In vivo pharmacodynamic characterization of a novel plectasin antibiotic, NZ2114, in a murine infection model.

NZ2114 is a novel plectasin derivative with potent activity against gram-positive bacteria, including multiply drug-resistant strains. We used the neutropenic murine thigh infection model to characterize the time course of antimicrobial activity of NZ2114 and determine which pharmacokinetic/pharmacodynamic (PK/PD) index and magnitude best correlated with efficacy. Serum drug levels following administration of three fourfold-escalating single-dose levels of NZ2114 were measured by microbiologic assay. Single-dose time-kill studies following doses of 10, 40, and 160 mg/kg of body weight demonstrated concentration-dependent killing over the dose range (0.5 to 3.7 log(10) CFU/thigh) and prolonged postantibiotic effects (3 to 15 h) against both Staphylococcus aureus and Streptococcus pneumoniae. Mice had 10(6.3) to 10(6.8) CFU/thigh of strains of S. pneumoniae or S. aureus at the start of therapy when treated for 24 h with 0.625 to 160 mg/kg/day of NZ2114 fractionated for 4-, 6-, 12-, and 24-h dosing regimens. Nonlinear regression analysis was used to determine which PK/PD index best correlated with microbiologic efficacy. Efficacies of NZ2114 were similar among the dosing intervals (P = 0.99 to 1.0), and regression with the 24-h area under the concentration-time curve (AUC)/MIC index was strong (R(2), 0.90) for both S. aureus and S. pneumoniae. The maximum concentration of drug in serum/MIC index regression was also strong for S. pneumoniae (R(2), 0.96). Studies to identify the PD target for NZ2114 utilized eight S. pneumoniae and six S. aureus isolates and an every-6-h regimen of drug (0.156 to 160 mg/kg/day). Treatment against S. pneumoniae required approximately twofold-less drug for efficacy in relationship to the MIC than did treatment against S. aureus. The free drug 24-h AUCs/MICs necessary to produce a stasis effect were 12.3 +/- 6.7 and 28.5 +/- 11.1 for S. pneumoniae and S. aureus, respectively. The 24-h AUC/MIC associated with a 1-log killing endpoint was only 1.6-fold greater than that needed for stasis. Resistance to other antimicrobial classes did not impact the magnitude of the PD target required for efficacy. The PD target in this model should be considered in the design of clinical trials with this novel antibiotic.

Dental manifestations of osteogenesis imperfecta and abnormalities of collagen I metabolism.

The in vitro protein-chemical features and the molecular background of osteogenesis imperfecta (OI), a heritable disorder of collagen I metabolism, have been elucidated in recent years. The aim of our study was to find the prevalence of dentinogenesis imperfecta (DI) and other dental anomalies in 88 patients with OI, to compare clinical with radiologic abnormalities, and to correlate these clinical/radiologic findings with the results of gel electrophoresis and molecular studies of collagen I. Twenty-eight percent of OI patients had DI. Most patients with DI had radiologic abnormalities, but some patients had radiologic signs compatible with DI, but no clinical signs of DI. OI type I patients with DI were more severely affected by OI than those without DI. In OI type III and IV, in contrast, there was no difference in overall severity between patients with and without DI. DI was not associated with any particular molecular aberration in any OI type. If defining DI from the presence of both clinical and radiologic signs, collagen I produced by cultured fibroblasts was qualitatively abnormal from all OI patients with DI. Some OI patients had dental abnormalities not resembling DI. A qualitative collagen abnormality could not be found in any of these patients. Denticles, i.e., calcifications within the pulpal cavity, were found more frequently in OI patients than in control subjects.

Immunoassay for urinary pyridinoline: the new marker of bone resorption.

Urinary pyridinoline (Pyd) and deoxypyridinoline (Dpd) are markers of bone resorption that are elevated above normal in subjects with metabolic bone disease. Total Pyd and Dpd, both free and peptide-bound forms, can be measured by HPLC after hydrolysis and cellulose chromatography. Since free Pyd is the major component of total Pyd in urine, we developed an immunoassay using free Pyd as an immunogen. This assay is much easier to perform than HPLC, requires no sample preparation, and correlates well with total Pyd measurement by HPLC (r = 0.97) and with urinary hydroxyproline (r = 0.90). The antiserum reacts most strongly with free Pyd and Dpd and minimally with glycosylated and large peptide-bound forms. The sensitivity of the Pyd immunoassay is less than 25 nM. The intraassay CV is 5-10%; the interassay CV is 10-15%. Analytic recovery studies indicated negligible sample interference. Furthermore, measurement of the Pyd in the same individuals over a 30 day time period exhibited minimal day-to-day variation. Thus, the Pyd immunoassay provides a rapid and easy method for evaluation of Pyd in urine. Pyd immunoassay may serve as a practical method of screening for metabolic bone disease and for monitoring therapeutic treatment.

Dental plaque and caries on permanent first molar occlusal surfaces in relation to sagittal occlusion.

