Pristinamycin in the treatment of MSSA bone and joint infection.

OBJECTIVES: The aim of this study was to evaluate pristinamycin in the treatment of MSSA bone and joint infection (BJI). PATIENTS AND METHODS: A retrospective, single-centre cohort study (2001-11) investigated outcome in adults receiving pristinamycin for MSSA BJI and pristinamycin-related adverse events (AEs). RESULTS: One hundred and two MSSA BJIs were assessed in 98 patients [chronic infection, 33.3%; and orthopaedic device-related infection (ODI), 67.6%]. Surgery was performed in 77.5% of total cases, and in all but three ODIs, associated with antibiotic therapy of a median total duration of 29.2 weeks. Pristinamycin was prescribed as a part of the initial intensive treatment phase (29.4%) and/or included in final maintenance therapy (83.3%) at a dose of 47.6 (45.5-52.6) mg/kg/day for 9.3 (1.4-20.4) weeks. AEs occurred in 13.3% of patients, consisting of gastrointestinal disorder (76.9%) or allergic reaction (23.1%), leading to treatment interruption in 11 cases. AEs were related to daily dose (OR, 2.733 for each 10 additional mg/kg/day; P = 0.049). After a follow-up of 76.4 (29.6-146.9) weeks, the failure rate was 34.3%, associated with ODI (OR, 4.421; P = 0.006), particularly when the implant was retained (OR, 4.217; P = 0.007). In most patients, the pristinamycin companion drug was a fluoroquinolone (68.7%) or rifampicin (21.7%), without difference regarding outcome. CONCLUSIONS: Pristinamycin is an effective, well-tolerated alternative therapeutic option in MSSA BJI, on condition that a daily dosage of 50 mg/kg is respected.

Linezolid in the Starter Combination for Multidrug-Resistant Tuberculosis: Time to Move on to Group Four?

Linezolid (LNZ), a group 5 antituberculous drug (unclear efficacy), was used in the starter regimens of 23 adults with multidrug-resistant tuberculosis. The LNZ-containing regimens were effective in achieving culture conversions and relapse-free outcomes. The most frequent LNZ-related side effect was neuropathy. We propose that LNZ should be reclassified among bactericidal second-line drugs.

Matrix and envelope coevolution revealed in a patient monitored since primary infection with human immunodeficiency virus type 1.

Lentiviruses, including human immunodeficiency virus type 1 (HIV-1), typically encode envelope glycoproteins (Env) with long cytoplasmic tails (CTs). The strong conservation of CT length in primary isolates of HIV-1 suggests that this factor plays a key role in viral replication and persistence in infected patients. However, we report here the emergence and dominance of a primary HIV-1 variant carrying a natural 20-amino-acid truncation of the CT in vivo. We demonstrated that this truncation was deleterious for viral replication in cell culture. We then identified a compensatory amino acid substitution in the matrix protein that reversed the negative effects of CT truncation. The loss or rescue of infectivity depended on the level of Env incorporation into virus particles. Interestingly, we found that a virus mutant with defective Env incorporation was able to spread by cell-to-cell transfer. The effects on viral infectivity of compensation between the CT and the matrix protein have been suggested by in vitro studies based on T-cell laboratory-adapted virus mutants, but we provide here the first demonstration of the natural occurrence of similar mechanisms in an infected patient. Our findings provide insight into the potential of HIV-1 to evolve in vivo and its ability to overcome major structural alterations.

Evolutionary dynamics of the glycan shield of the human immunodeficiency virus envelope during natural infection and implications for exposure of the 2G12 epitope.

Elucidation of the kinetics of exposure of neutralizing epitopes on the envelope of human immunodeficiency virus type 1 (HIV-1) during the course of infection may provide key information about how HIV escapes the immune system or why its envelope is such a poor immunogen to induce broadly efficient neutralizing antibodies. We analyzed the kinetics of exposure of the epitopes corresponding to the broadly neutralizing human monoclonal antibodies immunoglobulin G1b12 (IgG1b12), 2G12, and 2F5 at the quasispecies level during infection. We studied the antigenicity and sequences of 94 full-length envelope clones present during primary infection and at least 4 years later in four HIV-1 clade B-infected patients. No or only minor exposure differences were observed for the 2F5 and IgG1b12 epitopes between the early and late clones. Conversely, the envelope glycoproteins of the HIV-1 quasispecies present during primary infection did not expose the 2G12 neutralizing epitope, unlike those present after several years in three of the four patients. Sequence analysis revealed major differences at potential N-linked glycosylation sites between early and late clones, particularly at positions known to be important for 2G12 binding. Our study, in natural mutants, confirms that the glycosylation sites N295, N332, and N392 are essential for 2G12 binding. This study demonstrates the relationship between the evolving "glycan shield " of HIV and the kinetics of exposure of the 2G12 epitope during the course of natural infection.

Short communication: retrospective study to time the introduction of HIV type 1 non-B subtypes in Lyon, France, using env genes obtained from primary infection samples.

Using blood samples from primary HIV-1 infection (PHI) patients obtained in Lyon, France, we characterized the newly transmitted HIV-1 variants in this area during the 1992-1996 period. As PHI samples allowed the precise timing of the transmission event, we were able to date the introduction of non-B subtypes or recombinant forms of the virus in Lyon. Genomic DNA from 18 HIV-1-positive patients at primary infection was used to amplify the full-length env gene by nested PCR; after cloning, the gene was sequenced for subsequent phylogenetic analysis. Several non-B subtypes and recombinant forms of HIV-1 were identified among the 18 patients studied (1 subtype F1, 1 CRF01-AE, 2 subtype G and 2 CRF02-AG). We also found a new J/K recombinant form transmitted in 1995 and never described until now. The introduction of CRF02-AG in Lyon, France, occurred prior to 1992 and six transmission events including non-B subtypes were documented in the following 4 years. Heterosexual contacts appeared as the main introduction pathway for non-B subtypes or recombinant forms. Nevertheless, as transmission of these viruses occurred not only during travel to endemic regions, but also in France or Germany, we conclude that non-B strains entered Europe before the studied period. This retrospective study showed that even if subtype B remained prevalent in the spreading HIV-1 infection in Lyon between 1992 and 1996, non-B subtypes and circulating recombinant forms represented a significantly growing part.