Increasing pathomorphism of pulmonary tuberculosis: an observational study of slow clinical, microbiological and imaging response of lung tuberculosis to specific treatment. Which role for linezolid?

During recent years, a progressive emerging of tuberculosis occurred, related to the overall increased age of general population, primary and secondary (iatrogenic) immunodeficiencies, the availability of invasive procedures, surgical interventions and intensive care supports, bone marrow and solid organ transplantation, and especially the recent immigration flows of people often coming from areas endemic for tuberculosis, and living with evident social-economical disadvantages, and with a reduced access to health care facilities. Since January 2006, at our reference centre we followed 81 consecutive cases of pulmonary tuberculosis, with 65 of them which remained evaluable for the absence of extrapulmonary complications, and a continuative and effective clinical and therapeutic follow-up. The majority of episodes of evaluable pulmonary tuberculosis (49 cases out of 65: 75,4 percent) occurred in patients who immigrated from developing countries. In two patients multiresistant (MDR) Mycobacterium tuberculosis strains were found, while two more subjects (both immigrated from Eastern Europe) suffered from a disease due to extremely resistant (XDR) M. tuberculosis strains. Although enforcing all possible measures to increase patients' adherence to treatment (empowerment, delivery of oral drugs under direct control, use of i.v. formulation whenever possible), over 72 percent of evaluable patients had a very slow clinical, microbiological, and imaging ameliorement (1-6 months), with persistance of sputum and/or bronchoalveolar lavage (BAL) fluid positive for M.tuberculosis microscopy and/or culture for over 1-4 months (mean 9.2±3.2 weeks), during an apparently adequate treatment. When excluding patients suffering from XDR and MDR tuberculosis, in four subjects we observed that off-label linezolid adjunct together with at least three drugs with residual activity against tuberculosis, led to a significantly more rapid clinical-radiological improvement...

Increasing pathomorphism of pulmonary tuberculosis: an observational study of slow clinical, microbiological and imaging response of lung tuberculosis to specific treatment. Which role for linezolid?

During recent years, a progressive emerging of tuberculosis occurred, related to the overall increased age of general population, primary and secondary (iatrogenic) immunodeficiencies, the availability of invasive procedures, surgical interventions and intensive care supports, bone marrow and solid organ transplantation, and especially the recent immigration flows of people often coming from areas endemic for tuberculosis, and living with evident social-economical disadvantages, and with a reduced access to health care facilities. Since January 2006, at our reference centre we followed 81 consecutive cases of pulmonary tuberculosis, with 65 of them which remained evaluable for the absence of extrapulmonary complications, and a continuative and effective clinical and therapeutic follow-up. The majority of episodes of evaluable pulmonary tuberculosis (49 cases out of 65: 75,4%) occurred in patients who immigrated from developing countries. In two patients multiresistant (MDR) Mycobacterium tuberculosis strains were found, while two more subjects (both immigrated from Eastern Europe) suffered from a disease due to extremely resistant (XDR) M. tuberculosis strains. Although enforcing all possible measures to increase patients' adherence to treatment (empowerment, delivery of oral drugs under direct control, use of i.v. formulation whenever possible), over 72% of evaluable patients had a very slow clinical, microbiological, and imaging ameliorement (1-6 months), with persistance of sputum and/or bronchoalveolar lavage (BAL) fluid positive for M.tuberculosis microscopy and/or culture for over 1-4 months (mean 9.2+/-3.2 weeks), during an apparently adequate treatment. When excluding patients suffering from XDR and MDR tuberculosis, in four subjects we observed that off-label linezolid adjunct together with at least three drugs with residual activity against tuberculosis, led to a significantly more rapid clinical-radiological improvement and negative microbiological search, with consequent possibility to led to a protected discharge, supported by a sequential, oral therapy. Linezolid was also successfully employed in all the four patients with XDR or MDR pulmonary tuberculosis: among these patients, a definitive or temporarily negativization of respiratory secretions, and consequent discharge, was achieved only after linezolid adjunct. Notwithstanding the maintained microbiological susceptibility of M. tuberculosis strains responsible of the great majority of cases of pulmonary tuberculosis to first-line drugs, an unexpected tendency of patients to have a persistingly positive sputum and/or BAL, and to experience prolonged hospitalization for cure and isolation, has been recognized in the last years. No particularly suggestive radiological imaging seems predictive of a so prolonged course, so that we presently lack of clinical and imaging elements which may be predictive of this slow treatment response. The same is for demographic and epidemiological issues, eventual underlying diseases, and clinical presentation, so that a major problem for health care providers is to distinguish upon admission patients who will be prone to have slow therapeutic response and a related prolonged hospitalization. The novel oxazolidinone linezolid is characterized by an affordable in vitro activity against M. tuberculosis, and an extremely elevated intracellular concentration in respiratory tissues. Worldwide, increasing microbiological, pharmacological, and clinical evidences may recommend the use as linezolid adjunct as an off-label salvage treatment of pulmonary tuberculosis refractory to treatment, although not necessarily determined by resistant (MDR-XDR) M. tuberculosis strains. Randomized clinical trials including initially patients with ascertained chemioresistant tuberculosis, are strongly warranted.

