Dental treatment of Papillon-Lefèvre syndrome: 15-year follow-up.

A 9-year-old girl was initially treated for the periodontal component of Papillon-Lefèvre syndrome by extraction of all patient's erupted teeth, after unsuccessful clinical treatment with two different antibiotics. Follow-up dental records at age 24 showed the patient to have generalized gingivitis and poor oral hygiene; however, no additional teeth were lost or mobile. Radiographically, the alveolar crests, lamina dura, and periodontal ligament spaces appeared normal for a subject with missing teeth. Initially, the patient had depressed polymorphonuclear leukocyte (PMN) chemotaxis and adherence, as well as evidence of periodontal infection with Actinobacillus actinomycetemcomitans, (A.a.). The 6 and 15-year follow-ups showed normal PMN function and no detectable A.a. The improvement of the patient's PMN function was coincident with lack of detection of certain periodontopathic bacteria. If the PMN dysfunction of PLS is secondary to the infection, the reasons for the initiation of the disease still need to be clarified.

Antibiotic dosing in renal failure.

The Dosing in Renopathy by Easy-To-Use Multipliers (DREM) System is a simple method for dose adjustments of anti-infectives in renal insufficiency. The simple 2-step method involves: (1) estimating creatinine clearance (CLcr) from age, sex, and serum creatinine, and (2) calculating the adjusted dose or dosing interval with the use of multipliers. By multiplying the normal dose or dosing interval with the dose (CLcr/100) or interval (100'CLcr) multiplier, the adjusted dose or dosing interval is obtained, respectively. Dose estimates with this method are reasonably accurate and compare favorably with previously published methods of correction.

Depressed neutrophil chemotaxis in children suffering blunt trauma.

OBJECTIVE: Impaired neutrophil (PMN) function, due in part to release of immature PMNs into the circulation, contributes to the increased rate of infection observed in adults suffering blunt trauma. The objective of this study was to determine whether similar events occur in children. METHODS: We assessed PMN chemotaxis and PMN maturation in 25 children (7 young children and 18 adolescents) and 25 adults 1 to 9 days after suffering blunt trauma, and in healthy adult control subjects. PMN chemotaxis was determined using a standard micropore filter assay, whereas PMN maturation was determined with 31D8, a novel monoclonal antibody that binds to mature PMNs more avidly than immature PMNs and band forms. RESULTS: In patients suffering blunt trauma, mean PMN chemotactic values were similar among children (44.6 +/- 2.3 microns) and adults (41.3 +/- 2.1 microns) and both were significantly less than among healthy adults (53.5 +/- 2.4 microns, P < .0005). PMN chemotactic values increased significantly in the 9 days after trauma for both children and adults (F = 13.8, df = 1, P < .0002). Mean PMN 31D8 binding among children with trauma (92.5 +/- 5.2) was significantly less than among healthy adults (117.6 +/- 5.4, P < .0009). CONCLUSIONS: Impairment in PMN chemotaxis occurs in children after blunt trauma and is due in part to release of immature PMNs into the circulation.

Institution-specific patterns of infection and Gram's stain as guides for empiric treatment of patients hospitalized with typical community-acquired pneumonia.

STUDY OBJECTIVE: To determine the appropriateness of cefazolin as empiric treatment of typical, as opposed to atypical, bacterial community-acquired pneumonia at our institution. DESIGN: Combination of retrospective chart review and prospective determination of microbial susceptibilities and cefazolin-associated cost savings. SETTING: General acute-care referral hospital. PATIENTS: We evaluated the charts of patients discharged with a diagnosis of community-acquired pneumonia over a 10-year period. Gram's stains and culture results of sputum samples processed over 2 months were analyzed to determine the ability of the stains to predict positive Haemophilus influenzae cultures. The susceptibility and beta-lactamase status of clinical isolates of H. influenzae were determined. Cost savings of cefazolin as empiric treatment for community-acquired pneumonia were evaluated. MEASUREMENTS AND MAIN RESULTS: The frequency of H. influenzae pneumonia at our institution was 15% of the three major bacterial community-acquired pneumonias. Gram's stain was highly accurate in predicting the presence or absence of Haemophilus sp in sputum. Five patients had positive outcomes with cefazolin treatment despite being diagnosed with H. influenzae pneumonia. The organism isolates demonstrated intermediate sensitivity to cefazolin and 85% were beta-lactamase negative. Our program that encourages empiric use of cefazolin over cefuroxime for typical bacterial community-acquired pneumonia has allowed a modest projected annual cost savings of $24,000. CONCLUSIONS: We concluded that when Gram's stain of sputum does not show Haemophilus sp in patients with typical bacterial community-acquired pneumonia, empiric treatment with cefazolin is appropriate and results in cost savings.