This study examines the influence of sagittal occlusion on occlusal plaque formation in permanent first molars (PFM) in 72 7-10-yr-olds before loss of primary second molars. Of a total of 288 PFM, 140 (49%) were sealed and 23 (8%) filled. Occlusal plaque was recorded at two levels of examination: 1) visible plaque on the entire surface and 2) detailed macromorphologic mapping. Enamel caries was recorded after professional tooth cleaning. After 48 h without tooth brushing, plaque examinations were repeated. Stone models were used for 1) identification of interocclusal contact areas and 2) classification of sagittal molar occlusion. The detailed mapping of plaque on unfilled surfaces showed a clear pattern of preferential locations related to the macromorphology of the occlusal surfaces. Active caries was restricted to those anatomic structures where plaque accumulated. 48-h median plaque values on mandibular molars in normal and with one cusp distal occlusion were significantly lower (P < 0.01) compared to surfaces in 1/4, 1/2 and 3/4 distal molar occlusion. Maxillary molars with normal and with 1 cusp distal occlusion had lower median plaque values than other sagittal occlusion categories. In general, however, plaque scores were higher in maxillary teeth because more than 2/3 of these teeth were without occlusal contact in the distal part. Mandibular occlusal surfaces in normal and with one cusp distal occlusion had significantly fewer active lesions than teeth with 1/4, 1/2 and 3/4 cusp distal occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

[Indications and use of fissure sealants in public dental health care in Denmark. A questionnaire-investigation]. / Anvendelse og indikationsområde for fissurforseglinger i den offentlige tandpleje i Danmark. En spørgeskemaundersøgelse.

During the past decade usage of the fissure sealant technique for occlusal caries prevention has been increasingly recommended. This study explores variations in indications and usage of this technique in Denmark. A questionnaire was sent to 205 chief dental officers in the Danish Public Child Dental Health Service (PDHS) covering 90% of Danish children and to municipalities, where dental health to children is provided by private practitioners. More than half of the respondents did not use firmly defined criteria for fissure sealant application. Oral hygiene and previous caries experience were most often stated as indications. Actual usage of the sealant technique differed significantly from the PDHS and private clinics. Thus, 33% of the chief dental officers in the PDHS said that sealants were routinely applied to 8- and 13-year-olds, 43% to 30-80% of the children, and 15% used sealants to less than 10% of 8- and 13-year-olds. In contrast, only 5% of the private clinics reported routinely use of sealing technique, 22% used application to 30-80% of the children, while more than one third of the private practitioners used sealants to less than 10% of the 8- and 13-year-olds. In spite of the significant difference in sealant usage between PDHS and private practitioners, it was not possible to see a corresponding difference neither in caries prevalence nor in occlusal filling incidence. Moreover, analysis of PDHS caries prevalence data revealed that PDHS variations could not be explained by variations of risk in terms of social classes and caries incidence.(ABSTRACT TRUNCATED AT 250 WORDS)

[Plaque and gingivitis in children with cerebral palsy: relation to CP-diagnosis, mental and motor handicap]. / Plak og gingivitis hos børn med cerebral parese relateret til CP-diagnose, psykisk og motorisk handicap.

UNLABELLED: A total of 105 children with cerebral palsy aged 14 and 15 years born in the eastern Denmark comprised the study group. The children were classified according to CP-diagnosis, mental handicap, motor handicap and information on plaque index, gingivitis index, and toothbrushing habits were collected. The analysis showed that the values for plaque and gingivitis indices were significantly higher than those of the control group. The specific CP-diagnosis, the mental handicap and the motor handicap did not seem to have definite influence on the child's plaque and gingivitis indices. Children with the mildest mental and motor handicap seemed to have lower plaque and gingivitis indices than those of the severely handicapped children. The highest gingival scores (5.2) were seen when the child and the parents together were responsible for the child's toothbrushing. The gingival index was 4.0, when the parents brushed the child's teeth and 3.7 when the children brushed their teeth on their own. Only 7 children used an electric toothbrush. The average gingival index in this group was 3.0, which was nearly the same as that of the control group. CONCLUSION: 1. Oral hygiene planning of the CP-child can only be made when an individual evaluation has been performed. 2. CP-children's oral hygiene has to be controlled frequently.

Caries among children with cerebral palsy: relation to CP-diagnosis, mental and motor handicap.

A total of 105 children with cerebral palsy, born in eastern Denmark in 1968 or 1969, comprised the group studied here. They were classified by CP-diagnosis, motor handicap, mental handicap, speech, caries, with dental data statistically analyzed. The caries rate of the combined CP-group was significantly lower than that of the control group.

[Intrusion of primary teeth: case reports]. / Intrusion af primaere taender: et kasuistisk bidrag.

Three cases of intrusion of primary teeth are described. In all cases the intruded primary tooth was left without treatment and the tooth did not re-erupt. After eruption of the succedaneous permanent tooth the primary tooth was surgically removed. There was damage to the permanent tooth in two of the three cases.