Amplification of Antimicrobial Resistance in Gut Flora of Patients Treated with Ceftriaxone.

Although antibacterial therapy has an impact on human intestinal flora and the emergence of resistant bacteria, its role in the amplification of antimicrobial resistance and the quantitative exposure-effect relationship is not clear. An observational prospective study was conducted to determine whether and how ceftriaxone exposure is related to amplification of resistance in non-intensive care unit (non-ICU) patients. Serial stool samples from 122 extended-spectrum ß-lactamase-positive (ESBL+) hospitalized patients were analyzed by quantitative real-time PCR to quantify the resistant gene blaCTX-M Drug exposure was calculated for each patient by using a population pharmacokinetic model. Multi- and univariate regression and classification regression tree (CART) analyses were used to explore relationships between measures of exposure and amplification of blaCTX-M genes. Amplification of blaCTX-M was observed in 0% (0/11) of patients with no treatment and 33% (20/61) of patients treated with ceftriaxone. Stepwise regression analysis showed a significant association between amplification of blaCTX-M and the plasma area under the concentration-time curve from 0 to 24 h for the unbound fraction of the drug (fAUC0-24), the maximum concentration of drug in serum for the unbound fraction of the drug (fCmax), and the duration of ceftriaxone therapy. Using CART analysis, amplification of blaCTX-M was observed in 11/16 (69%) patients treated for >14 days and in 9/40 (23%) patients treated for ≤14 days (P = 0.0019). In the latter group, amplification was observed in 5/7 (71%) patients with an fAUC0-24 of ≥222 mg · h/liter and in 4/33 (12%) patients with lower drug exposures (P = 0.0033). A similar association was found for an fCmax of ≥30 mg/liter (63% versus 13%, P = 0.0079). A significant association was found between the amplification of blaCTX-M resistance genes and exposure to ceftriaxone. Both duration of treatment and degree of ceftriaxone exposure have a significant impact on the amplification of resistance genes. (The project described in this paper has been registered at ClinicalTrials.gov under identifier NCT01208519.).

Evidence-based recommendations for bowel cleansing before colonoscopy in children: a report from a national working group.

BACKGROUND: There are no current recommendations for bowel cleansing before colonoscopy in children. The Israeli Society of Pediatric Gastroenterology and Nutrition (ISPGAN) established an iterative working group to formulate evidence-based guidelines for bowel cleansing in children prior to colonoscopy. METHOD: Data were collected by systematic review of the literature and via a national-based survey of all endoscopy units in Israel. Based on the strength of evidence, the Committee reached consensus on six recommended protocols in children. Guidelines were finalized after an open audit of ISPGAN members. RESULTS: Data on 900 colonoscopies per year were accrued, which represents all annual pediatric colonoscopies performed in Israel. Based on the literature review, the national survey, and the open audit, several age-stratified pediatric cleansing protocols were proposed: two PEG-ELS protocols (polyethylene-glycol with electrolyte solution); Picolax-based protocol (sodium picosulphate with magnesium citrate); sodium phosphate protocol (only in children over the age of 12 years who are at low risk for renal damage); stimulant laxative-based protocol (e. g. bisacodyl); and a PEG 3350-based protocol. A population-based analysis estimated that the acute toxicity rate of oral sodium phosphate is at most 3/7320 colonoscopies (0.041 %). Recommendations on diet and enema use are provided in relation to each proposed protocol. CONCLUSION: There is no ideal bowel cleansing regimen and, thus, various protocols are in use. We propose several evidence-based protocols to optimize bowel cleansing in children prior to colonoscopy and minimize adverse events.

Plasma homocysteine, vitamin B12 and folate in Alzheimer's patients and healthy Arabs in Israel.

High plasma homocysteine (tHcy) is a risk factor for cardiovascular disease and stroke and Alzheimer's disease (AD). An inverse relationship has been reported between tHcy and plasma B12 and folate levels. Seventy-nine AD patients and 156 controls from three Arab villages in northern Israel participated. Plasma tHcy, B12 and folate levels were determined. Data were analyzed using univariate statistical tests and logistical regression with confounders. tHcy was significantly higher in AD patients (20.6+/-8.7 micromol/l) than in controls (16.4+/-6.5 micromol/l) (p=0.03) after correction for year of birth, gender and smoking status. Plasma B12 (322.9+/-136.0/350.5+/-175.3 pmol/l) and plasma folate (4.5+/-3.8/4.9+/-2.6 nmol/l) levels did not differ significantly between AD patients and controls. Subjects in the highest tHcy tertile or in the lowest B12 and folate tertiles did not have greater risk to develop AD. In this population residing in Arab villages in northern Israel, tHcy levels were significantly higher among AD patients than in controls. Plasma B12 and folate levels were lower among cases but were not significant. There was not a significant association between plasma tHcy, B12 and folate levels in controls or AD patients. High levels of tHcy may suggest the need for folate and vitamin B12 supplementation in this population.