Serum protein-binding characteristics of vancomycin.

A synthesis of studies of serum protein binding of vancomycin and its reported abnormal binding in serum with very high concentrations of immunoglobulin A (IgA) suggests that this antibiotic may be bound to more than one serum protein. Using an ultrafiltration method for separating free from bound drug and high-performance liquid chromatography to measure drug concentration, we studied the binding characteristics of vancomycin for alpha-1 acid glycoprotein, IgG, IgM, IgA, and albumin. The results showed that vancomycin does not bind to alpha-1 acid glycoprotein, IgG, or IgM. Major binding to albumin and IgA occurs, and total drug binding to serum proteins can be fully explained by binding to these two proteins. We calculated an N (number of binding sites per molecule) of 1.3 +/- 0.4 and a K (association constant) of 3.3 x 10(5) +/- 6.3 x 10(4) M-1 (NK = 4.3 x 10(5) M-1) for binding to IgA, whereas the corresponding NK value for albumin was only 527.5 M-1, indicating that vancomycin preferentially binds to IgA. Very high concentrations of IgA in serum (i.e., grams per deciliter), such as in patients with IgA myeloma, may result in the paradox of high (total) concentrations of vancomycin in serum that may be clinically ineffective.

Reduction of bacterial titers by low-dose aspirin in experimental aortic valve endocarditis.

Using a rabbit model of Staphylococcus aureus endocarditis, we studied the effects of aspirin on the natural progression of this infection. Compared with untreated animals, the aspirin-treated animals showed a 30% (P = 0.11) reduction in the weight of the vegetations and an 84% (P = 0.03) reduction in the bacterial titer of the vegetations.

Simplification of antibiotic dose adjustments in renal insufficiency: the DREM system.

Many clinicians, unassisted by reference books, are unable to make the required dose adjustment of antibiotics needed when a patient has renal insufficiency. We describe the DREM (dosing in renopathy by easy-to-use multipliers) system, which simplifies the understanding and the process of dose adjustment. DREM is a two-step process: Cockcroft and Gault estimation of creatinine clearance (CLcr) from age, sex, and serum creatinine and calculation of the adjusted dose or dosing interval by multipliers. If the normal dose is multiplied by the dose multiplier (CLcr/100) and the dosing interval by the interval multiplier (100/CLcr), the adjusted dose and interval, respectively, are obtained. Theoretical trough concentrations calculated with the DREM system correlated closely (r = 0.9) with actual concentrations obtained from doses calculated by the Hull and Sarubbi method in 23 patients. With DREM, gentamicin or tobramycin trough concentrations above 2 micrograms/ml were less likely to occur. The DREM system is a simple and easily remembered method for dose adjustments of certain anti-infective agents in renal insufficiency. Dose estimates with this method are reasonably accurate and compare favourably with other standard methods of correction.

Lomefloxacin concentrations in bone after a single oral dose.

We studied the penetration characteristics of lomefloxacin in bone in 30 patients with osteoarthritis undergoing total hip replacement. Patients were given a single oral 400 mg dose at various times from 1 to 12 hours prior to removal of bone samples. The peak plasma and bone (subchondral bone from femoral head) concentrations reached approximately 4.0 micrograms/mL at 2 hours post-dose and 3.0 micrograms/mL at 3 hours post-dose, respectively. At 12 hours post-dose both plasma and bone concentrations were still greater than 1.0 microgram/mL. Two hours after dosing the average bone-to-plasma ratio was greater than 0.6. These data indicate that a single 400 mg oral dose of lomefloxacin attains bone concentrations that are above its usual minimum inhibitory concentrations for susceptible organisms.

Characterization of a direct effect of phorbol myristate acetate on human neutrophil cell membrane using 31D8 monoclonal antibody.

