Cases Of Ototoxicity Research Articles

MDB-51. PHASE II INTERVENTIONAL STUDY TO EVALUATE THE SAFETY AND EFFICACY OF STANDARD AND HIGH-DOSE CHEMOTHERAPY COMBINED WITH CRANIOSPINAL IRRADIATION WITH PROTON THERAPY IN PATIENTS WITH METASTATIC MEDULLOBLASTOMA AND OTHER EMBRYONIC CANCERS: PRELIMINARY RESULTS

Abstract BACKGROUND The high risk medulloblastoma remains a leading cause of cancer-related death in children. METHODS A total of 18 patients have been enrolled from February 2018 to May 2022.The median age was 7,5 years (range; 12 males and 6 female). The protocol predicted the first phase of induction with 4 cycles of chemotherapy. After induction patients with favorable histology without evidence of disease were enrolled to proton therapy (with concomitant vinorelbine biweekly). The maintenance phase with Lomustine repeated every 9 weeks and vinorelbine every 3 weeks for overall 12-18 months (PR). Conversely LC/A MB, were subjected to consolidation phase with high dose of chemotherapy with tiothepa followed by autologous HSC transplant and successive maintenance phase of 6 months. RESULTS At October 2023, the median follow up was 24 months. After the induction phase 14 patients showed CR, 2 PR, 1PD, 1SD. At subsequent re-evaluations two with PR, showed disease control, one CR and the other SD and the patient with PD showed CR. Patient with SD showed an unchanged state of the disease. During the reporting period two patient died for progression of the underlying disease. At 24 months from the start of treatment the PFS was 75,4 % (95% CI: 34.1% - 87.6%) and at 15 months the OS was 86,1% (95% CI: 68.1% - 99.2%). The principal expected side effects of chemotherapy were hematology toxicity and 58% rate of GH deficiency. Among the unexpected side effect was CMV retinopathy with complete blindness and leukoencephalopathy after high dose of thiotepa and proton irradiation. We reported only one case of ototoxicity. CONCLUSIONS The use of proton therapy combined with intensive chemotherapy and myeloablative chemotherapy only in selected cases and always before irradiation has proven feasible and effective in the treatment of high-risk patients medulloblastomas and other embryonic tumors.

Ototoxicity associated with extended dalbavancin treatment for a shoulder prosthetic joint infection

BackgroundDalbavancin is a lipoglycopeptide antibiotic approved for treatment of skin and soft tissue infections, administered as a single or two-dose treatment. The extended half-life, good penetration into bone and synovial fluid, and bactericidal activity against gram-positive bacteria, including those in biofilm, make dalbavancin an appealing choice for treatment of bone and joint infections in outpatient settings. However, we present a rare case of ototoxicity associated with off-label extended dalbavancin treatment of a prosthetic joint infection.Case presentationA 55-year-old man with a prosthetic joint infection of the shoulder underwent off-label extended dalbavancin treatment, receiving a cumulative dose of 2500 mg. The patient experienced a gradual onset of hearing loss following the first dose, leading to a diagnosis of bilateral sensorineural hearing loss that persisted 1 year after dalbavancin was discontinued.ConclusionsThis case report highlights the importance of exercising caution when administering dalbavancin beyond approved dosing guidelines, and emphasizes the need for vigilance regarding the potential for ototoxicity.

Ototoxicity of Topical Antibiotic Ear Drops in Chronic Suppurative Otitis Media in Humans: A Review of the Literature.

An electronic search of the literature was performed for reported cases of ototoxicity associated with the use of topical antibiotic ear drops in humans. The dosage, duration, and type of ototoxic preparations involved were recorded. Due to the scant quantity of low-quality information that is currently available, there was uncertainty about the usefulness of topical antibiotics in enhancing the resolution of ear discharge in patients with chronic suppurative otitis media. However, despite this uncertainty, there are some data to show that using topical antibiotics in comparison to a placebo or in conjunction with a systemic antibiotic may be useful. Additionally, there is ambiguity regarding the relative efficacy of various kinds of antibiotics; it is impossible to say with absolute certainty whether quinolones are superior to or inferior to aminoglycosides. Although the adverse impact profiles of these two classes of chemicals varied, there are not enough data from the included trials to draw any conclusions about them. Negative effects were generally underreported.

Long-term vancomycin use had low risk of ototoxicity.

