumoniae sensitivity to the macrolides. However, despite macrolide administration, the duration of fever and cough was significantly longer in the children with macrolide-resistant M. pneumoniae infection, as was the duration of hospitalization and antibiotic administration. Moreover, in seven of the eight patients with macrolide-resistant M. pneumoniae infection (87.5%), the persistence of symptoms led to clarithromycin being replaced by levofloxacin, which was followed by the prompt resolution of fever and cough.
Table 1.
Comparison of children with community-acquired pneumonia and macrolide-resistant and macrolide-sensitive M. pneumoniae infection
| Demographic and finding | Result |
P value | |
|---|---|---|---|
| Macrolide-resistant M. pneumoniae (n = 8) | Macrolide-sensitive M. pneumoniae (n = 38) | ||
| Demographics | |||
| Gender, male/female | 6/2 | 18/20 | 0.16 |
| Mean age ± SD, yrs | 9.2 ± 4.1 | 6.6 ± 3.4 | 0.13 |
| Clinical findings upon admission | |||
| Cough, no. (%) | 8 (100.0) | 38 (100.0) | |
| Dyspnea, no. (%) | 2 (25.0) | 6 (15.8) | 0.61 |
| Respiratory rate, breaths/min | 41.4 ± 10.6 | 42.6 ± 11.3 | 0.91 |
| SpO2 in room air, mean % ± SD | 93.1 ± 3.9 | 94.5 ± 4.5 | 0.76 |
| Fever, no. (%) | 7 (87.5) | 38 (73.7) | 0.66 |
| Rales, no. (%) | 7 (87.5) | 29 (76.3) | 0.66 |
| Wheezing, no. (%) | 3 (37.5) | 14 (36.8) | 1.00 |
| Laboratory findings upon admission | |||
| White blood cell count, mean no./μl ± SD | 8,881 ± 3,670 | 10,193 ± 4,937 | 0.78 |
| Neutrophils, mean % ± SD | 60.9 ± 16.2 | 59.4 ± 14.4 | 0.89 |
| Lymphocytes, mean % ± SD | 28.2 ± 14.8 | 28.9 ± 11.9 | 0.92 |
| Monocytes, mean % ± SD | 6.4 ± 1.8 | 6.9 ± 2.5 | 0.39 |
| Eosinophils, mean % ± SD | 1.4 ± 1.1 | 2.4 ± 2.4 | 0.96 |
| Basophils, mean % ± SD | 0.4 ± 0.7 | 0.3 ± 0.2 | 0.49 |
| C-reactive protein, mean μg/dl ± SD | 19.6 ± 22.8 | 40.6 ± 48.4 | 0.18 |
| Radiographic findings upon admission | |||
| Alveolar CAP, no. (%) | 5 (62.5) | 26 (68.4) | 1.00 |
| Interstitial CAP, no. (%) | 3 (37.5) | 12 (31.6) | |
| Presence of pleural effusion, no. (%) | 1 (12.5) | 4 (10.5) | 1.00 |
| Outcomes during macrolide treatment | |||
| Total no. of febrile days, median (range) | 7 (3–15) | 4 (2–10) | 0.36 |
| No. of febrile days during macrolide administration, median (range) | 4 (1–10) | 1.5 (1–3) | 0.03 |
| No. of days with cough during macrolide administration, median (range) | 5 (1–14) | 2 (1–4) | 0.04 |
| No. of patients with a febrile period 48 h after macrolide administration (%) | 7 (87.5) | 2 (5.3) | <0.0001 |
| No. (%) of patients with a change of prescription after macrolide administration | 7 (87.5) | 10 (26.3) | 0.002 |
| Median duration of hospitalization, days (range) | 10 (2–32) | 4 (2–20) | 0.03 |
| Median duration of antibiotic therapy, days (range) | 28 (15–46) | 14 (10–21) | 0.02 |
These data seem to make a further contribution to the debate concerning the importance of treating M. pneumoniae infection with antibiotics and the clinical relevance of macrolide resistance. In CAP cases due to sensitive strains, macrolides appear useful because they reduce the duration of symptoms, although it is not clear whether their activity is due mainly to their antimicrobial or anti-inflammatory properties. However, the clinical relevance of macrolide resistance in hospitalized CAP patients seems to be limited to prolonging the symptoms of the disease and not to increasing the risk of complications. Another antibiotic, such as a fluoroquinolone, should be prescribed if the symptoms persist or if there are signs of clinical deterioration. However, before any final conclusions can be drawn, further data regarding the outcome of CAP cases that have severe clinical manifestations at presentation and due to macrolide-resistant M. pneumoniae strains are needed.