We found that 4-beta-phorbol 12-myristate 13-acetate (PMA) caused decreased expression of the polymorphonuclear neutrophil (PMN) surface antigen 31D8. In contrast to the rapid initiation of the oxidative burst caused by PMA, the effect was slow to start but increased during incubation periods up to 50 min. To study this apparent protein kinase C-independent late effect of PMA, we measured 31D8 expression in PMNs after incubation with various concentrations of PMA. The maximum PMA-induced inhibition was 76 +/- 2%, with an ID50 of 3.9 +/- 0.4 ng/ml. Oxidants and prooxidants (hydrogen peroxide, hypochlorite, taurine-chloramine, and ferrous iron, with or without H2O2) had no direct effect on 31D8 antigen expression. The following substances were not protective against the inhibitory affect of PMA: (1) antioxidants (superoxide dismutase, catalase, azide, dimethyl sulfoxide, Desferal, and ascorbate, with the exception of alpha-tocopherol), (2) inhibitors of protein kinase C (H7 and W7), (3) inhibitors of 5-lipoxygenase (A-63162, MK886, and high-dose indomethacin) and (4) inhibitors of cyclooxygenase (low-dose indomethacin). Myeloperoxidase-deficient PMNs had normal 31D8 antigen expression and a decrease of 31D8 antigen expression by PMA, as did normal PMNs. The inactive analog of PMA, 4-alpha-phorbol didecanoate, had no effect on 31D8 antigen expression. alpha-Tocopherol (50 micrograms/ml) and betamethasone (150 micrograms/ml) protected against the PMA effect by 30.5 +/- 7.3 (P less than .0005) and 52 +/- 15 (P less than 0.004) channels, respectively. These results indicate that PMA has a protein kinase C-independent late effect on human neutrophils, which can be prevented by pretreatment with alpha-tocopherol or the steroid betamethasone. These compounds probably exert their protective effect by membrane stabilization.

Characteristics of ceftriaxone binding to immunoglobulin G and potential clinical significance.

The interaction between immunoglobulin G (IgG) and ceftriaxone was studied. Using an ultrafiltration method, we performed dose ranging studies at a ceftriaxone concentration range of 1 to 720 micrograms/ml in the presence of various concentrations of human IgG, human serum albumin (HSA), and combinations of IgG and HSA at pH 7.4 and 37 degrees C. The results showed that ceftriaxone binding to IgG was nonlinear and was consistent with the presence of two binding sites that possess different binding capacities and affinities. Except for increased peak percent binding as the IgG concentration increased, the binding characteristics did not change with IgG concentration. Binding to HSA was consistent, with the presence of only one high-affinity binding site. A mathematical model based on the observed data was constructed; this model was used to predict protein binding at various concentrations of drug, IgG, HSA, or combinations of IgG and HSA in buffer and in plasma medium. Correlations between the observed versus the predicted values were excellent in both media. Simulations with the model indicated that patients with hypergammaglobulinemia have an increased potential of being exposed to prolonged subinhibitory concentrations of ceftriaxone if the drug is given once every 24 h.

A randomized trial of replacement antioxidant vitamin therapy for neutrophil locomotory dysfunction in blunt trauma.

Studies in patients with serious trauma indicate that the observed neutrophil (PMN) locomotory dysfunction is partly the result of auto-oxidation as shown by evidence of preactivation, diminished reducing capacity, and low serum and cellular ascorbic acid and alpha-tocopherol. To investigate whether replacement of the antioxidant vitamins ascorbic acid and alpha-tocopherol can improve the PMN locomotory defect, ascorbic acid, alpha-tocopherol, ascorbic acid and alpha-tocopherol, or placebo was administered to a total of 46 victims of blunt trauma. PMN locomotion was quantitated using a micropore filter assay. Locomotion data were analyzed by repeated measures analysis with a split plot design and data for days 2-6 after injury were compared. Compared with placebo, the antioxidants improved PMN locomotion. The mean differences in distance migrated (treated minus placebo) were ascorbic acid and alpha-tocopherol = 11.3 +/- 3.0 microns (one-tailed p = 0.001) (mean +/- SE); ascorbic acid = 4.7 +/- 3.4 microns (p = 0.19); and alpha-tocopherol = 3.3 +/- 2.9 microns (p = 0.27). Although both antioxidants given together produced the best results, a plot of the 95% confidence intervals indicates that ascorbic acid and alpha-tocopherol, either given alone, were also better than placebo. We conclude that antioxidant replacement therapy significantly improves the PMN locomotory abnormality in blunt trauma.

