Complications of Pulmonic Valve Endocarditis in Repaired Tetralogy of Fallot.

Transthoracic echocardiography plays a pivotal role in the diagnosis of complications, evaluation of hemodynamics, and management of patients with surgically repaired congenital heart disease. Late complications of surgically corrected tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease, include pulmonary regurgitation (PR), ventricular septal defect (VSD) patch leakage, and residual right ventricular outflow tract obstruction. We present a case of severe PR secondary to Bartonella endocarditis in an adult with a history of repaired TOF in which echocardiography was instrumental in the diagnosis of severe PR, residual VSD, and a right-to-left shunt through an unsuspected patent foramen ovale.

Propionibacterium acnes, Coagulase-Negative Staphylococcus, and the "Biofilm-like" Intervertebral Disc.

STUDY DESIGN: Patients scheduled for spinal surgery were screened prospectively for a microbial presence associated with intervertebral disc specimens. Inclusion was limited to patients requiring surgery for any of five conditions: study patients with cervical spine intervertebral herniation (IVH), lumbar spine IVH, lumbar spine discogenic pain, and control patients with idiopathic scoliosis/Scheurermann's kyphosis or trauma/neuromuscular deformity. Exclusion criteria included ongoing systemic infection, abnormal pre-operative white cell counts, documented or suspected spinal infection, or previous surgery to the involved disc. OBJECTIVE: The aim of this study was to test for an association between the presence of a bacterial entity in operated discs and a diagnosis of pathologic disc disease. SUMMARY OF BACKGROUND DATA: An association has been described between microbial colonization and progressive intervertebral disc degeneration in 36 herniation patients undergoing microdiscectomies. A total of 19 patients had positive cultures on long-term incubation, with Propionibacterium acnes present in 84% of discs. MATERIALS AND METHODS: Discs were harvested during surgery, using strict sterile technique. Each disc was divided, with half the sample sealed in a sterile, commercially prepared anaerobic culture transport container, and half fixed in formalin. Live specimens were cultured for bacteria at a university-affiliated laboratory in a blinded fashion. Fixed pathologic specimens were gram-stained and read by a board-certified pathologist. RESULTS: A total of 169 intervertebral discs from 87 patients were evaluated (46 males, 41 females). Positive cultures were noted in 76 of 169 discs (45%), with 34 discs positive for P. acnes and 30 discs positive for Staphylococcus. No pathologic evidence was seen of microorganisms, acute or chronic inflammation, or infection. Pooling the IVH and discogenic pain patients and contrasting them with control patients showed a significant association of IVH with positive bacterial cultures (χ = 15.37; P = 0.000088). CONCLUSION: Endemic bacterial biofilms are significantly associated with IVH and discogenic pain. LEVEL OF EVIDENCE: N/A.

Steady-state pharmacokinetics and pharmacodynamics of cefepime administered by prolonged infusion in hospitalised patients.

The objective of this study was to evaluate the steady-state pharmacokinetics and pharmacodynamics of cefepime administered by prolonged infusion in hospitalised patients requiring antimicrobial therapy. Nine patients received 1g every 8h (q8h), infused over 4h, and steady-state pharmacokinetic parameters were determined by non-compartmental and compartmental methods. Using these pharmacokinetic parameters, 5000-patient Monte Carlo simulations were performed to estimate the pharmacokinetic profiles for six prolonged-infusion dosing regimens. The probability of target attainment (PTA) was calculated at minimum inhibitory concentrations (MICs) ranging from 0.06 µg/mL to 32 µg/mL, and the cumulative fraction of response (CFR) was calculated for six Gram-negative pathogens using MIC data from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) (2005-2007, USA). The pharmacodynamic target was free cefepime concentrations remaining above the MIC for 60% of the dosing interval (60% fT>MIC). Mean ± standard deviation maximum and minimum serum concentrations, terminal elimination half-life, elimination rate constant, volume of distribution and systemic clearance of cefepime were 32.5 ± 13.5 µg/mL, 9.5 ± 5.2 µg/mL, 2.4 ± 0.7h, 0.316 ± 0.116 h(-1), 21.3 ± 6.5L and 6.6 ± 3.6L/h, respectively. At the susceptibility breakpoint of 8 µg/mL, the PTA was >90% for 1g and 2g q8h (4-h infusion) and 1g and 2g every 6h (q6h) (3-h infusion). For Pseudomonas aeruginosa, the CFR was 88.6% for 1g q8h (4-h infusion) and ≥ 92.7% for 2g q8h (4-h infusion) and 1g and 2g q6h (3-h infusion). Cefepime 1g q8h infused over 4h provides excellent target attainment for susceptible bacterial pathogens with MICs ≤8 µg/mL.

