Tuberculosis (TB) is the world’s second leading infectious killer. Cases of multidrug-resistant (MDR-TB) and extremely drug-resistant (XDR-TB) have increased globally. Therapeutic drug monitoring (TDM) remains a standard clinical technique for using plasma drug concentrations to determine dose. For TB patients, TDM provides objective information for the clinician to make informed dosing decisions. Some patients are slow to respond to treatment, and TDM can shorten the time to response and to treatment completion. Normal plasma concentration ranges for the TB drugs have been defined. For practical reasons, only one or two samples are collected post-dose. A 2-h post-dose sample approximates the peak serum drug concentration (Cmax) for most TB drugs. Adding a 6-h sample allows the clinician to distinguish between delayed absorption and malabsorption. TDM requires that samples are promptly centrifuged, and that the serum is promptly harvested and frozen. Isoniazid and ethionamide, in particular, are not stable in human serum at room temperature. Rifampicin is stable for more than 6 h under these conditions. Since our 2002 review, several papers regarding TB drug pharmacokinetics, pharmacodynamics, and TDM have been published. Thus, we have better information regarding the concentrations required for effective TB therapy. In vitro and animal model data clearly show concentration responses for most TB drugs. Recent studies emphasize the importance of rifamycins and pyrazinamide as sterilizing agents. A strong argument can be made for maximizing patient exposure to these drugs, short of toxicity. Further, the very concept behind ‘minimal inhibitory concentration’ (MIC) implies that one should achieve concentrations above the minimum in order to maximize response. Some, but not all clinical data are consistent with the utility of this approach. The low ends of the TB drug normal ranges set reasonable ‘floors’ above which plasma concentrations should be maintained. Patients with diabetes and those infected with HIV have a particular risk for poor drug absorption, and for drug–drug interactions. Published guidelines typically describe interactions between two drugs, whereas the clinical situation often is considerably more complex. Under ‘real–life’ circumstances, TDM often is the best available tool for sorting out these multi-drug interactions, and for providing the patient safe and adequate doses. Plasma concentrations cannot explain all of the variability in patient responses to TB treatment, and cannot guarantee patient outcomes. However, combined with clinical and bacteriological data, TDM can be a decisive tool, allowing clinicians to successfully treat even the most complicated TB patients.

Therapeutic drug monitoring in the treatment of tuberculosis: an update

https://projecteuclid.org/download/pdf_1/euclid.rmjm/1206459504

An Overview of Graphs Associated with Character Degrees And Conjugacy Class Sizes in Finite Groups

Fluoroquinolone antibiotics are commonly used to treat infections and are prescribed by general practitioners, medical specialists and surgeons. Tendon injury has been associated with the use of these medications but the risk associated with newer fluoroquinolones has not been established. The aim of this systematic review was to evaluate the evidence from observational studies to determine the strength of the association between fluoroquinolone use and tendinopathy, and to identify risk factors for this complication. We searched MEDLINE, EMBASE and the Cochrane Collaboration from inception through May 2013 to identify observational studies focused on tendon injury and fluoroquinolones. Studies with original data were selected for inclusion following the PRISMA guidelines. Of the 560 abstracts screened, 16 relevant studies were independently rated by three authors (WW, AS, DC) using the Newcastle-Ottawa Quality Assessment Scale, and assigned a quality score out of 9. High-quality studies (i.e. scored 4.5 or higher) are summarized in detail in this article. Data were independently extracted by two authors (WW, AS). Overall, 16 studies were included in our study. Eight were deemed to be of high quality and five specifically evaluated Achilles tendon rupture. In addition, three studies examined Achilles tendinitis, and three included tendon disorders (including any tendon rupture) as an outcome. Results from these studies suggest that individuals exposed to fluoroquinolones are at increased risk for Achilles tendon rupture, particularly within the first month following exposure to the drug (odds ratios ranged from 1.1 to 7.1). One study showed an increased risk of tendon rupture in those over 60 years of age. Five studies stated that individuals taking fluoroquinolones and oral corticosteroids are at increased risk for tendon injury compared with those taking fluoroquinolones alone. Four studies examined the differential effect of a limited number of fluoroquinolones. Ofloxacin had the highest risk of tendon injury in three of the studies. Included studies are observational in nature and rely on self-report, which may lead to misclassification or underestimation of tendon injury. Observational studies showed an increased risk of tendon injury, including tendon rupture and tendinitis, with exposure to fluoroquinolone antibiotic therapy. Although this complication appears to be rare, concomitant corticosteroids increase the risk for tendon injury, which varies depending on the fluoroquinolone used.

