1. WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Care and Research Institute, Tradate, Italy
2. E. Morelli Hospital, Reference Hospital for MDR and HIV/ TB, Sondalo, Italy
3. Supranational Reference Laboratory, S. Raffaele Institute, Milano, Italy
Extensively Drug Resistant Tuberculosis (XDR-TB) is a very serious form of TB against which our treatment weapons have lost the majority of, if not all, their power [1-5].
The term XDR-TB appeared for the first time only in March 2006, to describe a form of disease caused by strains of Mycobacterium tuberculosis
which were resistant not only to isoniazid and rifampicin (i.e., the definition of multidrug-resistant TB, MDR-TB), but also to at least three of the six classes of second-line anti-TB drugs (aminoglycosides, polypeptides, fluoroquinolones, thioamides, cycloserine and para-aminosalycilic acid) .
The definition was modified in October 2006 to define cases that are resistant to at least rifampicin and isoniazid, in addition to any fluoroquinolone, and to at least one of the three following injectable drugs used to treat TB: capreomycin, kanamycin and amikacin . Available evidence shows that 10 out of 21 countries that had at least one notified case of XDR-TB as of March 2007, are in, or bordering, Europe . Recently, the term “XXDR” was proposed  to define "extremely drug resistant" TB, i.e. the cases being resistant to all first- and second-line drugs with a proven activity against M. tuberculosis
Report on two XXDR cases in Italy
A study from Italy and Germany has recently demonstrated that the occurrence of XDR-TB, as currently defined, has both a clinical value (predicting poor outcome) and an operational implication (underlying the loss of first-line drugs coupled with key second-line ones) . The study reports on the first two cases that were resistant to all drugs tested. The cases have some similarities: both of them were young females, born in Italy and belonging to middle class families. Both of them were diagnosed and initially treated in non-specialised TB facilities where they received three different treatment courses for over 30 days before being admitted as MDR-TB to the reference hospital in Sondalo with a very severe clinical picture (extended bilateral cavities). Both died in 2003, before 50 years of age, after a long, unsuccessful treatment with all the available drugs without achieving bacteriological conversion.
Case 1 had acquired TB from her mother, who was already known to have MDR-TB. Case 1 in turn transmitted the disease to her daughter, who was diagnosed a localised form of TB (pre-clinical stage) at the age of 14 years and was declared cured after three years of treatment and a surgical intervention to remove the monolateral lesion. Case 1 was admitted to three different hospitals for a total of 422 days. She was prescribed, at different times, the following drugs: 1) first-line drugs: streptomycin, rifampicin, isoniazid, ethambutol and pyrazinamide; 2) second-line drugs: fluoroquinolones, ethionamide, amikacin, para-aminosalycilic acid, capreomycin, kanamycin and cycloserine; 3) additional drugs: rifabutin, clofazimine, dapsone, claritromycin and thiacetazon. The third treatment regimen, prescribed in the reference hospital, was followed for 94 months until death .
Drug susceptibility testing (DST) was performed for all the drugs mentioned above with the exception of dapsone, claritromycin and thiacetazon. Resistance was found on all the drugs tested.
Case 2 was admitted to two different hospitals for a total of 625 days. The patient was prescribed, at different times, the following drugs: 1) first-line drugs: streptomycin, rifampicin, isoniazid, ethambutol and pyrazinamide; 2) second-line drugs: fluoroquinolones, ethionamide, amikacin, para-aminosalycilic acid, capreomycin, kanamycin and cycloserine; 3) additional drugs: rifabutin, clofazimine, dapsone, claritromycin and thiacetazon. The last treatment regimen, prescribed in the reference hospital, was followed until death for 60 months .
According to DST, case 2 was found to be resistant to all the drugs with known anti-TB activity
In both cases the drug susceptibility tests showed that resistance to new drugs was acquired over time. Case 1 was initially mismanaged, and then admitted at the reference hospital being already resistant to the majority of the available drugs. Case 2 management and adherence to the regimen prescribed was sub-optimal before admission to the reference hospital.
Implications for surveillance
The reasons why a few drugs were not tested in case 2 (including lack of standardisation/guidelines on the drugs to be tested, limited effects of the drugs in clinical practice, evidence of resistance to another anti-leprosy drug – clofazimine, known adverse effects of thiacetazone, lack of poor substance to perform DST, etc.) explain why surveillance still has difficulties in identifying all existing XDR-TB cases. Few laboratories in Italy, as in other European countries, are equipped to perform DST for all the second line drugs necessary to define XDR-TB. Furthermore, in vitro testing is not considered reliable for some of the second-line drugs. It is really possible that a certain proportion of MDR-TB cases notified in Europe (particularly those already treated for TB in the past) are also XDR-TB.
Implications for control
All XDR- and about 50% of MDR-TB cases as reported in the study mentioned above  were previously treated for TB in the past. This finding, coupled with the unlucky story of the two cases mentioned above, suggests the major role played by mismanagement of TB cases and sub-optimal infection control in determining the emergence of the problem. Furthermore, the finding that immigration is significantly associated with the XDR-TB status (multivariate analysis, Italy-Germany study ) needs to be underlined.
Improvement of policies and practices is necessary if we want to reach TB elimination in Europe.