Electrocardiogram screening of deaf children for long QT syndrome: are we following UK national guidelines?

INTRODUCTION: Jervell-Lange-Nielsen syndrome is characterised by congenital deafness and a long QT interval on electrocardiography. AIM: (1) To survey UK national practice regarding electrocardiography screening of deaf children referred to cochlear implant centres, performed to evaluate for prolonged QT interval as recommended by national guidelines, and (2) to review local practice. METHODS: Data were collected via a questionnaire sent to all UK cochlear implant centres, and via review of the medical records of a local cochlear implant centre database. RESULTS: Eight (42 per cent) of the 19 cochlear implant centres surveyed performed electrocardiographic screening. Thirteen cases of long QT syndrome were reported in seven centres, with two related deaths. In our local cochlear implant centre, 14 (7.1 per cent) of 193 children had abnormal electrocardiograms; one definite long QT syndrome case and 13 borderline cases were identified. CONCLUSION: Despite clear national guidelines for electrocardiographic screening of deaf children, there is wide variation in practice. Our local practice of performing investigations, including electrocardiography, during magnetic resonance imaging sedation has been very successful. Electrocardiograms should be reviewed by trained clinicians, and corrected QT intervals should be calculated manually.

Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity.

The nephrotoxicity and ototoxicity associated with once-daily versus twice-daily administration of aminoglycosides was assessed in patients with suspected or proven gram-negative bacterial infections in a randomized, double-blind clinical trial. Patients who received therapy for >/=72 h were evaluated for toxicity. Patients also received concomitant antibiotics as deemed necessary for treatment of their infection. Plasma aminoglycoside concentrations, prospective aminoglycoside dosage adjustment, and serial audiologic and renal status evaluations were performed. The probability of occurrence of a nephrotoxic event and its relationship to doses and daily aminoglycoside exposure served as the main outcome measurement. One hundred twenty-three patients were enrolled in the study, with 83 patients receiving therapy for at least 72 h. For 74 patients plasma aminoglycoside concentrations were available for analysis, and the patients formed the group evaluable for toxicity. The primary infectious diagnosis for the patients who were enrolled in the study were bacteremia or sepsis, respiratory infections, skin and soft tissue infections, or urosepsis or pyelonephritis. Of the 74 patients evaluable for toxicity, 39 received doses twice daily and 35 received doses once daily and a placebo 12 h later. Nephrotoxicity occurred in 6 of 39 (15.4%) patients who received aminoglycosides twice daily and 0 of 35 patients who received aminoglycosides once daily. The schedule of aminoglycoside administration, concomitant use of vancomycin, and daily area under the plasma concentration-time curve (AUC) for the aminoglycosides were found to be significant predictors of nephrotoxicity by multivariate logistic regression analysis (P

In-vitro bactericidal activity of quinupristin/dalfopristin alone and in combination against resistant strains of Enterococcus species and Staphylococcus aureus.

In-vitro activities of quinupristin/dalfopristin, a semisynthetic injectable streptogramin, and vancomycin were compared against multidrug-resistant Enterococcus faecium and Enterococcus faecalis, methicillin-susceptible Staphylococcus aureus ATCC 25923 and a methicillin-resistant S. aureus (MRSA). Combinations of quinupristin/dalfopristin and/or vancomycin with ofloxacin or gentamicin were evaluated using the chequerboard technique. The only synergy observed was that between quinupristin/dalfopristin plus vancomycin and quinupristin/dalfopristin plus gentamicin against E. faecium (FIC index < 0.5). Time-kill curves were performed over 24 h with an inoculum of 1 x 10(7) cfu/mL and clinically achievable concentrations of quinupristin/dalfopristin, vancomycin, ofloxacin and gentamicin (6, 30, 5 and 5 mg/L, respectively). In time-kill studies, combinations of quinupristin/dalfopristin plus vancomycin and quinupristin/dalfopristin plus gentamicin were additive, not synergic, against E. faecium and achieved 99.9% killing in 21.2 h and 19.6 h, respectively. None of the combination regimens suppressed the regrowth of E. faecalis. Quinupristin/dalfopristin combined with vancomycin demonstrated consistent synergy against ATCC 25923 and the MRSA, achieving 99.9% killing in 12.1 h and 11.9 h, respectively. Overall, quinupristin/dalfopristin alone demonstrated inhibitory activity against E. faecium, but not against E. faecalis, and bactericidal activity was achieved only with quinupristin/dalfopristin in combination with vancomycin or gentamicin against E. faecium. Quinupristin/dalfopristin plus vancomycin was the most potent and reliable combination against both strains of S. aureus in time-kill studies.

