Curtis L. Smith

Chemical venous thromboembolic prophylaxis is safe and effective for patients with traumatic brain injury when started 24 hours after the absence of hemorrhage progression on head CT.

BACKGROUND Venous thromboembolism (VTE) continues to be an important complication for patients with trauma, including patients with intracranial hemorrhage. We implemented a protocol starting chemical prophylaxis 24 hours after the absence of progression of hemorrhage on computed tomography (CT) to increase consistency with the use of chemical venous thromboembolic prophylaxis in this population. The objective of this study was to review the protocol of VTE prophylaxis for patients with traumatic brain injury at our institution to determine whether it has been effective and safe in preventing VTE without increasing intracranial hemorrhage. METHODS A retrospective case series was conducted to study 205 patients with intracranial hemorrhage admitted to a Level I trauma center during a 24-month period. These patients were reviewed with respect to type of intracranial injury, need for surgery, injury severity, time to initiation of chemical prophylaxis, and progression of injury on brain CT. Patients with a hospital length of stay less than 3 days or nonstable CT were excluded in the analysis of administration of chemical prophylaxis. Time to chemical prophylaxis in relation to absence of progression on brain CT was examined as well as the subsequent risk of progression of hemorrhage and risk of VTE events. The overall rate of venous thromboembolism was compared with that of matched historical controls. RESULTS All patients received mechanical prophylaxis in the form of sequential compression devices. One hundred sixty-two intracranial hemorrhages were identified in 122 patients who met the study’s inclusion criteria. Of this group of patients who did not have progression of hemorrhage on follow-up CT, 76.2% received chemical prophylaxis during their hospitalization. No patients had progression of intracranial hemorrhage after initiation of chemical VTE prophylaxis, and no patients developed VTE. This represents a decrease of VTE from previous years. No other complications related to chemical VTE prophylaxis were identified. CONCLUSION A protocol based on an early use of chemical venous thromboembolic prophylaxis after the absence of progression of tramatic intracranial hemorrhage does not result in increased progression of intracranial hemorrhage and reduced the rate of venous thromboembolic events at our institution. LEVEL OF EVIDENCE Therapeutic study, level IV.

Tigecycline penetration into skin and soft tissue

BACKGROUND Tigecycline, a derivative of minocycline, has antibacterial activity against common pathogens associated with complicated skin and soft tissue infections (cSSTIs), including methicillin-resistant Staphylococcus aureus. At present, there is a paucity of data concerning its penetration into skin and soft tissue (SST). METHODS This study evaluated the penetration of tigecycline into SST in 25 patients (mean age, 52 years) with cSSTIs requiring surgical intervention. After a 100-mg loading dose, each patient received 50 mg of tigecycline infused intravenously over 1 h every 12 h. Blood samples were obtained on the day of surgery at 1 h (peak), during surgery, and 12 h (trough) after the beginning of a 50-mg infusion. A viable SST sample was harvested at the infection site. Tissue and concomitant serum concentrations were grouped into three time intervals: 2-4 h (median, 3 h), 5-7 h (median, 7 h), and 8-10 h (median, 9h), and analyzed for tissue penetration. RESULTS Tissue and blood samples were obtained one to six days (mean 2.5 days) after initiation of tigecycline treatment. The mean serum peak and trough concentrations of tigecycline were 0.56±0.25 mg/L and 0.26±0.12 mg/L, respectively. The mean tissue:serum ratios at the three study time periods were 3.8 (range 0.7-5.5), 5.2 (range 0.8-7.1), and 2.8 (range 0.8-8.8). CONCLUSIONS In general, we found higher concentrations of tigecycline in SST than in the serum at the same time point.

Tissue penetration and antimicrobial activity of standard- and high-dose trimethoprim/sulfamethoxazole and linezolid in patients with diabetic foot infection