Successful treatment of multi-resistant Pseudomonas aeruginosa osteomyelitis after allogeneic bone marrow transplantation with a combination of colistin and tigecycline.

A case of osteomyelitis caused by multidrug-resistant Pseudomonas aeruginosa is reported in a patient who underwent allogeneic bone marrow transplantation for acute lymphoblastic leukaemia. The patient was successfully treated by prolonged administration of a full dose of colistin and tigecycline, and surgical curettage with the positioning of resorbable calcium sulfate pellets loaded with colistin.

A puzzling microbiological and clinical discrepancy in the management of acute, severe skin-soft tissue and joint staphylococcal infection. In vitro antimicrobial susceptibility to glycopeptides, versus in vivo clinical efficacy of linezolid alone.

We present an intriguing case report of a septicemic post-elective surgical staphylococcal knee arthritis and cellulitis which did not respond to long-term courses of associated rifampicin and teicoplanin or vancomycin despite apparently favourable in vitro susceptibility assays, but rapidly resolved after i.v. followed by oral administration of linezolid. The lack of response to a two-week course of glycopeptides cannot be explained by the in vitro mimimum inhibitory concentrations (MIC90) of involved organisms, which showed full susceptibility of Staphylococcus aureus to vancomycin and teicoplanin, and sensitivity of an accompanying Staphylococcus epidermidis isolated from blood cultures to vancomycin and rifampicin, with borderline "intermediate" values found for teicoplanin. Since neither abscess formation nor bone involvement were of concern, effective glycopeptide and rifampicin penetration into infectious tissue should have been ensured. From a clinical point of view, only the introduction of a two-week i.v. linezolid followed by one more week of oral linezolid obtained a complete clinical and microbiological cure, and an unhoped-for functional success. When managing severe multiresistant gram-positive infections, in vitro activity should be carefully evaluated against expected drug penetration rates into the relevant infectious tissues.

Resolution of a Pseudomonas aeruginosa outbreak in a hematology unit with the use of disposable sterile water filters.

We observed a significant increase of Pseudomonas aeruginosa bacteremias during 2002. Eighty-five microbiological samples were taken from different potential sources of infection. Twenty-nine out of 46 specimens obtained from water taps, shower heads and siphons tested positive for Pseudomonas aeruginosa. Weekly pharyngeal and rectal swabs in high risk patients, use of tap water after running the tap for at least 5 minutes and use of weekly disposable sterile filters in all taps and showers resulted in a significant decrease in Pseudomonas aeruginosa bacteremias. Moreover, we observed a significant reduction in Pseudomonas aeruginosa-positive surveillance cultures after implementation of these measures.

Artificial intelligence techniques for monitoring dangerous infections.

The monitoring and detection of nosocomial infections is a very important problem arising in hospitals. A hospital-acquired or nosocomial infection is a disease that develops after admission into the hospital and it is the consequence of a treatment, not necessarily a surgical one, performed by the medical staff. Nosocomial infections are dangerous because they are caused by bacteria which have dangerous (critical) resistance to antibiotics. This problem is very serious all over the world. In Italy, almost 5-8% of the patients admitted into hospitals develop this kind of infection. In order to reduce this figure, policies for controlling infections should be adopted by medical practitioners. In order to support them in this complex task, we have developed a system, called MERCURIO, capable of managing different aspects of the problem. The objectives of this system are the validation of microbiological data and the creation of a real time epidemiological information system. The system is useful for laboratory physicians, because it supports them in the execution of the microbiological analyses; for clinicians, because it supports them in the definition of the prophylaxis, of the most suitable antibi-otic therapy and in monitoring patients' infections; and for epidemiologists, because it allows them to identify outbreaks and to study infection dynamics. In order to achieve these objectives, we have adopted expert system and data mining techniques. We have also integrated a statistical module that monitors the diffusion of nosocomial infections over time in the hospital, and that strictly interacts with the knowledge based module. Data mining techniques have been used for improving the system knowledge base. The knowledge discovery process is not antithetic, but complementary to the one based on manual knowledge elicitation. In order to verify the reliability of the tasks performed by MERCURIO and the usefulness of the knowledge discovery approach, we performed a test based on a dataset of real infection events. In the validation task MERCURIO achieved an accuracy of 98.5%, a sensitivity of 98.5% and a specificity of 99%. In the therapy suggestion task, MERCURIO achieved very high accuracy and specificity as well. The executed test provided many insights to experts, too (we discovered some of their mistakes). The knowledge discovery approach was very effective in validating part of the MERCURIO knowledge base, and also in extending it with new validation rules, confirmed by interviewed microbiologists and specific to the hospital laboratory under consideration.