ACKNOWLEDGMENTS
The study described in the letter was supported in part by a grant from the Italian Ministry of Health (Bando Giovani Ricercatori 2007).
The authors have no conflicts of interests to declare.
This study was approved by the Institutional Review Board of Giovanni XXIII Pediatric Hospital, University of Bari, Bari, Italy, and Università degli Studi di Milano, Milan, Italy. The written informed consent of both parents or a legal guardian was required, and the older children were asked to give their consent.
F.C. and I.C. visited the hospitalized patients, collected the swabs, and entered the data in the database. M.C. carried out the laboratory assays. N.P. and S.E. statistically analyzed the data, designed the study, and cowrote the manuscript. All of the authors read and approved the final manuscript.
Footnotes
Published ahead of print 5 December 2012
REFERENCES
- 1. Waites KB, Talkington DF. 2004. Mycoplasma pneumoniae and its role as a human pathogen. Clin. Microbiol. Rev. 17:697–728 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Li X, Atkinson TP, Hagood J, Makris C, Duffy LB, Waites KB. 2009. Emerging macrolide resistance in Mycoplasma pneumoniae in children: detection and characterization of resistant isolates. Pediatr. Infect. Dis. J. 28:693–696 [DOI] [PubMed] [Google Scholar]
- 3. Averbuch D, Hidalgo-Grass C, Moses AE, Engelhard D, Nir-Paz R. 2011. Macrolide resistance in Mycoplasma pneumoniae, Israel, 2010. Emerg. Infect. Dis. 17:1079–1082 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Cao B, Zhao CJ, Yin YD, Zhao F, Song SF, Bai L, Zhang JZ, Liu YM, Zhang YY, Wang H, Wang C. 2010. High prevalence of macrolide resistance in Mycoplasma pneumoniae isolates from adult and adolescent patients with respiratory tract infection in China. Clin. Infect. Dis. 51:189–194 [DOI] [PubMed] [Google Scholar]
- 5. Okada T, Morozumi M, Tajima T, Hasegawa M, Sakata H, Ohnari S, Chiba N, Iwata S, Ubukata K. 2012. Rapid effectiveness of minocycline or doxycycline against macrolide-resistant Mycoplasma pneumoniae infection in a 2011 outbreak among Japanese children. Clin. Infect. Dis. 55:1642–1649 [DOI] [PubMed] [Google Scholar]
- 6. Kawai Y, Miyashita N, Yamaguchi T, Saitoh A, Kondoh E, Fujimoto H, Teranishi H, Inoue M, Wakabayashi T, Akaike H, Ogita S, Kawasaki K, Terada K, Kishi F, Ouchi K. 2012. Clinical efficacy of macrolide antibiotics against genetically determined macrolide-resistant Mycoplasma pneumoniae pneumonia in paediatric patients. Respirology 17:354–362 [DOI] [PubMed] [Google Scholar]
- 7. Matsubara K, Morozumi M, Okada T, Matsushima T, Komiyama O, Shoji M, Ebihara T, Ubukata K, Sato Y, Akita H, Sunakawa K, Iwata S. 2009. A comparative clinical study of macrolide-sensitive and macrolide-resistant Mycoplasma pneumoniae infections in pediatric patients. J. Infect. Chemother. 15:380–383 [DOI] [PubMed] [Google Scholar]
- 8. Chironna M, Sallustio A, Esposito S, Perulli M, Chinellato I, Di Bari C, Quarto M, Cardinale F. 2011. Emergence of macrolide-resistant strains during an outbreak of Mycoplasma pneumoniae infections in children. J. Antimicrob. Chemother. 66:734–737 [DOI] [PubMed] [Google Scholar]