OBJECTIVES The purpose of this study was to conduct a pharmacokinetic and pharmacodynamic evaluation of high (320/1600 mg) and standard (160/800 mg) doses of trimethoprim/sulfamethoxazole and linezolid in outpatients with mild diabetic foot infections (DFIs). METHODS Both viable skin/soft tissue from the infection site and serum were obtained at various times after antibiotic administration from 18 patients (6 per study group) being treated with linezolid, standard doses of trimethoprim/sulfamethoxazole or high doses of trimethoprim/sulfamethoxazole during a follow-up clinic visit. These samples were assayed for drug concentrations by liquid chromatography in tandem with mass spectrometry. Patient sera were also utilized in time-kill assays against two strains of Staphylococcus aureus and three strains of β-haemolytic streptococci. RESULTS The mean tissue/serum ratio for linezolid was 0.46 (range, 0.18-0.71). The mean tissue/serum ratio for trimethoprim was 1.2 (range, 0.3-4.5) for both standard and high doses, and 0.23 (range, 0.1-0.46) and 0.36 (range, 0.14-1.28) for standard and high doses of sulfamethoxazole, respectively. Linezolid exhibited inhibitory activity in time-kill assays against strains of S. aureus (0.45 ± 0.5 log10 cfu/mL) and β-haemolytic streptococci (2.2 ± 0.6 log10 cfu/mL), while trimethoprim/sulfamethoxazole exhibited bactericidal (>3 log kill) activity against all of these isolates. These findings were consistent for each sampling time and for high as well as standard doses of trimethoprim/sulfamethoxazole. CONCLUSIONS This pharmacokinetic/pharmacodynamic study found that trimethoprim/sulfamethoxazole exhibits good skin/soft tissue penetration in patients with DFIs as well as bactericidal activity in serum against strains of S. aureus and β-haemolytic streptococci.

Local Therapy for Cytomegalovirus Retinitis

OBJECTIVE: To examine the role of intraocular therapy in the management of cytomegalovirus (CMV) retinitis associated with AIDS. DATA SOURCES: A MEDLINE search was conducted for the years 1980–1997. In addition, relevant articles were cross-referenced to screen for additional information. The AIDS/HIV Treatment Directory was searched for information on ongoing studies. STUDY SELECTION/DATA EXTRACTION: Data regarding the use of local antiviral therapy for CMV retinitis are cited. Emphasis was placed on randomized, controlled trials, but descriptive studies are also included. DATA SYNTHESIS: Intraocular drug administration is an alternative therapy for CMV retinitis that avoids some of the disadvantages associated with systemic treatment. Intravitreal ganciclovir 200–2000 μg once weekly has been studied in a number of nonrandomized studies. Although initially effective, intravitreal ganciclovir is associated with a significant relapse rate and development of contralateral CMV retinitis. Intraocular ganciclovir implants offer the advantage of less frequent interventions and constant drug concentrations in the vitreous. Time to progression is significantly longer in patients receiving implants versus intravenous therapy; however, there is a higher incidence of contralateral eye retinitis and extraocular CMV disease with the implants. Currently, the intraocular implant is being studied in combination with oral ganciclovir to decrease the incidence of systemic CMV disease. Foscarnet and cidofovir have also been administered intravitreally for CMV retinitis. Cidofovir may offer the advantage of a long intracellular half-life, which would allow infrequent dosing; however, further study is needed to determine a safe and effective intraocular dosage. CONCLUSIONS: Systemic therapy continues as standard management for CMV retinitis. Local therapy has some advantages and disadvantages, but larger, randomized, controlled trials comparing systemic therapy with local therapy must be completed to define its exact role. Data from an ongoing trial of local plus oral therapy will better define this role.

Pharmacokinetics and Monte Carlo Simulations of Doripenem in Patients with Febrile Neutropenia

Background: Doripenem is a group 2 carbapenem with enhanced in vitro activity against gram-negative bacteria including Pseudomonas aeruginosa. There is a paucity of pharmacokinetic/pharmacodynamic data on doripenem in patients with febrile neutropenia. Objective: To conduct a pharmacokinetic evaluation of 2 doses of doripenem in patients with febrile neutropenia and provide probability estimates of attaining effective drug exposure against common gram-negative pathogens. Methods: We obtained multiple blood samples from 12 adults with febrile neutropenia who were receiving either 500 mg or 1000 mg of intravenous doripenem over 4 hours every B hours. Following at least 2 doses, serum concentrations were measured in each subject at 1, 4, 6, and 8 hours after initiation of a dose by a validated high-performance liquid chromatography assay. The derived pharmacokinetic parameters from these serum levels were used to perform a 5000-patient Monte Carlo simulation against bacteria with minimal inhibitory concentrations (MICs) of 0.008-64 mg/L to determine probability estimates of the time in which unbound drug concentrations remain above the MIC (fT>MIC). Results: The mean pharmacokinetic parameters in these patients were a volume of distribution of 43.9 L, an elimination rate constant of 0.37 h-1, a total clearance of 14.4 L/h, and an area under the concentration-time curve of 57.6 mg·h/L. An optimal probability of target attainment (40% fT>MIC) of 90% was obtained against bacteria with MICs ≤2 mg/L and ≤4 mg/L with 500-mg and 1000-mg doses, respectively. Adverse events associated with doripenem were not observed. Conclusions: The findings from this analysis of doripenem suggest that higher doses, as well as prolonged infusions, may be necessary to optimally treat selected gram-negative bacteria (eg, P. aeruginosa) in patients with febrile neutropenia.