A decade surveillance study of Mycobacterium xenopi disease and antimicrobial susceptibility levels in a reference teaching hospital of northern Italy: HIV-associated versus non-HIV-associated infection.

OBJECTIVE AND METHOD: The aim of our survey is to investigate the epidemiology and in vitro antimicrobial susceptibility levels of 35 consecutive Mycobacterium xenopi strains responsible for confirmed disease at a University Hospital from 1993 to 2002 and to identify eventual differences in the in vitro sensitivity profile between the 17 strains isolated from patients with HIV disease and the 18 isolates cultured from non-HIV-infected individuals. RESULTS: The involvement of lower airways accounted for 88.6% of cases; but atypical pulmonary findings, including cavitation and a prominent inflammatory reaction, recently emerged in HIV-infected patients successfully treated with HAART, which raises the possible role of immune reconstitution syndrome in the clinical pathomorphism of this opportunistic disease. When compared with non-HIV-infected patients, patients with HIV disease had a lower mean age and a tendency to suffer from late relapses. The greatest overall in vitro sensitivity rate was registered for capreomycin and protionamide (100% of strains) followed by kanamicin (96.6%), whereas susceptibility rates for the first-line compounds such as ethambutol, isoniazid, and rifampicin were slightly lower (85.7% to 91.4%). No temporal variation in the susceptibility index was seen over the study decade. Non-HIV-infected patients experienced a higher frequency of M. xenopi isolates that proved to be resistant to at least one tested compound compared with HIV-associated episodes, despite the heavy and prolonged exposure of HIV-infected patients to broad spectrum antimicrobials, which included agents effective on atypical mycobacteria. Only one HIV-positive patient developed rifampicin resistance in his third disease recurrence. CONCLUSION: A rapid diagnosis, a reliable differentiation between colonization and disease, and an optimal therapeutic choice for atypical mycobacterial disease (including M. xenopi one) are still serious challenges for clinicians and bacteriologists who treat immunocompromised patients, such as those with HIV disease. In the immunocompromised host, diagnostic difficulties posed by late identification and eventually concurrent opportunistic disorders add their negative effects to therapeutic problems due to the unpredictable in vitro susceptibility profile of atypical mycobacteria, such as M. xenopi.

Proposal to elevate the genetic variant MAC-A, included in the Mycobacterium avium complex, to species rank as Mycobacterium chimaera sp. nov.

The possibility that the strains included within the Mycobacterium avium complex (MAC), but not belonging either to M. avium or to Mycobacterium intracellulare, may be members of undescribed taxa, has already been questioned by several taxonomists. A very homogeneous cluster of 12 strains characterized by identical nucleotide sequences both in the 16S rDNA and in the 16S-23S internal transcribed spacer was investigated. Similar strains, previously reported in the literature, had been assigned either to the species M. intracellulare on the basis of the 16S rDNA similarity or to the group of MAC intermediates. However, several phenotypical and epidemiological characteristics seem to distinguish these strains from all other MAC organisms. The unique mycolic acid pattern obtained by HPLC is striking as it is characterized by two clusters of peaks, instead of the three presented by all other MAC organisms. All of the strains have been isolated from humans and all but one came from the respiratory tract of elderly people. The clinical significance of these strains, ascertained for seven patients, seems to suggest an unusually high virulence. The characteristics of all the strains reported in the literature, genotypically identical to the ones described here, seem to confirm our data, without reports of isolations from animals or the environment or, among humans, from AIDS patients. Therefore, an elevation of the MAC variant was proposed and characterized here, with the name Mycobacterium chimaera sp. nov.; this increases the number of species included in the M. avium complex. The type strain is FI-01069T (=CIP 107892T=DSM 44623T).

Role of Mycobacterium xenopi disease in patients with HIV infection at the time of highly active antiretroviral therapy (HAART). Comparison with the pre-Haart period.