Comparative in vitro activities of LY191145, a new glycopeptide, and vancomycin against Staphylococcus aureus and Staphylococcus-infected fibrin clots.

Bactericidal activities of LY191145, an investigational glycopeptide, and vancomycin against Staphylococcus aureus were evaluated. Only LY191145 at a concentration 16-fold greater than the MIC was able to achieve 99.9% killing against methicillin-susceptible S. aureus (ATCC 25923; 8.0 h). Both agents demonstrated 99.9% killing against methicillin-resistant clinical isolate S. aureus MRSA67 over 24 h at concentrations 4-, 8-, and 16-fold greater than the MIC, but bacteria were killed at a more rapid rate by LY191145 (1.63 versus 5.02 h; P < 0.001). Against strain ATCC 25923- and MRSA67-infected fibrin clots, total reductions by LY191145 and vancomycin over 72 h were not statistically significantly different at a concentration 16 times the MIC (1.12 +/- 0.31 and 1.23 +/- 0.13 and 1.40 +/- 0.17 and 1.36 +/- 0.37 CFU/g; respectively). Increasing the drug concentration to 50 times the MIC did not alter the values significantly, and there was no statistically significant difference between the two agents. Overall, LY191145 exhibited more rapid bactericidal activity than vancomycin against S. aureus, and a concentration 16-fold greater than the MIC appears to be optimal.

Bactericidal killing activities of cefepime, ceftazidime, cefotaxime, and ceftriaxone against Staphylococcus aureus and beta-lactamase-producing strains of Enterobacter aerogenes and Klebsiella pneumoniae in an in vitro infection model.

Cefepime (CP) is a new injectable cephalosporin with a broad spectrum of activity and stability against common chromosomally and plasmid-mediated beta-lactamases. The bactericidal activities of CP, ceftazidime (CZ), cefotaxime (CTX), and ceftriaxone (CAX) against reference and clinical strains of Staphylococcus aureus, an isogenic pair of Enterobacter aerogenes strains (wild type and a CZ-resistant derepressed mutant), and a Klebsiella pneumoniae isolate possessing a TEM-10 beta-lactamase were investigated in a two-compartment pharmacodynamic in vitro infection model which simulates human pharmacokinetics. An inoculum of approximately 10(6) CFU/ml was used in all model experiments. Antibiotics were administered to simulate the following regimens: CP at 2 g every 12 h (q12h), CZ at 2 g q8h, CTX at 2 g q8h, and CAX at 2 g q24h. Human albumin was added during experiments with CAX and staphylococci to simulate protein binding. Samples were removed at multiple time points over a 48-h period to determine the inoculum size for time-kill curves. Development of resistance was detected by inoculating samples obtained at 0, 24, and 48 h onto antibiotic-containing agar plates. The time to 99.9% killing was used to compare drug regimens. Against staphylococci, the time to bacterial eradication was significantly delayed with CAX-albumin. All regimens had similar activities against the wild-type Enterobacter strain; however, regrowth was noted with CZ, CTX, and CAX against the CZ-resistant strain. There were no differences between the CP, CTX, and CAX regimens against K. pneumoniae. Of interest, no regrowth of any organism was noted with CP. These data indicate that CP has activity against S.aureus and CZ-resistant gram-negative bacilli.

Pharmacodynamics of ceftazidime administered as continuous infusion or intermittent bolus alone and in combination with single daily-dose amikacin against Pseudomonas aeruginosa in an in vitro infection model.