Comparative pharmacodynamics of intermittent and prolonged infusions of piperacillin/tazobactam using Monte Carlo simulations and steady-state pharmacokinetic data from hospitalized patients.

BACKGROUND: Prolonging the infusion of a beta-lactam antibiotic enhances the time in which unbound drug concentrations remain above the minimum inhibitory concentration (fT>MIC). OBJECTIVE: To compare the pharmacodynamics of several dosing regimens of piperacillin/tazobactam administered by intermittent and prolonged infusion using pharmacokinetic data from hospitalized patients. METHODS: Steady-state pharmacokinetic data were obtained from 13 patients who received piperacillin/tazobactam 4.5 g every 8 hours, infused over 4 hours. Monte Carlo simulations (10,000 pts.) were performed to calculate pharmacodynamic exposures at 50% fT>MIC for 4 intermittent-infusion regimens (3.375 g every 4 and 6 h, 4.5 g every 6 and 8 h) and 4 prolonged-infusion regimens (2.25 g, 3.375 g, 4.5 g, and 6.75 g every 8 h [4-h infusion]) of piperacillin/tazobactam using pharmacokinetic data for piperacillin. Cumulative fraction of response (CFR) was calculated using MIC data for 6 gram-negative pathogens (Meropenem Yearly Susceptibility Test Information Collection, 2004-2007), and probability of target attainment (PTA) was calculated at MICs ranging from 1 microg/mL to 64 microg/mL. RESULTS: The CFR for 3.375 g every 4 hours (intermittent infusion) and 3.375-4.5 g every 8 hours (prolonged infusion) greater than or equal to 90.3% for Escherichia coli, Serratia marcescens, and Citrobacter spp. Increasing the prolonged-infusion dose to 6.75 g improved the CFR to greater than 90% for Enterobacter spp. For every regimen evaluated, the CFR was less than 90% for Klebsiella pneumoniae and Pseudomonas aeruginosa. At an MIC of 16 microg/mL, PTA was greater than 90% for one intermittent-infusion regimen (3.375 g every 4 h) and 3 prolonged-infusion regimens (> or = 3.375 g every 8 h), but no regimen achieved a PTA greater than 90% at an MIC of 64 microg/mL. CONCLUSIONS: At doses greater than or equal to 3.375 g every 8 hours, 4-hour infusions of piperacillin/tazobactam achieved excellent target attainment with lower daily doses compared with standard regimens at MICs less than or equal to 16 microg/mL.

Steady-state pharmacokinetics and pharmacodynamics of piperacillin/tazobactam administered by prolonged infusion in hospitalised patients.

The objective of this study was to evaluate the steady-state pharmacokinetics and pharmacodynamics of piperacillin/tazobactam, administered by prolonged infusion, in hospitalised patients requiring antimicrobial therapy. Thirteen patients received 4.5 g every 8 h (q8h), infused over 4 h, and pharmacokinetic parameters were determined by non-compartmental methods. Monte Carlo simulations (10,000 patients) were performed to calculate the cumulative fraction of response (CFR) for seven gram-negative pathogens using minimum inhibitory concentration (MIC) data from the Meropenem Yearly Susceptibility Test Information Collection (2004-2007, USA) as well as the probability of target attainment (PTA) at MICs ranging from 1 microg/mL to 64 microg/mL. The pharmacodynamic target was free piperacillin concentration remaining above the MIC for 50% of the dosing interval. Mean+/-standard deviation maximum and minimum serum concentrations, half-life, volume of distribution at steady-state and systemic clearance of piperacillin were 108.2+/-31.7 microg/mL, 27.6+/-26.3 microg/mL, 2.1+/-1.2 h, 22.1+/-4.0 L and 8.6+/-3.0 L/h, respectively. The CFR was > 90% for Escherichia coli, Serratia marcescens and Citrobacter spp., 88.6% for Enterobacter spp., 87% for Klebsiella pneumoniae, 85.5% for Pseudomonas aeruginosa and 52.8% for Acinetobacter spp. The PTA was 100%, 81.1% and 12.3% at MICs of < or = 16 microg/mL, 32 microg/mL and 64 microg/mL, respectively. Piperacillin/tazobactam 4.5 g q8h infused over 4 h provides excellent target attainment for bacterial pathogens with MICs < or = 16 microg/mL. However, the CFR was < 90% for four of the seven gram-negative pathogens evaluated.