Viral Load as a Surrogate End Point in HIV Disease

OBJECTIVE: To examine the role of viral load as a surrogate end point for HIV disease progression and death. DATA SOURCES: A MEDLINE search was conducted for the years 1990–March 2001. In addition, relevant articles were cross-referenced to screen for additional information. STUDY SELECTION AND DATA EXTRACTION: Data regarding the validity of viral load as a surrogate end point for disease progression or death are cited. Emphasis was placed on randomized, controlled trials, but descriptive studies are also included. DATA SYNTHESIS: Recently, viral load has emerged as an important biomarker for monitoring HIV disease and antiretroviral therapy. Both baseline viral load and changes in viral load with time predict HIV disease progression and death. In fact, disease progression increases consistently once viral load exceeds 10 000 copies/mL, and AIDS and death primarily occur in patients with viral loads >100 000 copies/mL. Changes that occur in viral load after initiation of antiretroviral therapy, however, do not fully explain the entire treatment effect. Also, separate comparisons of antiretroviral regimens may demonstrate similar differences in viral load changes but not similar differences in disease progression. CONCLUSIONS: Viral load is an important monitoring parameter for HIV disease and antiretroviral therapy. However, changes in viral load do not explain the entire clinical improvement that occurs after initiation of therapy. Although viral load is a clinically important surrogate end point for HIV disease, it cannot fully account for all associated treatment effects.

Fungicidal activity of anidulafungin in serum from patients does not correlate to its susceptible breakpoint against Candida spp.

A et al. A multicenter trial of the efficacy and safety of tigecycline versus imipenem/cilastatin in patients with complicated intra-abdominal infections. BMC Infect Dis 2005; 5: 88. 2 Ellis-Grosse EJ, Babinchak T, Dartois N et al. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 comparison studies with vancomycin-aztreonam. 3 Tanaseanu C, Bergallo C, Teglia O et al. Integrated results of 2 phase 3 studies comparing tigecycline and levofloxacin in community-acquired pneumonia. 4 Curcio D. Tigecycline for treating bloodstream infections: a critical analysis of the available evidence. 6 Jenkins I. Linezolid-and vancomycin-resistant Enterococcus faecium endocarditis: successful treatment with tigecycline and daptomycin. 7 Schutt AC, Bohm NM. Multidrug-resistant Enterococcus faecium endocarditis treated with combination tigecycline and high-dose daptomycin. 9 Florescu I, Beuran M, Dimov R et al. Efficacy and safety of tigecycline compared with vancomycin or linezolid for treatment of serious infections with methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococci: a Phase 3, multicentre, double-blind, randomized study. 10 Cunha BA. Once-daily tigecycline therapy of multidrug-resistant and non-multidrug-resistant Gram-negative bacteraemias. 12 Anthony K, Fishman N, Linkin D et al. Clinical and microbiological outcomes of serious infections with multidrug-resistant Gram-negative organisms treated with tigecycline. A Phase 3, open-label, non-comparative study of tigecycline in the treatment of patients with selected serious infections due to resistant Gram-negative organisms including Enterobacter species, Acinetobacter baumannii and Klebsiella pneumoniae. Use of tigecycline for the treatment of prolonged bacteraemia due to a multiresistant VIM-1 and SHV-12 b-lactamase-producing Klebsiella pneumoniae epidemic clone. Clinical experience of serious infections caused by Enterobacteriaceae producing VIM-1 metallo-b-lactamase in a Greek university hospital. 18 Rolston K, Raad I, Hachem R et al. Tigecycline use in cancer patients with serious infections. A report on 110 cases from a single institution. Fungicidal activity of anidulafungin in serum from patients does not correlate to its susceptible breakpoint against Candida spp. Sir, Echinocandins, such as anidulafungin, are now considered a primary treatment for patients with suspected candidiasis or candidaemia. 1 Common Candida spp. are highly susceptible to these antifungal agents and .99% of isolates are inhibited by 2 mg/L, the current susceptible breakpoint. 2 In vitro time – kill studies find that echinocandins are fungicidal against Candida spp. at concentrations achieved in serum. 3 A major concern with the results from in vitro studies is the absence of testing in the presence of serum proteins. The echinocandins are highly …

