Simon Tiberi

In this thesis we address key topics encountered by people with drug-resistant (DR) tuberculosis (TB) in and outside the intensive care unit (ICU). The first part of the discussion focuses on treating patients with multidrug-resistant (MDR)-TB with repurposed drugs like carbapenems with beta-lactamase inhibitors. The second part of the discussion reports on the management of TB in the ICU and evaluates the use of intravenous drugs versus oral drugs. Notably, this thesis provides insights on the current gaps in management of TB patients with extensively drug resistance (XDR) and severe forms of the disease. Summary PART 1, beta-lactams In chapter 2 we present a multicenter observational study comparing the effectiveness and safety of imipenem/clavulanate versus meropenem/clavulanate in treating MDR and extensively drug-resistant XDR TB. The study included 180 patients, of which 96 were treated with meropenem/clavulanate and 84 with imipenem/clavulanate. Our results showed that meropenem/clavulanate was possibly more effective, with higher sputum smear and culture conversion rates and better treatment success rates compared to the imipenem/clavulanate group. Adverse events were rare and similar between the two groups, indicating that both regimens were well tolerated. The findings from this chapter are significant for people with MDR- and especially people with bedaquiline resistant XDR-TB with few therapeutic options. Furthermore the study highlights that meropenem/clavulanate-containing regimens could be more effective than imipenem/clavulanate-containing regimens. This information can guide clinicians in choosing the most effective treatment options, potentially leading to higher sputum culture conversion rates and better overall treatment success. The similar safety profiles of both regimens also provides reassurance of the tolerability and safety of these treatments. In chapter 3, the effectiveness and safety of meropenem/clavulanate-containing regimens in treating MDR- and XDR-TB is evaluated. The study included 264 patients, 96 treated with meropenem/clavulanate and 168 with meropenem/clavulanate-sparing regimens. The study reported that meropenem/clavulanate was effective in achieving sputum smear and culture conversion rates similar to those of the control group, despite the meropenem/clavulanate group having more severe disease and resistance to a larger number of drugs (one of the reasons why meropenem/clavulanate was used). Adverse events were few and mainly gastrointestinal, further confirming the safety and tolerability of meropenem/clavulanate. This chapter underscores the effectiveness and safety of meropenem/clavulanate containing regimens in treating MDR- and XDR-TB, especially in challenging patients with severe disease and high drug resistance. For patients, this means that meropenem/clavulanate can be a viable treatment option that offers a good efficacy and safety profile. The findings support the use of meropenem/clavulanate as part of a comprehensive treatment plan DR TB. In chapter 4, we compared the effectiveness and safety of imipenem/clavulanate added to an optimized background regimen (OBR) which at that time was a minimum of 20 months versus OBR control regimens in treating MDR- and XDR-TB. The study included 84 patients treated with imipenem/clavulanate-containing regimens and 168 controls treated with OBR alone. The results showed that imipenem/clavulanate-containing regimens achieved similar or lower sputum smear and culture conversion rates and treatment success rates compared to the control group. Adverse events were minor and infrequent, indicating that imipenem/clavulanate was well tolerated. The results from this chapter indicate that adding imipenem/clavulanate to an optimized background regimen does not significantly improve treatment outcomes compared to the OBR alone. For patients, this suggests that while imipenem/clavulanate is well tolerated, it may not provide additional benefits over existing treatment regimens. This information can help clinicians make informed decisions about the inclusion of imipenem/clavulanate in treatment regimens. In chapter 5, we present a case study of a person with XDR-TB who developed renal Fanconi syndrome while receiving a meropenem/amoxicillin-clavulanate-containing regimen. The patient experienced symptoms such as hypophosphatemia, metabolic acidosis, proteinuria, and glycosuria, consistent with generalized proximal tubular dysfunction. The condition improved upon discontinuation of the meropenem/amoxicillin-clavulanate regimen. This case calls attention to the potential for renal Fanconi syndrome as an adverse event associated with long-term use of meropenem/amoxicillin-clavulanate in treating DR-TB. Clinicians can use this information to implement appropriate monitoring protocols and make timely adjustments to treatment regimens to ensure patient safety and to monitor patients for potential renal complications during treatment. The combined findings from these chapters provide valuable insights into the effectiveness and safety of carbapenem-containing regimens for treating MDR- and XDR-TB. They highlight the potential benefits of meropenem/clavulanate and the need for careful monitoring of adverse events. For people with XDR-TB, these insights could lead to more effective and safer treatment options, and lives saved. PART 2, intensive care In chapter 6, a systematic review of studies on the outcomes of people with pulmonary TB admitted to ICUs is provided. The review included 17 studies, with a total of 947 cases. The findings revealed that mortality rates for people with TB in ICU ranged from 29% to 95%, with a mean of 52.9%. The most common reason for ICU admission was acute respiratory failure. Negative predictors of outcome included hospital-acquired infections, the need for mechanical ventilation and vasopressors, delayed initiation of anti-TB treatment, multiple organ failure, and higher severity scores. The review also reported that existing severity scoring systems, such as APACHE II and SAPS II, often underestimate mortality in people with TB. The chapter emphasizes the need for earlier detection and treatment initiation to improve outcomes for people critically ill with TB. In chapter 7, we report on a multicentric international observational study conducted by the International Severe TB and Rehabilitation Working Group of the Global Tuberculosis Network. The study included 434 TB patients aged over 15 years, admitted to ICUs across Europe, Asia, and Latin America from 2005 to 2018. Key findings include that over half of the patients were sputum smear-positive, and 85.7% were culture-positive. Most patients required invasive mechanical ventilation, vasopressor support, and steroids. Only 48.4% had TB medications initiated before or during ICU admission. The overall mortality rate was 54.8%, with 33.4% achieving treatment success. Intravenous (IV) anti-TB drugs were administered to 43% of participants, with levofloxacin and amikacin being the most used. IV treatment lasting longer than 10 days was associated with better outcomes. IV rifampicin was linked to a lower mortality rate (35.7%) compared to those who did not receive it (51.7%). We conclude that the high mortality rates seen in ICU TB patients necessitate improved management strategies. IV anti-TB drugs, particularly IV rifampicin, show potential benefits, suggesting the need for further prospective studies. Early screening and start of standardized treatment protocols could improve patient outcomes in high-incidence areas.