Type 4 cyclic adenosine monophosphate phosphodiesterase as a therapeutic target in chronic lymphocytic leukemia.

Theophylline, a drug known to inhibit several classes of adenosine 3'5' cyclic monophosphate (cAMP) phosphodiesterases (PDEs), induces apoptosis in chronic lymphocytic leukemia (CLL) cells. Because the PDE target for theophylline in CLL remains unknown, we examined the ability of isoform-specific PDE inhibitors to increase cAMP levels and induce apoptosis in primary CLL cells. Reverse transcriptase-polymerase chain reaction of purified CLL cDNA amplified transcripts for PDE1B, 4A and 4B. The type 4 PDE inhibitor rolipram but not the type 1 inhibitor vinpocetine increased CLL cAMP levels. Rolipram-inhibitable (type 4) but not calcium-calmodulin augmented (type 1) PDE enzyme activity was detected in CLL samples. In samples from 13 of 14 CLL patients, rolipram induced apoptosis in a dose-dependent fashion over a 48-hour period. Interleukin-2 (IL-2)-cultured whole mononuclear cells (WMC) and anti-Ig stimulated CD19(+) B cells were resistant to the induction of apoptosis by rolipram while unstimulated CD19(+) B cells, which had a high basal apoptotic rate, were more sensitive. Rolipram stimulated elevations in cAMP levels in all four of these cell populations, suggesting that they differed in sensitivity to cAMP-induced apoptosis. Consistent with this hypothesis, incubation with the cell permeable cAMP analog dibutyryl-cAMP induced apoptosis in CLL cells and unstimulated B cells but not in IL-2-cultured WMC or anti-Ig stimulated B cells. These data identify PDE4 as a family of enzymes whose inhibition induces apoptosis in CLL cells.

Functional imaging, the frontal lobes, and dementia.

A 58-year-old man developed progressive difficulty with comprehension and verbal output with dementia. Positron emission tomography with 18F 2-fluoro-2-deoxy-D-glucose demonstrated asymmetrical frontal and anterior temporal lobe loss of glucose use. Scopolamine infusion (0.3 mg) did not influence memory. Postmortem studies revealed evidence of Pick's disease, with Pick bodies, loss of somatostatin, preservation of choline acetyltransferase and immunostaining with neurofilament antibodies. Pharmacological challenge and positron imaging offer valuable means for the noninvasive assessment of dementing illness. The contributions of functional imaging to our knowledge of frontal involvement in dementing illness are reviewed.

Computed axial tomographic scanning of the thigh: an alternative method of nutritional assessment in pediatrics.

In this study we compared the findings of computed axial tomographic (CT) scanning of the thigh with the findings of arm anthropometry and urinary creatinine determinations to assess nutrition in children with inflammatory bowel disease receiving total parenteral nutrition. All 14 children received our standard solution for total parenteral nutrition as well as prednisone and sulfasalazine (Azulfidine) therapy. All patients were assessed by arm anthropometry, 24-hour urine collections for creatinine clearance, and CT scanning of the thigh during total parenteral nutrition. Arm muscle and fat area were estimated by anthropometry, and those in the thigh were estimated by CT scanning. Our results show the total muscle area from the CT scan can predict muscle mass calculated from the urinary creatinine excretion rates. In addition, there is a close correlation between the thigh muscle area as measured by CT scanning and the muscle area calculated from urinary creatinine excretion rates. In addition, the comparison of thigh muscle area and thigh fat area to the midarm muscle area and midarm fat area, respectively, showed that the thigh is a better predictor of muscle than fat in the midarm. We conclude that the total thigh muscle area is a better predictor of muscle mass as compared to the midarm muscle area. In addition, the CT scan cut at the level of the thigh in children and adolescents with inflammatory bowel disease can provide valuable information about the thigh compartment and analyses of different cross-sectional areas of the thigh.

Possible pseudoresistance of Streptococcus pneumoniae to penicillin G in a patient with a mixed pneumococcus-Staphylococcus aureus pneumonia.

We report the case of a 53-year-old woman with a mixed pneumococcus-staphylococcus pneumonia, in which both organisms were recovered from both sputum and blood. Streptococcus pneumoniae persisted in sputum 48 hours after initiation of high-dose intravenous penicillin G. When nafcillin was substituted for penicillin G, both pneumococci and staphylococci were eradicated from blood and sputum. This strain of Streptococcus pneumoniae was highly susceptible to penicillin G, but the associated strain of Staphylococcus aureus was not. The staphylococcus produced large amounts of a penicillin -degrading betalactamase . We reviewed the records of ten cases of pneumococcus pneumonia from the Wayne State University-Detroit Medical Center admitted from March 1978 to April 1981, in which sputum cultures were repeated within one to ten days after penicillin G had been initiated. At second cultures of sputum, Streptococcus pneumoniae was recovered in none of these latter cases. We further showed that on a blood agar culture plate in the presence of penicillin G, a beta-lactamase positive strain of Staphylococcus aureus allowed growth of Streptococcus pneumoniae. Therefore, despite penicillin therapy, Staphylococcus aureus in sputum may facilitate the persistence of Streptococcus pneumoniae.

