Treatment of Chronic Hematogenous Osteomyelitis in Children With Antibiotic Impregnated Calcium Sulphate.

BACKGROUND: The purpose of this study was to evaluate the clinical and radiologic outcome of chronic hematogenous osteomyelitis (CHOM) in children, treated with single-stage debridement and dead space management using antibiotic impregnated calcium sulphate pellets. METHODS: The authors retrospectively evaluated a consecutive series of 34 patients who presented with CHOM from 2011 to 2017. In each case, CHOM was classified according to the Beit CURE classification. Following thorough surgical debridement, the resulting dead space in the bone was filled with the antibiotic impregnated beads before primary closure. RESULTS: Of the 31 patients available for follow up, effective regeneration of bone was confirmed in all cases, with radiographic bone healing typically observed at around 12 weeks. None of the children required reoperation for infection and none had recurrence of infection at the time of final review. The beads were completely absorbed within 3 months. No systemic adverse reactions to the local delivery of antibiotics were observed in this study. CONCLUSIONS: The authors found that single-stage debridement in conjunction with antibiotic impregnated calcium sulphate was an effective means of treating CHOM in children, with effective eradication of infection in every case. LEVEL OF EVIDENCE: Level IV-Retrospective case series. See instructions for authors for a complete description of levels of evidence.

Daptomycin for Pediatric Gram-Positive Acute Hematogenous Osteomyelitis.

BACKGROUND: We prospectively evaluated efficacy and safety of daptomycin versus active comparator in children with acute hematogenous osteomyelitis (AHO). METHODS: Randomized, controlled, double-blind, global, multicenter, phase 3 trial. Patients 1-17 years of age with suspected/confirmed AHO requiring hospitalization and intravenous therapy were randomized 1:1 to intravenous daptomycin (once-daily, age-adjusted doses) or comparator (vancomycin, nafcillin or equivalent) ≥4 days, followed by oral therapy (14-42 days total). Primary endpoint: protocol-defined clinical improvement by Day 5 in the modified intention-to-treat (MITT) population (confirmed AHO, ≥1 dose of study treatment); differences between study arms were evaluated using a prespecified 15% noninferiority margin for daptomycin. RESULTS: Seventy-three patients per arm received treatment. Pathogens were isolated from 62% of patients (83% methicillin-susceptible Staphylococcus aureus, 9% methicillin-resistant S. aureus [MRSA]). Clinical improvement by Day 5 was observed in 55/71 (78%) daptomycin- and 58/70 (83%) comparator-treated MITT patients (95% confidence interval [CI]: -19.4, 7.4). This difference was not statistically significant; however, daptomycin did not meet the prespecified 15% noninferiority margin, since the lower bound of the 95% CI extended below 15%. Overall, 82% of daptomycin and 87% of comparator patients achieved clinical cure at the test-of-cure visit (secondary endpoint). More comparator patients had treatment-emergent (63% vs. 46%) and treatment-related (18% vs. 7%) adverse events. CONCLUSIONS: Differences between daptomycin and comparator for the primary endpoint were not statistically significant; however, prespecified noninferiority criteria for daptomycin were not met. With insufficient cases of confirmed MRSA, we could not evaluate daptomycin for MRSA AHO. Our nonvalidated protocol design yields valuable information for implementing future trials in AHO (ClinicalTrials.gov NCT01922011).

Is Hypercalcemia a Frequent Complication following Local Use of Calcium Sulfate with Antibiotics for the Treatment of Extremity Posttraumatic Osteomyelitis? A Preliminary Study.