Tendon Injury and Fluoroquinolone Use: A Systematic Review

Importance Bacteremia causes considerable morbidity among children with acute leukemia and those undergoing hematopoietic stem cell transplantation (HSCT) There are limited data on the effect of antibiotic prophylaxis in children Objective To determine the efficacy and risks of levofloxacin prophylaxis in children receiving intensive chemotherapy for acute leukemia or undergoing HSCT Design, setting, and participants In this multicenter, open-label, randomized trial, patients (6 months-21 years) receiving intensive chemotherapy were enrolled (September 2011-April 2016) in 2 separate groups-acute leukemia, consisting of acute myeloid leukemia or relapsed acute lymphoblastic leukemia, and HSCT recipients-at 76 centers in the United States and Canada, with follow-up completed September 2017 Interventions Patients with acute leukemia were randomized to receive levofloxacin prophylaxis for 2 consecutive cycles of chemotherapy (n = 100) or no prophylaxis (n = 100) Those undergoing HSCT were randomized to receive levofloxacin prophylaxis during 1 HSCT procedure (n = 210) or no prophylaxis (n = 214) Main outcomes and measures The primary outcome was the occurrence of bacteremia during 2 chemotherapy cycles (acute leukemia) or 1 transplant procedure (HSCT) Secondary outcomes included fever and neutropenia, severe infection, invasive fungal disease, Clostridium difficile-associated diarrhea, and musculoskeletal toxic effects Results A total of 624 patients, 200 with acute leukemia (median [interquartile range {IQR}] age, 11 years [6-15 years]; 46% female) and 424 undergoing HSCT (median [IQR] age, 7 years [3-14]; 38% female), were enrolled Among 195 patients with acute leukemia, the likelihood of bacteremia was significantly lower in the levofloxacin prophylaxis group than in the control group (219% vs 434%; risk difference, 216%; 95% CI, 88%-344%, P = 001), whereas among 418 patients undergoing HSCT, the risk of bacteremia was not significantly lower in the levofloxacin prophylaxis group (110% vs 173%; risk difference, 63%; 95% CI, 03%-130%; P = 06) Fever and neutropenia were less common in the levofloxacin group (712% vs 821%; risk difference, 108%; 95% CI, 42%-175%; P = 002) There were no significant differences in severe infection (36% vs 59%; risk difference, 23%; 95% CI, -11% to 56%; P = 20), invasive fungal disease (29% vs 20%; risk difference, -10%; 95% CI, -34% to 15%, P = 41), C difficile-associated diarrhea (23% vs 52%; risk difference, 29%; 95% CI, -01% to 59%; P = 07), or musculoskeletal toxic effects at 2 months (114% vs 163%; risk difference, 48%; 95% CI, -16% to 112%; P = 15) or at 12 months (101% vs 144%; risk difference, 43%; 95% CI, -34% to 120%; P = 28) between the levofloxacin and control groups Conclusions and relevance Among children with acute leukemia receiving intensive chemotherapy, receipt of levofloxacin prophylaxis compared with no prophylaxis resulted in a significant reduction in bacteremia However, there was no significant reduction in bacteremia for levofloxacin prophylaxis among children undergoing HSCT

/pdf/effect-of-levofloxacin-prophylaxis-on-bacteremia-in-children-3cab4j8eyj.pdf

Effect of Levofloxacin Prophylaxis on Bacteremia in Children With Acute Leukemia or Undergoing Hematopoietic Stem Cell Transplantation: A Randomized Clinical Trial.