Studies of in vitro synergy between several beta-lactam and aminoglycoside antibiotics against endocarditis strains of Pseudomonas aeruginosa.

Ten strains of Pseudomonas aeruginosa isolated from patients with endocarditis (1969-1975) and eight similar strains (1980) were assayed for minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) to several aminoglycosides (gentamicin, tobramycin, amikacin) and beta-lactam antibiotics (ticarcillin, piperacillin, azlocillin, moxalactam and MKO 787). In vitro synergy (1969-1975 series) between beta-lactam and aminoglycoside antibiotics was shown uniformly with azlocillin (100 per cent) followed by moxalactam (80 per cent), piperacillin and ticarcillin (66 per cent) and MKO 787 (13.3 per cent). Results were similar in 1980. Synergy of azlocillin was demonstrated with five strains previously not showing synergy between carbenicillin and an aminoglycoside. In 1980 four of eight patients infected with pseudomonads that were not synergistically affected in vitro were refractory to treatment with the piperacillin-aminoglycoside combination. In vitro synergy of the infecting strain is necessary for successful medical treatment of patients with P. aeruginosa infective endocarditis.

New observations on vitiligo and ocular disease.

We examined 223 consecutive patients with vitiligo for ocular disease and 154 consecutive patients with uveitis for vitiligo to better determine the nature of the relationship between vitiligo and ocular disease. Of the 129 patients whose uveitis had an unknown cause, seven (5.4%) had cutaneous depigmentation, poliosis, or early graying of hair. The incidence is 0.5% in the general population (P less than .02). None of the 25 patients whose uveitis had a known cause had vitiligo. Eleven (4.8%) of 223 patients with vitiligo had uveitis at the time of the study or had had it within the previous two years. Of 27 patients in whom vitiligo was associated with cutaneous melanoma, five (18.5%) had had uveitis within the previous two years. In three of these five, the uveitis began within one month of the appearance of cutaneous changes. Evidence of old chorioretinal scars were present in 69 of 223 patients with vitiligo (30.9%) but in only two of 148 control patients (P less than .001). Sixty of 223 patients with vitiligo (26.9%) had evidence of hypopigmentation or atrophy of the retinal pigment epithelium, or both, not related to old chorioretinitis or macular degeneration but only six of 148 controls did (P less than .001).

Current problems in the treatment of infective endocarditis due to Pseudomonas aeruginosa.

Mortality from pseudomonas infective endocarditis remains high despite optimal use of available antibacterial agents. Infection of the tricuspid valve is subacute, but involvement of the mitral or aortic valve precipitates more serious disease. Most valvular infections are due to a single pseudomonad immunotype, but 20% of cases are mixed infections. Antimicrobial susceptibility tests and tests of synergy by beta-lactam and aminoglycoside antibiotics in combination were performed on 30 isolates of Pseudomonas aeruginosa. Azlocillin was the most effective beta-lactam in combination with an aminoglycoside; MKO 787 was least effective. Among the aminoglycosides tested, netilmicin was the most effective. Medical treatment combined with valvulectomy (without valve replacement) is now standard treatment for refractory right-sided endocarditis at this medical center. A high dose of aminoglycoside in combination with a beta-lactam has proved efficacious. For left-sided infection, immediate valve replacement accompanied by a six-week course of the high dose-combined drug regimen is recommended. Newer beta-lactam antibiotics, such as piperacillin, may be limited in usefulness due to beta-lactamase inactivation.

Action spectra of topical psoralens: a re-evaluation.

The action spectra for producing minimal phototoxic erythema with topical 0.I% trimethyl psoralen (TMP) and 8-methoxypsoralen (8-MOP) were determined with a double monochromator in the range of 295-380 nm. both psoralens induced photosensitivity in the range of 313-365 nm; TMP was 54% more effective than 8-MOP. There was no difference in the dose needed to produce minimal UV erythema or phototoxic erythema with 8-MOP and TMP at 295 and 305 nm, but at 313 nm with 8-MOP, photosensitivity was enhanced 3.5 times, and with TMP, sensitivity was enhanced 5.5 times. The peak sensitivity with 8-MOP was at 330 nm and for TMP it was 335 nm. No photosensitivity occurred above 380 nm. Results suggest that TMP and 8-MOP are significantly photoreactive at 320-335 nm. Commonly used UV-A light sources show peak emission around 360 nm. If there is a relationship between development of erythema and therapeutic effectiveness than this raises the possibility of alternative UV light sources for phototherapy with psoralens.