Case study: chronic femoropopliteal prosthetic graft infection with exposed graft.

One of the most feared complications following vascular reconstruction is infection due to the attendant risks of limb loss, sepsis, or death. The reported incidence of infection following infrainguinal prosthetic graft infection is 2.5% with associated mortality rates and amputation rates of 18% and 41%, respectively. There are several options in treating infected prosthetic infrainguinal bypass grafts. Some authors have advocated complete removal of the infected graft with concomitant in situ revascularization using autogenous tissue or extra-anatomic bypass using either autogenous or prosthetic material, depending upon the clinical circumstances. Other authors have advocated attempting graft preservation to decrease the risk of amputation. Infected, thrombosed grafts are generally treated with graft excision alone with care taken to preserve collateral flow. The treatment options may also be influenced by the type of infection, as infections caused by gram-negative bacteria are thought to be more virulent than those associated with gram-positive bacteria. We recently treated a patient with an 18-month history of an exposed prosthetic graft in the groin, which was infected by Proteus mirabilis. Despite the extended period of graft exposure and despite gram-negative bacteria being the causative organism, the patient reported only intermittent drainage of pus from the groin. The management of this unusual infection forms the basis of this report.

Steady-state pharmacokinetics and pharmacodynamics of meropenem in hospitalized patients.

STUDY OBJECTIVE: To evaluate the steady-state pharmacokinetics and pharmacodynamics of meropenem 500 mg every 6, 8, and 12 hours, based on renal function, in hospitalized patients. DESIGN: Prospective, open-label, steady-state pharmacokinetic study. SETTING: One tertiary care medical center and one community hospital. PATIENTS: Twenty adult patients (12 men, 8 women) with suspected or documented bacterial infections requiring antimicrobial therapy. INTERVENTION: Patients received 30-minute infusions of meropenem 500 mg every 6 hours (group 1), every 8 hours (group 2), or every 12 hours (group 3) based on estimated creatinine clearances greater than 60, 40-60, or 10-39 ml/minute, respectively. MEASUREMENTS AND MAIN RESULTS: Serial blood samples were collected after 2 or more days of therapy. Meropenem concentrations were determined by high-performance liquid chromatography, and pharmacokinetic data were analyzed by noncompartmental methods. Monte Carlo simulations (10,000 patients) were performed to calculate the cumulative fraction of response (CFR) for a percentage of the dosing interval that free drug concentrations remain above the minimum inhibitory concentration (fT>MIC) of 40% by using pharmacokinetic data for each group and MIC data for seven gram-negative pathogens from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC, 2004-2005) database. Maximum and minimum serum concentrations (mean +/- SD) were 29.2+/-9.8 and 2.4+/-1.1 microg/ml, 33.2+/-8.5 and 3.8+/-2.7 microg/ml, and 33.5+/-4.7 and 4.9+/-1.6 microg/ml for groups 1, 2, and 3, respectively. The half-life values were 2.5+/-0.9, 3.4+/-1.3, and 6.1+/-1.4 hours, and the values for volume of distribution at steady state were 29.3+/-8.7, 23.8+/-8.1, and 28.7+/-8.6 L for groups 1, 2, and 3, respectively. For all three groups, the CFR was greater than 90% for the enteric pathogens and Pseudomonas aeruginosa and 82.4-85.2% for Acinetobacter species. CONCLUSION: Pharmacodynamic analyses suggest that regimens of meropenem 500 mg every 6, 8, or 12 hours, adjusted for renal function, are acceptable for treatment of infections caused by enteric gram-negative pathogens and P. aeruginosa. However, more aggressive dosing or alternative dosing strategies may be necessary for Acinetobacter species.

Selection of a gyrA mutation and treatment failure with gatifloxacin in a patient with Streptococcus pneumoniae with a preexisting parC mutation.