BACKGROUND AND SETTING: A reliable and timely clinical, radiological, and bacteriological diagnosis, and an optimal treatment of non-tubercular mycobacteriosis (including Mycobacterium xenopi disease), remain an unanswered challenge for clinicians facing immunocompromised patients, including those with HIV infection. OBJECTIVE: The aim of our survey is to report the frequency, and the epidemiological, immunological, microbiological, clinical, and therapeutic features of all confirmed HIV-associated M. xenopi disease observed from 1993-2002, with special attention paid to eventual differences that emerged after the introduction of potent antiretroviral therapy (highly active antiretroviral therapy, HAART), on the basis of an international literature update. DESIGN AND RESULTS: Our series of 17 consecutive confirmed M. xenopi infections retrieved in 14 out of 3000 patients followed for HIV disease complications raises a broad series of clinical, diagnostic, therapeutic, and prophylactic concerns. The great majority of M. xenopi disease involved the lower respiratory tract, but atypical features including cavitation and prominent exudative features became apparent in patients successfully treated with HAART, pointing out the possible role of the so-called immune reconstitution syndrome in these episodes. CONCLUSIONS: Diagnostic problems represented by late or missed identification due to slow culture and frequently concomitant opportunistic disorders, join therapeutic difficulties due to the unpredictable in vitro antimicrobial susceptibility profile of these organisms, selection of treatment and chemoprophylaxis according with clinical-radiological and microbiological suspicion, and concomitantly administered medications.

[Methicillin-resistant Staphylococcus aureus: a three-year epidemiological and microbiological survey of high-risk patients]. / Staphylococcus aureus meticillino-resistente: tre anni di sorveglianza epidemiologica e microbiologica delle infezioni nel paziente ad alto rischio.

In order to assess the frequency, and epidemiological and microbiological features, of respiratory and blood stream infection due to methicillin-resistant Staphylococcus aureus in high-risk patients, all S. aureus strains cultured from reliable clinical specimens (respiratory secretions obtained by tracheo-bronchial aspirate or bronchoalveolar lavage, or blood cultures), were prospectively evaluated over a three-year period, in six inpatient wards selected on the ground of an elevated frequency of severe and/or nosocomially-acquired infections, because of the prevalence of immunocompromised patients, organ transplant recipients, or need of intensive care. Repeatedly positive cultures obtained from a single patient within 30 days were considered as one isolate. Of 507 S. aureus strains responsible for pneumonia or sepsis in the selected wards, 317 (62.5%) proved methicillin-resistant, in absence of significant variations throughout the study period, and according to the specimen origin. Methicillin-resistant S. aureus strains prevailed over sensitive ones in all examined wards (from a 95% rate of the respiratory intensive care unit, to 55.9% of the pneumology department), save the neonatal and pediatric intensive care unit (41.4%). Most of methicillin-resistant S. aureus isolates were recovered from lower airways, compared with blood cultures (p<.0001). The majority of the 317 methicillin-resistant strains were found in the general intensive care unit (42.6%), followed by the pneumology department (18%), and the respiratory intensive care unit (16.4%). Among methicillin-resistant S. aureus strains, a broad variation of sensitivity to other antimicrobial agents was observed: from 3.3% of erythromycin, to 76.9% of chloramphenicol, and 79.7% of cotrimoxazole; glycopeptide antibiotics remained effective against all cultured strains. In our three-year survey of more than 500 episodes of documented staphylococcal infection involving high-risk patients, methicillin resistance was a very common feature, observed at a greater frequency than that reported in literature studies focusing on surgical, pneumological, or intensive care settings. A long-term microbiological monitoring of high-risk inpatient wards may allow a continued update of local antimicrobial susceptibility maps, and significantly add to both chemoprophylaxis and empiric treatment strategies of patients which are either immunocompromised or hospitalized for a long period.

[Reduction of antibiotic resistance of Enterococcus faecalis in infections of the genitourinary tract]. / Riduzione dell'antibiotico-resistenza di Enterococcus faecalis in isolati urinari.

Antimicrobial susceptibility levels of Enterococcus faecalis isolated from urine were followed up at our University Hospital during three years (1999-2001), in order to evaluate the trend of antibiotic resistance of this common community-acquired pathogen of the genito-urinary tract. One thousand and 249 consecutive strains were examined, and a surprisingly low resistance profile was detected. As a result, penicillin , ampicillin, nitrofurantoin and piperacillin may still represent first-line agents in our area when community-acquired urinary tract enterococcal infections is of concern, pending in vitro susceptibility studies.

Fatal Campylobacter jejuni bacteraemia in patients with AIDS.

Two fatal cases of Campylobacter jejuni septicaemia in patients with AIDS were characterised by severe HIV-related immunodeficiency, negative stool cultures and presentation during hospitalisation, developing a clinical picture of fulminant septic shock despite therapy with appropriate antibiotics. Campylobacter spp. are important opportunist pathogens in HIV disease and may cause a septicaemic illness in the absence of enteric disease.