BACKGROUND: Previous study had reported hypercalcemia as a frequent complication (20%) following local use of antibiotic-eluting calcium sulfate (CS) during treatment of periprosthetic joint infections (PJIs). However, whether this complication may occur in patients who receive local CS implantation for management of posttraumatic osteomyelitis (OM) remains unclear. METHODS: Between April 2016 and May 2017, we included 55 patients with extremity posttraumatic OM who received local antibiotic-loaded CS therapy. Serum calcium levels were detected preoperatively and on the 1st, 3rd, and 7th postoperative days (PODs). Comparisons were performed regarding serum calcium levels among the four time points and between two different CS volume groups (≤ 20 cc group and > 20 cc group). Additionally, potential associations were examined regarding CS volume and preoperative calcium level with postoperative calcium levels, respectively. RESULTS: Altogether 46 males and 9 females were included, with a median CS volume of 20 cc. Outcomes showed that prevalence of asymptomatic hypocalcemia was more frequent, with 16.4% before surgery and 60%, 53.8%, and 25% on the 1st, 3rd, and 7th PODs, respectively. Hypercalcemia was not found in any patients, at any time point. In addition, significant differences were identified regarding serum calcium levels among different time points, suggesting significantly decreased calcium levels on the 1st (P < 0.001) and 3rd PODs (P < 0.001) and back to near preoperative level on the 7th POD (P = 0.334). However, no statistical differences were observed regarding serum calcium levels between the two CS volume groups at any time points (P > 0.05). Moreover, no significant links were identified between CS volume and postoperative calcium levels (P > 0.05). Serum calcium levels on the 3rd (P = 0.019) and 7th PODs (P = 0.036) were significantly associated with the preoperative calcium level. CONCLUSIONS: In contrast to what had occurred in PJI patients, asymptomatic hypocalcemia appeared to be more frequent in this cohort with posttraumatic OM. Hypercalcemia may be an infrequent complication before and after local CS use for the treatment of extremity posttraumatic OM.

Combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded PMMA in the treatment of chronic osteomyelitis.

BACKGROUND: Chronic post-traumatic and postoperative osteomyelitis is a refractory disease which results in significant morbidity and mortality. The effect of combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded polymethyl methacrylate (PMMA) was unknown. METHODS: Fifty-one patients suffering from chronic post-traumatic or postoperative osteomyelitis of the lower extremities were included in the retrospective investigation. The patients were assigned to the study group of the combination therapy with antibiotic-loaded calcium sulfate and antibiotic-loaded PMMA or the control group of the antibiotic-loaded PMMA. Hematological parameters, eradication of infection, rate of infection recurrence and reoperation rate were evaluated during the follow-up. RESULTS: The cases were followed up for an average of 24 months (range, 15-48 months) after the first-stage surgical operation. In the study group, all the patients revealed complete calcium sulfate resorption at an average of 6 weeks (range, 30-60 days). In the study group, infection was primarily eradicated in 92.31% (24 of 26) of patients and re-operation rate of 7.69% (2 of 26) after the first-stage surgery. Two patients underwent further surgical operation in the study group. One case achieved infection eradication in the recurrent two cases, with a secondary infection eradication rate of 96.15% (25 of 26). There was no persistent infection in the study group. In the control group, infection was eradicated in 64.00% (16 of 25) of patients and re-operation rate was 36.00% (9 of 25) after the first-stage surgery. Nine patients in the control group underwent further surgical operation. Two case achieved infection eradication in these cases who suffered from persistent or recurrent infection, with a secondary infection eradication rate of 72.00% (18 of 25). There was more re-operation rate in the control group (PMMA group, 9 vs combination therapy group, 2; P = 0.034). CONCLUSION: The combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded PMMA possibly achieved more effective control of infection in the treatment of osteomyelitis through synergistic effect. The immediate structural stabilization and higher concentration of antibiotic at the local site of infection may be achieved through the combination of biodegradable and non-biodegradable devices in the treatment of chronic post-traumatic and postoperative osteomyelitis. The study was retrospectively registered at 11/16/2016 (TRN: NCT02968693).

Pharmacokinetics and pharmacodynamics of oral cephalexin in children with osteoarticular infections.

