IntroductionA profound impairment of immune functions occurs in individuals infected with human immunodeficiency virus type 1 (HIV-1). Both the cellular and the humoral arms of the immune system are unable to control the infection, which ultimately results in severe exhaustion of several lymphocyte functions and increased susceptibility to secondary and opportunistic infections. Major immunologic defects occur in the B-cell compartment. 1 Polyclonal B-cell activation is demonstrated by hypergammaglobulinemia and spontaneous antibodies' (Abs) production by cultured peripheral lymphocytes 2,3 ; additional signs of B-cell abnormality are the high incidence of B-cell tumors 4 and the deregulated expression of several surface molecules like Fas, Fas ligand (FasL), CD5, CD21, and CD27. 5-8 B-cell hyperactivity is also accompanied by functional defects since humoral immune responses following immunization are severely impaired in HIV-1-infected subjects and B lymphocytes from patients are poorly responsive to in vitro stimulation. [9][10][11] Several mechanisms may account for the B-cell abnormalities in HIV-1 infection. A direct effect of virus replication or viral proteins on B-cell function has been shown 12 and sustained by the observation that polyclonal B-cell activation is strongly reduced following effective antiretroviral treatment. 13-15 HIV-driven unbalanced production of several cytokines like tumor necrosis factor ␣ (TNF-␣), interleukin 6 (IL-6), IL-10, and IL-15 has also been involved in B-cell dysfunctions. [16][17][18] Defective T-cell help may account for B-cell unresponsiveness to T-cell-dependent antigens. 19,20 The defect of B cells in HIV-1 infection appears, however, to be intrinsic since it begins early during infection preceding functional and quantitative defects in T-helper activity and cannot be restored by allogenic normal CD4 ϩ T cells in vitro. 3,21 The mechanisms inducing hypergammaglobulinemia in HIV-1 infection are only partially known. Activation driven by CD4 ϩ T cells, monocytes, and natural killer (NK) cells through CD40-CD40 ligand (CD40L) interaction and an inappropriate cytokine supply may have a relevant role in inducing abnormal differentiation of B cells. 17,22 In addition, HIV-1 itself may directly affect B-cell activation and dysfunction, inducing the appearance of a subset of CD21 Ϫ B cells which have been proposed to contribute to increased antibody production. 23,24 A recent work by Hunziker et al 25 has suggested that naive B cells represent an important source of hypergammaglobulinemia and autoantibody production in chronic viral infections.Because of the lack of protective humoral immunity, HIV-1-infected individuals receive vaccination against several pathogens. However, many studies have reported an impaired humoral immune response in most of the patients after vaccination. [9][10][11]26,27 From the Microbiology and Tumor Biology Center, Karolinska Institutet, and the Gay Men's Health Clinic, The Soder Hospital, Stockholm, Sweden; the Swedish Institute for Infectious...

In recent years, Mycoplasma pneumoniae strains that are clinically resistant to macrolide antibiotics have occasionally been encountered in Japan. Of 76 strains of M. pneumoniae isolated in three different areas in Japan during 2000 to 2003, 13 strains were erythromycin (ERY) resistant. Of these 13 strains, 12 were highly ERY resistant (MIC, >256 g/ml) and 1 was weakly resistant (MIC, 8 g/ml). Nucleotide sequencing of domains II and V of 23S rRNA and ribosomal proteins L4 and L22, which are associated with ERY resistance, showed that 10 strains had an A-to-G transition at position 2063 (corresponding to 2058 in Escherichia coli numbering), 1 strain showed A-to-C transversion at position 2063, 1 strain showed an A-to-G transition at position 2064, and the weakly ERY-resistant strain showed C-to-G transversion at position 2617 (corresponding to 2611 in E. coli numbering) of domain V. Domain II and ribosomal proteins L4 and L22 were not involved in the ERY resistance of these clinical M. pneumoniae strains. In addition, by using our established restriction fragment length polymorphism technique to detect point mutations of PCR products for domain V of the 23S rRNA gene of M. pneumoniae, we found that 23 (24%) of 94 PCR-positive oral samples taken from children with respiratory infections showed A2063G mutation. These results suggest that ERY-resistant M. pneumoniae infection is not unusual in Japan.Mycoplasma pneumoniae is a pathogen causing human respiratory infections such as atypical pneumonia, mainly in children and younger adults. In the chemotherapy of M. pneumoniae infection in children, erythromycin (ERY) and clarithromycin (CLR) among 14-membered macrolides and the 15-membered macrolide azithromycin (AZM) are usually considered the first-choice agents in Japan. Although there was no report on the isolation of ERY-resistant M. pneumoniae before 2000 in Japan, we found that ca. 20% of M. pneumoniae strains isolated from patients from 2000 to 2003 were ERY resistant. These results are consistent with pediatricians' impression that antibiotics such as ERY, CLR, and clindamycin (CLI) are not effective for some patients with M. pneumoniae infection.It is well known that the macrolide-lincosamide-streptogramin B (MLS) antibiotics inhibit protein synthesis by binding to domain II and/or domain V of 23S rRNA (3, 26). Lucier et al. (10) and Okazaki et al. (17) found that an A-to-G transition or A-to-C transversion at position 2063 (corresponding to 2058 in Escherichia coli numbering) or 2064 of the 23S rRNA gene resulted in high resistance to macrolide antibiotics. No point mutation was found in domain II of 23S rRNA of the ERYresistant M. pneumoniae strains used in the present study.We report here the prevalence of macrolide-resistant M. pneumoniae infection in Japan. By using 13 ERY-resistant M. pneumoniae strains, we investigated the mechanisms of resistance to MLS antibiotics. Furthermore, we established restriction fragment length polymorphism (RFLP) techniques to detect point mutations in domain V of 23S rRNA...