Modulation of neonatal neutrophil function by pentoxifylline.

Immunomodulating agents are being investigated for treatment of infection in newborn infants where morbidity and mortality remain high despite the continued development of new antibiotics. We studied the effect of the methylxanthine pentoxifylline on polymorphonuclear leukocyte (PMN) chemotaxis, F-actin content, and phagocytic activity as measured by nitroblue tetrazolium reduction and H2O2 production in neonates and adults to determine whether pentoxifylline might be useful in augmenting PMN function. The drug was found to have a dose-dependent effect on both neonatal and adult PMN function with enhancement at lower concentrations and suppression at higher concentrations. PMN chemotaxis increased 42% (p less than 0.01) in neonates and 16% (p less than 0.05) in adults at 100 micrograms/mL of pentoxifylline and it decreased 4 and 25%, respectively, at 4000 micrograms/mL. PMN nitroblue tetrazolium reduction increased by 34% in neonates and 23% (p less than 0.05) in adults at 100 micrograms/mL of pentoxifylline and decreased by 52 (p less than 0.01) and 74% (p less than 0.01), respectively, at 2000 micrograms/mL. Similar dose-dependent responses were noted with F-actin content and H2O2 production. These and other observations support the hypothesis that pentoxifylline has a broad range of effects on PMN but that a primary effect is alteration of PMN deformability. Pentoxifylline has potential clinical use as an immunomodulator in augmenting impaired PMN function in neonates and other immunocompromised hosts or in suppressing excessive PMN activity in certain disease processes.

The role of cellular maturation in neutrophil heterogeneity.

Previous studies have shown that many neutrophil (PMN) characteristics are heterogeneous but the origin of PMN heterogeneity is unknown. It is unclear if PMN functional heterogeneity is secondary to maturational differences or due to distinct subpopulations of cells that possess different functional capacities. The PMN 31D8 antigen is a useful probe for evaluation of PMN subpopulations. The majority of PMNs (approximately 85%) exhibit a high intensity fluorescence after 31D8 monoclonal antibody (MoAb) labeling (31D8 enriched or "bright" PMNs) as determined by flow cytometric analysis. These cells are more functional than cells with low intensity fluorescence (31D8 diminished or "dull" PMNs). Various immunologic, clonogenic and functional techniques were used to study the expression of the 31D8 antigen in HL-60 cells and myeloid cells in order to evaluate antigenic and functional heterogeneity during morphologic maturation. The results of this study indicate that the percentage of 31D8 antigen positive (31D8 antigen enriched and diminished) bone marrow cells increases from 20 +/- 11% in myeloblast cells to 68 +/- 10% in promyelocytes, 93 +/- 2% in myelocytes and 99 +/- 1% in bands and PMNs. 31D8 antigen enriched cells first appear at the myelocyte stage (32 +/- 10%) and increase in bands (52 +/- 13%), marrow PMNs (62 +/- 13%) and peripheral blood PMNs (88 +/- 4%). These data indicate that the heterogeneous expression of 31D8 antigen in PMNs is due, at least in part, to maturational differences within the PMN population and raise the possibility that other heterogeneously expressed PMN characteristics are also maturationally derived. They also suggest that 31D8 antigenic expression may be a more precise indicator of myeloid functional maturation than maturation as identified by cellular morphology.

Efficacy, toxicity, and pharmacokinetics of pentoxifylline and its analogs in experimental Staphylococcus aureus infections.