Heel pain is a common presenting symptom in ambulatory clinics. There are many causes, but a mechanical etiology is most common. Location of pain can be a guide to the proper diagnosis. The most common diagnosis is plantar fasciitis, a condition that leads to medial plantar heel pain, especially with the first weight-bearing steps in the morning and after long periods of rest. Other causes of plantar heel pain include calcaneal stress fracture (progressively worsening pain following an increase in activity level or change to a harder walking surface), nerve entrapment (pain accompanied by burning, tingling, or numbness), heel pad syndrome (deep, bruise-like pain in the middle of the heel), neuromas, and plantar warts. Achilles tendinopathy is a common condition that causes posterior heel pain. Other tendinopathies demonstrate pain localized to the insertion site of the affected tendon. Posterior heel pain can also be attributed to a Haglund deformity, a prominence of the calcaneus that may cause bursa inflammation between the calcaneus and Achilles tendon, or to Sever disease, a calcaneal apophysitis in children. Medial midfoot heel pain, particularly with continued weight bearing, may be due to tarsal tunnel syndrome, which is caused by compression of the posterior tibial nerve as it courses through the flexor retinaculum, medial calcaneus, posterior talus, and medial malleolus. Sinus tarsi syndrome occurs in the space between the calcaneus, talus, and talocalcaneonavicular and subtalar joints. The syndrome manifests as lateral midfoot heel pain. Differentiating among causes of heel pain can be accomplished through a patient history and physical examination, with appropriate imaging studies, if indicated.

Diagnosis of heel pain.

Objective: To investigate the association between the use of fluoroquinolone agents and the risk of tendinitis in a large population-based case-control study. Methods: The study was performed by linking automated health databases from the Region of Lombardia, Italy. Cases were patients aged ≥18 years who had a hospital discharge diagnosis of non-traumatic tendinitis in 2002–3. For each case, up to five controls were randomly selected among those eligible for inclusion in the study. A conditional logistic regression model was used to estimate the odds ratio of tendinitis associated with the current, recent and past use of fluoroquinolones. Odds ratios were adjusted for exposure to other antibacterials and other drugs. Results: 22 194 cases and 104 906 controls met the inclusion criteria. Current use of fluoroquinolones significantly increased the risk of tendon disorders as a whole (odds ratio [OR] = 1.7; 95% CI 1.4, 2.0), tendon rupture (OR = 1.3; 95% CI 1.0, 1.8) and rupture of the Achilles’ tendon (OR = 4.1; 95% CI 1.8, 9.6). Concomitant use of corticosteroids and fluoroquinolones increased the risk of both tendon rupture (OR = 3.1; 95% CI 1.5, 6.3) and rupture of the Achilles’ tendon (OR = 43.2; 95% CI 5.5, 341.1). Discussion: Evidence that exposure to fluoroquinolones is associated with the sudden occurrence of tendinitis is supported by this large population-based study. We can estimate that a single case of rupture of the Achilles’ tendon would occur for every 5958 persons treated with fluoroquinolones (95% CI 2148, 23 085). The corresponding number needed to harm is 979 (95% CI 122, 9172) for patients who concomitantly use corticosteroids and 1638 (95% CI 351, 8843) for those aged >60 years. Conclusion: Clinicians should be aware of this adverse effect, and the increased risk for fluoroquinolone-associated tendinitis in elderly patients with corticosteroid use must be considered when these agents are prescribed.

Evidence of tendinitis provoked by fluoroquinolone treatment: a case-control study.

On finite solvable groups in which normality is a transitive relation

Applications of a graph related to conjugacy classes in finite groups

On finite groups with nilpotent Sylow-normalizers

Subgrouppermutability in a finite group is studied, in order to distinguish between irreducible and reducible groups and to give a bound for the diameter. A simple nonabelian finite group is irreducible and its diameter is less or equal16 while a reducible group is forced to be soluble and the bound of the diameter of such a group is 4.

/pdf/finite-groups-and-subgroup-permutability-4kixprgwrk.pdf

Anna Gillio Berta Mauri

Papers

Evidence of tendinitis provoked by fluoroquinolone treatment: a case-control study.

On finite solvable groups in which normality is a transitive relation

Applications of a graph related to conjugacy classes in finite groups

On finite groups with nilpotent Sylow-normalizers

Finite groups and subgroup-permutability