Although the fluoroquinolones are presently used to treat tuberculosis primarily in cases involving resistance or intolerance to first-line antituberculosis therapy, these drugs are potential first-line agents and are under study for this indication However, there is concern about the development of fluoroquinolone resistance in Mycobacterium tuberculosis, particularly when administered as monotherapy or as the only active agent in a failing multidrug regimen Treatment failures as well as relapses have been documented under such conditions With increasing numbers of fluoroquinolone prescriptions and the expanded use of these broad-spectrum agents for many infections, the selective pressure of fluoroquinolone use results in the ready emergence of fluoroquinolone resistance in a diversity of organisms, including M tuberculosis Among M tuberculosis, resistance is emerging and may herald a significant future threat to the long-term clinical utility of fluoroquinolones Discussion and education regarding appropriate use are necessary to preserve the effectiveness of this antibiotic class against the hazard of growing resistance

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(03)00671-6.pdf

Fluoroquinolones, tuberculosis, and resistance

Tobacco smoking is associated with increased prevalence of various diseases, both in the respiratory tract and in distal organs. The possibility that tobacco smoke induced changes in immune and inflammatory processes may play a part in the aetiology and pathogenesis of many of these diseases was first recognised in the mid 1960s. The ensuing decade witnessed a steadily increasing research effort centred on toxicological aspects of chronic inhalation of tobacco smoke in relation to immune and inflammatory cell function in experimental animals. This work (reviewed by Holt and Keast') defined a discrete pattern of change in animals during the course of tobacco smoke exposure, with the following salient features: (1) systemically, biphasic fluctuations were observed in primary T cell dependent humoral and cellular immune responses, initial enhancement during the first few months of exposure eventually giving way to suppression in chronically exposed animals; (2) T cell independent immune responses (for example, to bacterial polysaccharide antigens) and secondary immune responses dependent on T memory cells remained normal in these animals; (3) an immediate and profound suppression of T cell function was noted in the respiratory tract, together with (4) the steady development of an expanded and functionally altered population of alveolar macrophages. Recognition of the possibility that similar effects occur in man has provided the impetus for various direct studies on aspects of immune and inflammatory cell functions in human smokers. Furthermore, it has become accepted practice to segregate the smokers within \"control\" populations, particularly in studies using bronchoalveolar lavage. The available data from these human studies are reviewed below in the light of the information available from earlier animal experiments.

https://thorax.bmj.com/content/thoraxjnl/42/4/241.full.pdf

Immune and inflammatory function in cigarette smokers.

Antibiotics can interact directly with the immune system. This is a review of the immunomodulating effects of antibiotics. The Medline database on CD-ROM was searched for the years 1987 to 1994 using the following search string: “thesaurus explode antibiotics / all AND (thesaurus explode immune-system / drug effects ORthesaurus immune-tolerance / drug effects).” Aspects of the immune system studied were aspects of phagocyte functions: phagocytosis and killing, and chemotaxis and aspects of lymphocyte functions: lymphocyte proliferation, cytokine production, antibody production, delayed hypersensitivity and natural killer-cell activity. In order to quantify and to compare immunomodulatory properties of antibiotics we calculated an “immune index,” defined as: number of positive statements — number of negative statements/total number of statements. Concerning phagocytosis, positive effects were observed for cefodizime, imipenem, cefoxitin, amphotericin B and clindamycin and negative effects for erythromycin, roxithromycin, cefotaxime, tetracycline, amplicillin and gentamicin. Clindamycin, cefoxitin and imipenem induce enhancement of chemotaxis, whereas cefotaxime, rifampicin and teicoplanin decrease chemotaxis. Regarding lymphocyte proliferation, cefodizime has the strongest stimulating effect, whereas tetracycline has the strongest negative effect. Except for erythromycin and amphotericin B the number of statements reported is too small to be conclusive for the interpretation of effects on cytokine production. Erythromycin and amphotericin B appear to stimulate cytokine production. As to antibody production, cefodizime has the strongest positive effect, whereas josamycin, rifampicin and tetracycline have marked negative effects. For delayed hypersensitivity and the natural killer-cell activity the number of statements is too small for any single antibiotic to be conclusive. There are three markedly immuno-enhancing antibiotics (imipenem, cefodizime and clindamycin) and eight markedly immuno-depressing antibiotics (erythromycin, roxithromycin, cefotaxime, tetracycline, rifampicin, gentamicin, teicoplanin and ampicillin).