BACKGROUND: Osteoarticular infections lead to significant morbidity in children. Cephalexin has in vitro activity against methicillin-susceptible Staphylococcus aureus, a predominant pathogen in osteoarticular infection. However, cephalexin pharmacokinetics (PK) and pharmacodynamics (PD) are poorly described in children. This study described cephalexin PK in children treated for osteoarticular infection and assessed the proportion of children achieving surrogate PK/PD target for efficacy in methicillin-susceptible S. aureus infection. METHODS: Children with osteoarticular infection, 1 to 18 years of age, were eligible for this study if they were receiving oral cephalexin per standard of care. PK plasma samples were collected at specified times after multiple doses. PK parameters were estimated using noncompartmental analysis. PK/PD target for efficacy was calculated using the child's PK parameters, minimum inhibitory concentration (MIC) of the isolate when available and previously described MIC of 2 and 4 mg/L. RESULTS: Twelve children were enrolled and PK profiles were obtained from 11 of them. Median age was 7 years, and median cephalexin dose was 40 mg/kg/dose every 8 hours. Median apparent oral clearance, apparent oral volume of distribution and elimination half-life (T1/2) were 0.29 L/h/kg, 0.44 L/kg and 1.1 h, respectively. Time above MIC (T>MIC) was greater than 40% of the dosing interval in 100%, 90% and 80% of the children when MICs were 0.25, 2 and 4 mg/L, respectively. CONCLUSIONS: Oral cephalexin achieved optimal plasma exposure and was well tolerated in children with osteoarticular infection. Correlation between osteoarticular infection clinical outcome and PK/PD parameters needs further evaluation.

Efficacy of leukocyte- and platelet-rich plasma gel (L-PRP gel) in treating osteomyelitis in a rabbit model.

Leukocyte- and platelet-rich plasma gel (L-PRP gel), a new autologous product which was previously utilized in several surgical procedures to enhance tissue healing, is now increasingly used as a promising treatment method for infections. In this study, we investigated the antibacterial property of L-PRP gel against Methicillin-resistive Staphylococcus aureus (MRSA, ATCC 43300) in a rabbit model of osteomyelitis. Tibial osteomyelitis was induced in 40 New Zealand white rabbits using the MRSA strain. Three weeks after induction, the rabbits with tibial osteomyelitis were randomly divided into four groups: Control group (no treatment); Van group (debridement and parenteral treatment with vancomycin alone); L-PRP gel + Van group (debridement and local L-PRP gel injection, plus parenteral treatment with vancomycin); L-PRP gel group (debridement and local L-PRP gel injection). All rabbits were sacrificed 6 weeks after debridement. The antibacterial efficacy was evaluated by radiological, microbiological, and histological examinations. Newly formed bone was also quantified. The best therapeutic efficacy, including infection elimination and bone defect repair, was observed in the L-PRP gel + Van group. Although not comparable to vancomycin, L-PRP gel also exibited antimicrobial efficacy in vivo. We believe that a combination of L-PRP gel and antibiotics could be a favorable alternative for the treatment of osteomyelitis.

[The immunomodulator ximedon lowers the level of induced DNA damages in bone marrow and peripheral blood cells: the possibilities for immunogenetic correction]. / Immunomoduliator ksimedon snizhaet uroven' indutsirovannykh povrezhdenii DNK v kletkakh kostnogo mozga i perifericheskoi krovi: vozmozhnosti immunogeneticheskoi korrektsii.

It was established in experiments on albino unbred mice and during treatment of patients with osteomyelitis that 30 mg/kg of ximidon suppresses the formation of micronuclear polychromatophilic erythrocytes found in the bone marrow of mice and peripheral blood of patients with chronic osteomyelitis. The interrelationship of the results obtained with the modulating effect of ximidon on the mitochondrial, thiol, and adenylate cyclase-dependent mechanisms of cell regulation is discussed.

The effect of antibacterial agents on plasma vitamin C levels.