We compared the pharmacodynamics and killing activity of ceftazidime, administered by continuous infusion and intermittent bolus, against Pseudomonas aeruginosa ATCC 27853 and ceftazidime-resistant P. aeruginosa 27853CR with and without a single daily dose of amikacin in an in vitro infection model over a 48-h period. Resistance to ceftazidime was selected for by serial passage of P. aeruginosa onto agar containing increasing concentrations of ceftazidime. Human pharmacokinetics and dosages were simulated as follows: half-life, 2 h; intermittent-bolus ceftazidime, 2 g every 8 h (q8h) and q12h; continuous infusion, 2-g loading dose and maintenance infusions of 5, 10, and 20 micrograms/ml; amikacin, 15 mg/kg q24h. There was no significant difference in time to 99.9% killing between any of the monotherapy regimens or between any combination regimen against ceftazidime-susceptible P. aeruginosa. Continuous infusions of 10 and 20 micrograms/ml killed as effectively as an intermittent bolus of 2 g q12h and q8h, respectively. Continuous infusion of 20 micrograms/ml and an intermittent bolus of 2 g q8h were the only regimens which prevented organism regrowth at 48 h, while a continuous infusion of 5 micrograms/ml resulted in the most regrowth. All of the combination regimens exhibited a synergistic response, with rapid killing of ceftazidime-susceptible P. aeruginosa and no regrowth. Against ceftazidime-resistant P. aeruginosa, none of the ceftazidime monotherapy regimens achieved 99.9% killing. The combination regimens exhibited the same rapid killing of the resistant strain as occurred with the susceptible strain; however, regrowth occurred with all regimens. The combination regimens of continuous infusion of 20 micrograms/ml plus amikacin and intermittent bolus q8h or q12h plus amikacin continued to be synergistic. Overall, continuous infusion monotherapy with ceftazidime at concentrations 4 to 5 and 10 to 15 times the MIC was as effective as an intermittent bolus of 2 g q12h (10 to 15 times the MIC) and q8h (25 to 35 times the MIC), respectively, against ceftazidime-susceptible P. aeruginosa. Combination therapy with amikacin plus ceftazidime, either intermittently q8h or by continuous infusion of 20 micrograms/ml, appeared to be effective and exhibited synergism against ceftazidime-resistant P. aeruginosa.

Pharmacodynamics of RP 59500 alone and in combination with vancomycin against Staphylococcus aureus in an in vitro-infected fibrin clot model.

The bactericidal activity and emergence of resistance to RP 59500 (quinupristin/dalfopristin) when it was administered alone and in combination with vancomycin against fibrin clots that have been infected with methicillin-susceptible Staphylococcus aureus ATCC 25923 or methicillin-resistant S. aureus (MRSA) 67 were evaluated in an in vitro pharmacodynamic infected fibrin clot model. Fibrin clots were infected with S. aureus to achieve an inoculum of approximately 10(9) CFU/g. Antibiotics were administered to simulate pharmacokinetics in humans: RP 59500 (7.5 mg/kg of body weight) every 8 h and vancomycin (15 mg/kg) every 12 h over 72 h. Preliminary test tube time-kill experiments with an inoculum of approximately 10(5) CFU/ml suggested that RP 59500 was more rapid in achieving a 99.9% reduction in the number of CFU per milliliter than vancomycin against ATCC 25923 (6.94 versus 24 h; P = 0.0003) and MRSA 67 (6.77 versus 17.03 h; P = 0.004). At a higher inoculum (approximately 10(8) CFU/ml), 99.9% kill was achieved only with the combination regimen against ATCC 25923 and MRSA 67 (10.9 and 10.5 h, respectively), with total reductions of 6.35 and 6.33 log10 CFU/ml over 24 h, respectively. In the fibrin clot model, RP 59500 was more effective than vancomycin in reducing organism titers over 72 h. In the fibrin clot model, the most optimal therapy was the combination regimen.

Pharmacodynamics of levofloxacin, ofloxacin, and ciprofloxacin, alone and in combination with rifampin, against methicillin-susceptible and -resistant Staphylococcus aureus in an in vitro infection model.