Immunomodulating effects of antibiotics: Literature review

Results: Of the 420 isolates, 52 (12.4%), 26 (6.2%), 26 (6.2%) and 30 (7.1%) were resistant to isoniazid, rifampicin, ethambutol and streptomycin, respectively. Multidrug resistance was found in 5.0% of isolates. For all tested FQs, the susceptibility rate was higher than 97%. Resistance to any first-line drug and isolation from a patient with prior anti-tuberculous treatment were correlated with FQ resistance. Multidrug resistance had the strongest correlation with FQ resistance (19% of isolates). Neither the previous use of FQs nor the duration of FQ exposure was correlated with the FQ susceptibility. Of the 14 FQ-resistant isolates, five (35.7%) had gyrA mutations (four D94G and one A90V) and another one (7.1%) had a gyrB mutation (N538D). Conclusions: This study found FQ resistance in 3.3% of all clinical isolates of M. tuberculosis .F Q resistance was correlated with first-line drug resistance and prior anti-tuberculous treatment, suggesting the need for routine FQ susceptibility testing in patients with these characteristics.

Fluoroquinolone resistance in Mycobacterium tuberculosis isolates: associated genetic mutations and relationship to antimicrobial exposure

Bronchoalveolar lavage (BAL) is increasingly used in the assessment of pulmonary diseases in children. However, reference values for cellular and non-cellular constituents of BAL fluid in children are lacking. We have studied the differential cytology of BAL fluid in 48 children aged 3-16 years (mean age +/- SD 7.9 +/- 3.5 yrs) undergoing elective surgery for nonpulmonary illnesses. A flexible bronchoscope (Pentax 3.5 or 4.9 mm) was wedged in the middle lobe or one of its segments. BAL was performed with 3x1 ml-kg-1 body weight of normal saline warmed to body temperature. The first sample was studied separately; subsequent samples were pooled for analysis. The mean recovery was 58 +/- 15%. Significantly more granulocytes and less lymphocytes were found in the first, as compared to the pooled, sample. Total cell counts were highly variable and ranged from 0.5-57.1 x 10(4) ml-1. Macrophages were the predominant cell type, with a mean percentage of 81.2 +/- 12.7%. The relative proportion of lymphocytes was higher than that reported in most studies of adult volunteers (16.1 +/- 2.4%). No age dependency was observed for either cell type. The mean percentage of granulocytes was 2.5 +/- 3.3%. Absolute granulocyte counts were significantly higher in children under 8 yrs of age. This study provides the first reference data on BAL differential cytology in children without pulmonary disease and will be the basis for future investigations of BAL in paediatric lung diseases.

https://erj.ersjournals.com/content/erj/7/10/1865.full.pdf

Differential cytology of bronchoalveolar lavage fluid in normal children

Bronchoalveolar lavage was performed on 12 healthy volunteers, comprising 6 smokers and 6 nonsmokers, of ages between 21 and 52 years The aim was to define normal variability of certain biochemical,

Bronchoalveolar lavage in the normal lung. First of three parts: protein, enzymatic and ionic features.

We confirm the higher in vitro activity of LFX compared to older fluoroquinolones. Furthermore, in a limited number of MDR TB patients, second-line regimens comprising LFX 500 mg b.i.d. administered in a range of 9-24 months were well tolerated and safe.

Clinical use of Levofloxacin in the long-term treatment of drug resistant tuberculosis.