Pentoxifylline (PTX), a drug that improves neutrophil function in vitro, has been shown to protect neonatal mice against death from experimental staphylococcal infection in vivo at a dose of 50 mg/kg. Using a total of 774 neonatal mice, the effects of various doses of PTX were examined and compared with the effects of three analogs: HWA-448, HWA-285, and A81-3138. A subcutaneous abscess was induced with 10(8) Staphylococcus aureus, and drug or saline was given daily subcutaneously from 2 days before to 4 days after infection. Noninfected animals (given saline without S. aureus) had 0% mortality (0 of 66), and infected animals without drug (given saline) had a mortality of 70% (161 of 231). PTX and HWA-448 showed the greatest protection among the drugs tested at 15 mg/kg with mortality rates of 27 and 38%, respectively (Kaplan-Meier method, P = 0.0001 and 0.0004, respectively). HWA-285 was most protective at 25 mg/kg (mortality, 45%; P = 0.0046) and A81-3138 was most protective in animals at 15 mg/kg (mortality, 42%; P = 0.0045). PTX, HWA-448, HWA-285, and A81-3138 at doses of 200, 100, 100, and 50 to 75 mg/kg, respectively, were toxic as shown by worsened weight loss and increased mortality in animals when compared with infected animals without drug. PTX and its analogs decrease mortality from experimental infections at lower doses but are toxic at higher doses. Pharmacokinetic characteristics of the drugs were similar except that HWA-285 produced lower concentrations in serum and A81-3138 showed a dose-dependent kinetics (longer half-life at a higher dose).

Aspergillus endocarditis: cure without surgical valve replacement.

We have reported a case of fungal native valve endocarditis due to Aspergillus sp in which cure was effected by medical therapy alone. An infected sternectomy wound from a previous aortic valve replacement was considered a contraindication to surgery.

Additional evidence of autoxidation as a possible mechanism of neutrophil locomotory dysfunction in blunt trauma.

Previous studies in victims of blunt injury suggest that the observed neutrophil (PMN) locomotory dysfunction is, in part, due to autoxidation. To further clarify the occurrence and significance of autoxidation, we studied changes in levels of glutathione in PMN and of ascorbic acid and alpha-tocopherol in serum and blood cells of postsurgical and blunt trauma patients. Levels of total, reduced, and oxidized glutathione in PMN from trauma patients were similar to normal controls. Serum and cellular ascorbic acid and alpha-tocopherol levels dropped significantly after injury and remained below normal control levels during the 7 to 8-day study period. Low serum alpha-tocopherol was partially explainable on the basis of changes in serum lipids. When serum samples of trauma patients were thawed unprotected without pyrogallol, there was significant loss of recoverable alpha-tocopherol, whereas no significant losses occurred with unprotected thawed normal sera. Less total reducing capacity was observed in PMN of trauma patients compared with normal controls. These findings indicate that synthesis and regeneration capacity of glutathione are intact but that the levels of the consumable antioxidants, ascorbic acid, and alpha-tocopherol are compromised after injury. These results add further support to the hypothesis that autoxidation occurs in trauma.

Effects of intravenous fat infusion on neonatal neutrophil and platelet function.

Intravenous fat (Intralipid) is used extensively as a major component of parenteral nutrition for patients in the neonatal intensive care unit. Abnormalities of polymorphonuclear leukocyte (PMN) and platelet number or function related to Intralipid infusion have been reported although conflicting results exist. In order to examine potential adverse hematologic effects of Intralipid, 10 ill neonates were studied before and after a 16-hr infusion of 1 g/kilo of Intralipid. PMN count, chemokinesis, chemotaxis, and aggregation were unchanged pre- and post intralipid infusion. Platelet count, bleeding time, and platelet aggregation were also unchanged. Similar results were obtained in vitro when neonatal and adult PMNs and platelets were incubated in Intralipid and their function analyzed. These findings suggest that short-term, low-dose Intralipid has no measurable impact on neonatal PMN or platelet activity and support its use in neonates even in the presence of infection or thrombocytopenia.

Pitfalls in testing drug uptake by leukocytes using radiolabeled drugs and an explanation of conflicting results with clindamycin.

Although studies of drug uptake by leukocytes use similar methods, the results reported are sometimes vastly different. To determine the possible reasons for this, we studied neutrophil uptake of [3H]-clindamycin using the most frequently used density gradient centrifugation method and the volume probes 3H2O and [3H]-polyethylene glycol. We found that the [3H]-clindamycin available to investigators had undergone radiolytic decomposition; thus, its microbiologic activity was only 20% of its original potency. By thin-layer chromatography and autoradiography, four extra label-bearing regions were observed with [3H]-clindamycin. Results of neutrophil uptake studies have shown a drop of cellular:extracellular concentration ratios from 40:1 in 1981 to 10:1 in 1982 and 1987.