An 81-year-old woman had pneumonia caused by Streptococcus pneumoniae (levofloxacin Etest minimum inhibitory concentration [MIC] 1.5 microg/ml) and was treated with intravenous gatifloxacin 200 mg/day. After 3 days of therapy, repeat sputum cultures were positive for S. pneumoniae, which was resistant to levofloxacin (Etest MIC > 32 microg/ml). The isolate obtained before therapy showed a preexisting parC mutation of aspartic acid-83 to asparagine (Asp83-->Asn), and the isolate obtained during therapy showed an acquired gyrA mutation from serine-81 to phenylalanine (Ser81-->Phe) and a second parC mutation from lysine-137 to Asn (Lys137-->Asn). Both isolates were the same strain, as determined with pulsed-field gel electrophoresis. This case demonstrates the potential for resistance to emerge during 8-methoxy fluoroquinolone therapy for fluoroquinolone-susceptible S. pneumoniae with a preexisting parC mutation. Additional clinical failures with a fluoroquinolone may occur unless these first-step parC mutants can be identified to assist clinicians in selecting appropriate antimicrobial therapy.

Delayed ABLC prophylaxis after allogeneic stem-cell transplantation.

Invasive fungal infections (IFI) are frequent causes of mortality after allogeneic stem-cell transplantation (SCT). A very important risk factor for IFI is the use of steroids. We used a risk-based chemoprevention in an open-labelled pilot study. All patients received oral fluconazole or itraconazole (200-400 mg day(-1)) during their neutropenic episode. Starting on day +30, patients receiving prednisone > or =30 mg day(-1) were switched to twice weekly Amphotericin-B-lipid-complex (ABLC) in a dose of 4 mg kg(-1). Patients receiving lower steroid doses continued on the fluconazole/itraconazole prophylaxis. Between 1999 and 2002, 100 patients were enrolled and followed for IFI for 1 year. Seven patients were started on therapeutic daily ABLC treatment before day +30 because of documented or suspected IFI; four had definite or probable aspergillosis, and two had candidaemia. Thirty patients did not need prophylactic ABLC; only one developed candidaemia. Sixty-three patients received ABLC prophylaxis for a median of 52 days (range: 1-289). Seven of these patients developed IFI; one definite and two probable cases of aspergillosis, one case of probable Trichosporon beigelii infection, and three cases of candidaemia. The twice weekly ABLC was well tolerated. This risk-based chemoprevention appears to be effective and might diminish the role of steroids as risk factor for IFI after allogeneic SCT. The relatively high incidence of early IFI suggests that additional prophylaxis for IFI may be indicated for poor-risk patients prior to day +30.

Azithromycin treatment failure in community-acquired pneumonia caused by Streptococcus pneumoniae resistant to macrolides by a 23S rRNA mutation.

In this report, we describe an azithromycin treatment failure in community-acquired pneumonia. During the first three days of azithromycin, the patient's symptoms worsened, and she was subsequently admitted to the hospital. Blood cultures were positive for a penicillin-susceptible, macrolide-resistant S. pneumoniae. DNA sequencing revealed an A2059G mutation in domain V of the 23S rRNA. To our knowledge, this is the first clinical report of an azithromycin failure in the treatment of S. pneumoniae resistant to macrolides by this mechanism.

Levofloxacin treatment failure in a patient with fluoroquinolone-resistant Streptococcus pneumoniae pneumonia.

The frequency of fluoroquinolone-resistant Streptococcus pneumoniae has increased as fluoroquinolone administration for treatment of respiratory tract infections has increased. Levofloxacin treatment failed in a patient who had pneumococcal pneumonia and had received three previous courses of levofloxacin therapy. Susceptibility testing revealed high-level resistance to levofloxacin (minimum inhibitory concentration [MIC] > 32 microg/ml), and cross-resistance to moxifloxacin (MIC 4 microg/ml), trovafloxacin (6 microg/ml), and gatifloxacin (12 microg/ml). Sequencing of the quinolone-resistance determining region revealed a mutation of serine-81 to phenylalanine (Ser81-->Phe) in the gyrA region of DNA gyrase and a Ser79-->Phe mutation in the parC region of topoisomerase IV The patient was treated successfully with intravenous ceftriaxone followed by oral cefprozil. Clinicians must be aware of local resistance patterns and the potential for fluoroquinolone treatment failures in patients with infections caused by S. pneumoniae.