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The list of extrapulmonary manifestations due to Mycoplasma pneumoniae infection can be classified according to the following three possible mechanisms derived from the established biological activity of M. pneumoniae; (1) a direct type in which the bacterium is present at the site of inflammation and local inflammatory cytokines induced by the bacterium play an important role (2) an indirect type in which the bacterium is not present at the site of inflammation and immune modulations, such as autoimmunity or formation of immune complexes, play an important role, and (3) a vascular occlusion type in which obstruction of blood flow induced either directly or indirectly by the bacterium plays an important role. Recent studies concerning extrapulmonary manifestations have prompted the author to upgrade the list, including cardiac and aortic thrombi as cardiovascular manifestations; erythema nodosum, cutaneous leukocytoclastic vasculitis, and subcorneal pustular dermatosis as dermatological manifestations; acute cerebellar ataxia, opsoclonus-myoclonus syndrome, and thalamic necrosis as neurological manifestations; pulmonary embolism as a respiratory system manifestation; and renal artery embolism as a urogenital tract manifestation. Continuing nosological confusion on M. pneumoniae–induced mucositis (without skin lesions), which may be called M. pneumoniae-associated mucositis or M. pneumoniae-induced rash and mucositis separately from Stevens-Johnson syndrome, is argued in the dermatological manifestations. Serological methods are recommended for diagnosis because pneumonia or respiratory symptoms are often minimal or even absent in extrapulmonary manifestations due to M. pneumoniae infection. Concomitant use of immunomodulators, such as corticosteroids or immunoglobulins with antibiotics effective against M. pneumoniae, can be considered as treatment modalities for most severe cases, such as encephalitis. Further studies would be necessary to construct a comprehensive therapeutic strategy, covering microbiology (antibiotics), immunology (immunomodulators), and hematology (anticoagulants). The possible influence of the emergence of macrolide-resistant M. pneumoniae on extrapulmonary manifestations, which can be considered of limited clinical threat in Japan where the resistant rate has currently decreased, is discussed on the basis of unique biological characteristics of M. pneumoniae, the smallest self-replicating organism.

Some patients with Mycoplasma pneumoniae infection are clinically resistant to antibiotics such as erythromycin, c1arithromycin, or clindamycin. We isolated M. pneumoniae from such patients and found that one of three isolates showed a point mutation in the 238 rRNA gene. Furthermore, 141 EM-sensitive clinical isolates of M. pneumoniae were cultured in broth medium containing 100 fLglml of erythromycin (EM). Among 11 EM-resistant strains that grew in the medium, point mutations in the 238 rRNA were found in 3 strains at A2063G, 5 strains at A2064G and 3 strains at A2064C. The relationship between the point mutation pattern of these EM-resistant strains and their resistance phenotypes to several macrolide antibiotics was investigated.

Macrolide-resistant Mycoplasma pneumoniae (MR M. pneumoniae) has been isolated from clinical specimens in Japan since 2000. A comparative study was carried out to determine whether or not macrolides are effective in treating patients infected with MR M. pneumoniae. The clinical courses of 11 patients with MR M. pneumoniae infection (MR patients) treated with macrolides were compared with those of 26 patients with macrolide-susceptible M. pneumoniae infection (MS patients). The total febrile days and the number of febrile days during macrolide administration were longer in the MR patients than in the MS patients (median of 8 days versus median of 5 days [P ‫؍‬ 0.019] and 3 days versus 1 day [P ‫؍‬ 0.002], respectively). In addition, the MR patients were more likely than the MS patients to have had a change of the initially prescribed macrolide to another antimicrobial agent (63.6% versus 3.8%; odds ratio, 43.8; P < 0.001), which might reflect the pediatrician's judgment that the initially prescribed macrolide was not sufficiently effective in these patients. Despite the fact that the febrile period was prolonged in MR patients given macrolides, the fever resolved even when the initial prescription was not changed. These results show that macrolides are certainly less effective in MR patients.Mycoplasma pneumoniae is a common pathogen causing community-acquired respiratory tract infection mainly in children and young adults. Macrolides are generally considered to be the first-choice agents for treatment of M. pneumoniae infection. Although tetracyclines and fluoroquinolones are effective against M. pneumoniae, these agents are not recommended for children because of their toxicity. Tetracyclines can cause depression of bone growth, permanent gray-brown discoloration of the teeth, and enamel hypoplasia when given during tooth development. Although the clinical importance of fluoroquinolones has not been demonstrated, they produce cartilage erosion in young animals. Thus, these agents should be given only when there is no alternative (15).As reported by Lucier et al. (9) and Okazaki et al. (14), an A-to-G transition or A-to-C transversion at position 2063 or 2064 of domain V of the M. pneumoniae 23S rRNA gene results in resistance to macrolide antibiotics. We have previously reported the isolation of macrolide-resistant (MR) M. pneumoniae from ca. 20% of clinical specimens collected from pediatric patients in Japan (11). Most of those isolates were highly resistant to 14-membered ring macrolides (MIC, Ͼ256 g/ml) and moderately resistant to 15-and 16-membered ring macrolides.Even in the cases of patients infected with MR M. pneumoniae, some pediatricians had the impression that there was a good response to macrolide therapy (11). There is a similar debate about the management of infection due to pneumococci. As noted in The Infectious Diseases Society of America (IDSA) guidelines for community-acquired pneumonia management (10), despite the increase of resistant isolates, a corresponding increase has not been seen in...

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