Bronchoalveolar lavage, performed on 15 healthy volunteers, enabled quantification and characterization of the alveolar cell populations. The subjects studied were 8 nonsmokers (5 males, 3 females) and 7 smokers (6 males, 1 female). It was found that in the smokers the macrophages increased compared with nonsmokers, both in absolute number (419,000 vs. 138,000/ml; p less than 0.005) and in percentage (93.8 +/- 3.0 vs. 88.1 +/- 4.8%; p less than 0.02), causing a significant increase in the total number of cells recovered after bronchoalveolar lavage (471,000 vs. 163,000/ml; p less than 0.005). Lymphocytes and neutrophils do not significantly vary in the two groups, even though among the smokers there is a tendency for the concentration of these cells to increase in the lavage liquids. The importance of the data obtained from healthy subjects lies in the possibility thus afforded of having reference values for the study of various lung pathologies with bronchoalveolar lavage.

Bronchoalveolar lavage in the normal lung. 2. Cell distribution and cytomorphology.

To evaluate the possibility of quantifying alveolar dust burden in conditions of exposure to silica, four groups of subjects were submitted to bronchoalveolar lavage (BAL): 10 healthy control subjects and 39 patients affected by diffuse interstitial lung disease (DILD) never exposed to dust, 23 silicotic patients and 12 chronic bronchitis patients with a history of occupational exposure to silica dust. Five to ten million BAL recovered cells were analysed with an energy-dispersive X-ray microanalysis (EDXA) system to determine the silicon content, expressed in a semi-quantitative way as silicon to sulphur (Si/S) ratio. The results were independent of smoking habit. The Si/S median values (interquartile range in brackets) for the four groups were 0.53 (0.5-0.65), 0.60 (0.41-0.8), 1.23 (1.06-1.39), 1.31 (1.11-1.97), respectively. Silicotics and simply exposed individuals did not show a significant discrepancy, but they were both significantly different in comparison with normal and DILD patients without history of exposure (p less than 0.001). 14.3% false negative cases were found, and 4.1% false positive cases (none among normal subjects). We did not see any significant relationships between the amount of silicon and the duration of exposure or the degree of chest X-ray involvement. A study of cytocentrifuge slides from the same subjects by polarizing light microscopy revealed a lower sensitivity (34% false negative cases).(ABSTRACT TRUNCATED AT 250 WORDS)

https://erj.ersjournals.com/content/erj/5/7/798.full.pdf

Semi-quantitative X-ray microanalysis of bronchoalveolar lavage samples from silica-exposed and nonexposed subjects

We studied the activity of human alveolar macrophages (HAMs) obtained by bronchoalveolar lavage (BAL) from human lungs. In particular, we studied in vitro phagocytosis and bacterial killing in basal conditions and in the presence of miocamycin (MOM), a macrolide antibiotic. At a dose of 600 mg every 12 hours, MOM concentrations in the serum were 2.60 micrograms/ml 1 hour after administration and 0.75 microgram/ml 8 h after. The antibiotic cannot be assayed by the microbiological method in the acellular liquid of alveolar lavage. After penetrating the HAMs, it can be detected at a concentration of about 0.4 mcirograms/1.10(6) HAMs. MOM was able to penetrate HAM cytoplasm without altering their vitality. As a matter of fact, the Trypan blue exclusion dye test was not modified after long incubation in the presence of MOM. The HAMs, resuspended in a RPMI 1640 enriched medium, were able to phagocytize either live Staphylococci or inert Latex beads of 1 micron. MOM stimulated the HAM phagocytosis on both Staphylococci and Latex beads. The increase in Latex phagocytosis, a relatively inert substance on which MOM should not be active, is a confirmation of the antibiotic's directed stimulation of the HAMs. Finally, we have seen that the HAMs, which were noteworthy in killing the phagocytized bacteria, were stimulated by MOM after only 30 minutes of contact with the antibiotic.

G. Velluti

Papers

Bronchoalveolar lavage in the normal lung. First of three parts: protein, enzymatic and ionic features.

Clinical use of Levofloxacin in the long-term treatment of drug resistant tuberculosis.

Bronchoalveolar lavage in the normal lung. 2. Cell distribution and cytomorphology.

Semi-quantitative X-ray microanalysis of bronchoalveolar lavage samples from silica-exposed and nonexposed subjects

Activities of human alveolar macrophages (HAMs). Note 1: Observations on phagocytosis and bacterial killing in the presence of miocamycin