Previous report on the estimation of plasma ascorbic acid levels in patients with chronic osteomyelitis indicated that the plasma ascorbic acid level is reduced in patients on antibiotics. The plasma study of the effects of anti-bacterial agents on plasma ascorbic acid in vitro, was carried out to substantiate the hypothesis than these agents lower plasma ascorbic acid levels. Increasing amounts of each of seven anti-bacterial agents: ampicillin, chloramphenicol, cefotaxime, gentamycin, benzyl and procaine penicillin combination (seclopen), co-trimoxazole, and streptomycin significantly (P < 0.01, r = -0.9587) reduced plasma vitamin C levels in vitro. There was moderate but insignificant reduction in plasma vitamin C levels with clindamycin (r = -0.799). The reduction of the plasma vitamin C levels observed in the presence of the eighth anti-bacterial agent, clindamycin, lacked significance (r = -0.799). The cause of this reduction of plasma vitamin C levels by anti-bacterial agents in vitro is not yet understood. A supplement of vitamin C may be required in patients on anti-bacterial agents.

[Antibiotic-containing collagen sponge in therapy of osteitis]. / Antibiotikahaltiges Kollagenvlies in der Osteitistherapie.

In 1988, we treated 47 patients with acute or chronic osteitis by means of a new industrial collagenous sponge containing gentamicin (Sulmycin Implant) as an adjuvant measure. The local surgical management was standard: total excision of all avascular or infected soft tissue and bone, stabilization of pseudarthrosis, the improvement of local circulation and the condition of the soft tissue by means of local or free flaps before autologous bone grafting and antibiotics administered according to the test results. In cases of instability AO external fixation was used. One or two Sulmycin Implants (10 x 10 cm) containing 130 or 260 mg gentamicin were placed in the remaining small cavities or in the transplanted autologous spongy bone. Gentamicin was measured in the wound exsudate for 3-5 days; during this time we found bactericidal concentration in these exsudates. The wounds healed in 44 patients, but we had a persistent fistula in 3 patients (6.3%). We see collagen-gentamicin sponges as being very useful in the treatment of osteitis. It seems to reduce delayed bone transplantation in infected areas.

Therapy with hyperbaric oxygen for experimental osteomyelitis due to Staphylococcus aureus in rabbits.

Hyperbaric oxygen (HBO) is used as adjunctive therapy of chronic osteomyelitis, but its efficacy remains controversial. A recently developed rabbit model for osteomyelitis due to Staphylococcus aureus was used to compare the results of treatment with HBO, cephalothin, a combination of both, or no treatment. Cultures of bone were positive in 10 (91%) of 11 control animals (untreated), five (36%) of 14 animals treated with HBO, eight (47%) of 17 treated with cephalothin, and six (40%) of 15 treated with HBO plus cephalothin. All three treatment groups differed significantly from untreated controls in the number of positive cultures obtained (P less than 0.01), but there were no significant differences among treatment groups. In vitro growth and killing curves (1.0 microgram of cephalothin/ml) constructed after exposure to HBO revealed no change from parallel control studies in ambient air. These data demonstrate that therapy with HBO is at least as effective as antibiotic therapy. The therapeutic effectiveness of HBO does not appear to be related to antibacterial activity.

Antibiotics in the treatment of chronic staphylococcal osteomyelitis.

Fourteen patients with chronic osteomyelitis were treated with oral penicillin, oxacillin, or cloxacillin at a dose of 5 gm/day, plus 0.5 gm of probenecid (Benemid) three or four times per day. Treatment was continued for 2 1/2 to six months. In ten patients, evidence of osteomyelitis disappeared and there has been no recurrence during follow-up periods varying from six months to 2 1/2 years. Significant hepatotoxicity was encountered in two patients; one similar patient, not in this series but receiving a similar regimen of antibiotic, developed leukipenia. Thus, patients with chronic osteomyelitis appear to benefit from such a therapeutic program, but they must be monitored closely for hepatic or hematologic toxicity.