Is There a Role for Fluconazole in the Treatment of Vulvovaginal Candidiasis

OBJECTIVE: To review the data describing the use of fluconazole in the treatment of vulvovaginal candidiasis (VVC). DATA IDENTIFICATION: A MEDLINE search of the English-language literature and a bibliographic review of pertinent articles examining the use of fluconazole in the treatment of VVC. STUDY SELECTION AND DATA EXTRACTION: Relevant open and controlled studies reporting on the efficacy, associated adverse effects, or both of fluconazole for the treatment of VVC are reviewed. Appropriate conclusions and/or data are extracted from each article and described. DATA SYNTHESIS: Studies comparing fluconazole with ketoconazole and topical antifungal agents such as clotrimazole and miconazole have shown fluconazole to be equally efficacious with minimal adverse effects. Most of these trials used single-dose fluconazole, which would theoretically lead to a high degree of medication compliance. Fluconazole also has shown promise at diminishing VVC relapse or recurrence, possibly because of more complete vaginal and rectal eradication of Candida species. Pharmacoeconomically, single-dose fluconazole therapy is cost-effective; however, the recent approval of miconazole and clotrimazole by the Food and Drug Administration for over-the-counter use may limit this potential advantage. CONCLUSIONS: Until additional data are available, fluconazole may be considered a treatment alternative for women with VVC who experience frequent relapses or recurrences, or for those who are noncompliant with standard therapy.

Using Estimated Creatinine Clearance for Individualizing Drug Therapy: A Reassessment:

Estimates of renal function are frequently used to design individual dosing regimens. The accuracy of these estimates naturally influences their ability to predict certain pharmacokinetic parameters and appropriate drug dosages. Creatinine clearance is the most widely used estimate of renal function. Many formulas have been developed to provide a quick, relatively accurate prediction of creatinine clearance and, supposedly, the glomerular filtration rate (GFR). However, an understanding of the limitations associated with creatinine clearance estimations raises questions concerning their reliability as an aid in individualizing drug therapy. Many factors such as disease states, age, diet, analytical variations, and drug interactions affect the relationship between estimates and measures of creatinine clearance and GFR. As a result, creatinine clearance estimates using these formulas are often poor reflections of measured creatinine clearance or GFR. Also, studies comparing measured creatinine clearance with more accurate methods of assessing renal function (i.e., inulin) reveal errors that are often exaggerated as renal function declines. Therefore, estimated creatinine clearance is twice removed from the associated pharmacokinetic parameter. Despite these limitations, no other clinically relevant and convenient assessment of renal function is available. The authors recommend that the appropriate caveats be considered when using these tools clinically. For drugs with narrow therapeutic indices, estimates of creatinine clearance should only be used to establish initial dosing regimens, with subsequent therapy based on parameters generated from concentration determinations.

A Pharmacokinetic/Pharmacodynamic Analysis of Ceftaroline Prophylaxis in Patients with External Ventricular Drains

BACKGROUND Ceftaroline is a broad-spectrum cephalosporin antibiotic with activity against drug-resistant bacteria, including strains of methicillin-resistant Staphylococcus aureus (MRSA), and may be useful to prevent and treat ventriculostomy-related infections (VRIs). The purpose of this study was to analyze the pharmacokinetics and pharmacodynamics of prophylactic ceftaroline in neurosurgical patients with an external ventricular drain (EVD). METHODS Adult patients in the neurosurgical intensive care unit with an EVD were given prolonged prophylaxis with ceftaroline. Serum and cerebral spinal fluid (CSF) were obtained simultaneously at 2, 6, and 12 h after initiation of the fourth dose of ceftaroline and concentrations were measured by a liquid chromatography tandem mass spectrometry assay. Time-kill curves against isolates of coagulase-negative S. aureus, methicillin-sensitive S. aureus, MRSA, and Streptococcus pneumoniae were determined in serum and CSF at each collection time point. RESULTS A total of five patients with a mean age of 63 y and mean weight of 83 kg were enrolled. The mean CSF:serum penetration ratios of ceftaroline were 0.005 (0.5%), 0.021 (2.1%), and 0.043 (4.3%) at 2, 6, and 12 h, respectively. The mean ceftaroline exposure ratio area under the curve (AUC)csf/AUCserum) was 0.011 (1.1%). Bactericidal activity at each collection time point was observed against each strain of staphylococci from serum samples and a penicillin-sensitive strain of S. pneumoniae from CSF samples. CONCLUSION This investigation suggests that ceftaroline could have clinical utility for the prevention of VRIs in patients with EVDs.