The pharmacodynamic properties of levofloxacin (an optically active isomer of ofloxacin), ofloxacin, and ciprofloxacin, alone and in combination with rifampin, were evaluated over 24 to 48 h against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus (MSSA 1199 and MRSA 494, respectively) in an in vitro infection model. The incidence of the emergence of resistance among the test strains was also determined. The fluoroquinolones were administered to simulate dosage regimens of 200 mg, 400 mg given intravenously (i.v.) every 12 h (q12h), and 400 and 800 mg given i.v. q24h. Rifampin was dosed at 600 mg i.v. q24h. Although the MICs and MBCs of the quinolones were similar (< or = 0.49 microgram/ml), levofloxacin was the most potent agent in time-kill studies on the basis of the time required to achieve a 99.9% reduction in the number of log10 CFU per milliliter (e.g., with the regimen of levofloxacin [400 mg q24h, 6.5 h] versus ofloxacin [12.5 h], P < 0.024, and levofloxacin versus ciprofloxacin [6.5 versus 9.0 h], P < 0.0017) against MSSA 1199. The killing activity of levofloxacin was similar to that of ofloxacin against MRSA 494 (time to achieve a 99.9% reduction in the number of log10 CFU per milliliter, 11.1 versus 13.8 h, respectively). Levofloxacin and ofloxacin dosed once daily demonstrated greater bactericidal activity than when they were dosed twice daily against MSSA 1199. Resistance to levofloxacin or ofloxacin was not observed with any dosage regimen. Furthermore, resistance to ofloxacin was not detected when the half-life was reduced from 6 to 3 h. Regrowth and stable resistance (65-fold increase in the MIC for MSSA 1199; 16-fold increase in the MIC for MRSA 494) were noted within 24 h of exposure to ciprofloxacin at 200 mg q12h. Combination therapy with rifampin prevented the emergence of resistance to ciprofloxacin. Neither DNA gyrase alteration nor an energy-dependent efflux process mediated by the norA gene appeared to be responsible for the resistance observed. Our data suggest that with levofloxacin there is a more rapid onset of bactericidal activity than with ofloxacin or ciprofloxacin against MSSA 1199 and that the activity of levofloxacin is similar to that of ofloxacin but better than that of ciprofloxacin against MRSA 494. Resistance was noted only after exposure to the low dose of ciprofloxacin. Resistance to ofloxacin did not develop even when the pharmacokinetics of the drug were set to equal those of ciprofloxacin, suggesting that ofloxacin differs from ciprofloxacin irrespective of time of exposure. The resistance to ciprofloxacin that developed in our vitro model may be mediated by the cfx-ofx locus, which has been shown to be associated with low-level fluoroquinolone resistance. Overall, levofloxacin demonstrated potent bactericidal activity against S. aureus, without the emergence of resistance in our infection model. Quinolones dosed once daily were more effective than equivalent dosages administered twice daily. The addition of rifampin was not synergistic but prevented the emergence of ciprofloxacin resistance.

Bactericidal activities of teicoplanin, vancomycin, and gentamicin alone and in combination against Staphylococcus aureus in an in vitro pharmacodynamic model of endocarditis.

We adapted an in vitro pharmacodynamic model of infection to incorporate simulated endocardial vegetations. The bactericidal activities of teicoplanin, vancomycin, gentamicin, and various combinations of these drugs were studied against a strain of methicillin-susceptible Staphylococcus aureus obtained from a patient being treated for endocarditis at Detroit Receiving Hospital. Bacteria were grown overnight, concentrated, and added to a mixture of cryoprecipitate (80%) and thrombin (10%) to achieve approximately 5 x 10(9) CFU/g. Fibrin clots (8 to 10) were suspended into the model, removed at 24, 48, and 72 h in duplicate, weighed, and homogenized in 1.25% trypsin. Control experiments were conducted to characterize the growth kinetics. The following antibiotics were administered to simulate the pharmacokinetics of the drugs in humans: teicoplanin at 3 and 15 mg/kg of body weight, vancomycin at 15 mg/kg, and gentamicin at 1 mg/kg. Fibrin clot samples used to detect resistance were plated on antibiotic-containing tryptic soy agar plates. For the teicoplanin and vancomycin regimens, protein binding to cryoprecipitate, thrombin, and fibrin clot was determined to be 32, 43, and 50% and 26, 28, and 29%, respectively. In comparison with no treatment, vancomycin or teicoplanin at 15 mg/kg or either of these regimens combined with gentamicin significantly reduced bacterial counts (P < 0.0001). Monotherapy with teicoplanin at 3 mg/kg or gentamicin resulted in no killing activity. Combination treatment with teicoplanin at 3 mg/kg and gentamicin resulted in the killing of approximately 2 log10 CFU/g by 72 h and the development of resistance to gentamicin. The results obtained with the in vitro model of endocarditis are similar to the results reported by several investigators with the rabbit model of infective endocarditis. This unique infection model is useful for designing initial drug dosage regimens and may be predictive of drug efficacy against infective endocarditis.

Effects of pelleted or crumbled diets on the performance and the development of the digestive organs of broilers.

Two types (mash and crumble) of the starter ration (for 0 to 4 weeks of age) and two types (mash and pellets) of the finisher ration (for 4 to 8 weeks of age) were fed to broilers in a 2 X 2 factorial arrangement. Chicks fed the crumbled starter diet gained more weight and consumed more feed (P less than .01). Pelleting the finisher diet also significantly (P less than .01) improved weight gain and feed intake. Feeding the crumble during the starter period significantly (P less than .05) decreased gizzard weight at 4 weeks of age. Pelleting the finisher diet also significantly (P less than .01) reduced weights of the digestive tract and the gizzard at 8 weeks of age, compared to those fed the mash diet.