Vancomycin is a commonly used antibiotic with potent activity against Gram-positive organisms, but prolonged use and high doses can lead to toxicity. While vancomycin-associated nephrotoxicity is widely reported, few cases of ototoxicity have been described. The objective of this study was to determine the prevalence of negative changes in audiograms in patients receiving long-term intravenous (IV) vancomycin and to identify high-risk patients who need audiogram monitoring. This was an IRB approved, cross-sectional study performed at an academic medical center from 1/2012-3/2019. Patients who were prescribed IV vancomycin for ≥ 14 days and had baseline and follow-up weekly audiometry were included. All data was extracted from the electronic medical record. The primary endpoint was worsening audiogram while on vancomycin. Descriptive and bivariate statistics were used to describe the patient population. 424 patients were screened for inclusion; 92 received at least two audiograms while on vancomycin. Fifty-three percent of patients were men, the median (IQR) patient age was 44 (34-58) years, and 8% of patients had an estimated Cockcroft-Gault creatinine clearance ≤ 30 mL/min or received hemodialysis. The median (IQR) vancomycin exposure up until the last recorded audiogram was 30 (17-42) days. Vancomycin indications were: 53 (58%) bone and joint infections, 17 (18%) infective endocarditis, 10 (11%) bacteremia, 12 (13%) other infections. Seven (8%) patients experienced a worsening change in hearing from baseline, two (2%) of them suffered mild loss, two (2%) had mild to moderate loss, and three (3%) developed moderate-to-severe hearing loss. In bivariate analyses, no variables were found to be associated with a worsening change in audiogram, including baseline abnormal audiogram, age ≥ 40 years, elevated serum vancomycin levels, or vancomycin doses ≥ 4 grams/day. The prevalence of negative changes in audiograms among patients receiving long-term intravenous vancomycin was low. The utility of routine audiogram testing in this population remains questionable except in high-risk patients; however, larger prospective studies with controls may be warranted to further explore the risk of ototoxicity.

SIDE EFFECTS MONITORING OF AMINOGLYCOSIDE ANTIBIOTIC IN HOSPITALIZED PATIENTS

Objective: The aim of this study was to monitor the side effects in patients who received aminoglycoside antibiotics at the inpatient service ofFatmawati Hospital from March to May 2017.Methods: This was an observational study based on data collected through patient interview, prescribing information, and medical records. Datawere collected on all inpatients treated with aminoglycosides during the study period (total sampling method). The Naranjo algorithm was used toassess the causality of the observed effects.Results: The data from 33 patients were evaluated, among whom 14 (42.4%) developed nephrotoxicity and 5 (15.2%) had ototoxicity. Based on theNaranjo algorithm analysis, the five cases of ototoxicity were categorized as probable drug side effects. No correlation was found between any of theside effects and either age (p=0.726) or sex (p=0.620).Conclusion: In this evaluation of the side effects attributable to aminoglycoside antibiotics in hospitalized patients, nephrotoxicity was the mostcommon, followed by ototoxicity. The latter was deemed probable drug-related side effects based on the Naranjo algorithm. Of the other side effects,twice as many were considered probable as those thought to be possible drug side effects. Neither age nor sex was significantly related to the adverseeffects secondary to gentamicin or amikacin.

Adverse effects of a single dose of gentamicin in adults: a systematic review.

To systematically review the frequency and type of adverse events associated with a single dose of intravenous or intramuscular gentamicin in adults, for any indication, in studies where a comparator was available. A review protocol was developed and registered (PROSPERO: CRD42013003229). Studies were eligible for review if they: recruited participants aged ≥16years; used gentamicin intramuscularly or intravenously as a single one-off dose; compared gentamicin to another medication or placebo; and monitored adverse events. MEDLINE, EMBASE, Cochrane Library, trial registries, conference proceedings and other relevant databases were searched up to November 2016. Risk of bias was assessed on all included studies. In total, 15 522 records were identified. After removal of duplicates, screening of title/abstracts for relevance and independent selection of full texts by two reviewers, 36 studies were included. Across all the included studies, 24 107 participants received a single one-off dose of gentamicin (doses ranged from 1mgkg-1 to 480mg per dose). Acute kidney injury was described in 2520 participants receiving gentamicin. The large majority of cases were reversible. There were no cases of ototoxicity reported in patients receiving gentamicin. A meta-analysis was not performed due to study heterogeneity. A significant number of patients saw a transient rise in creatinine after a single dose of gentamicin at doses up to 480mg. Persistent renal impairment and other adverse events were relatively rare.

P061 Safety of Single Dose Gentamicin Compared with Multiple Dose Regimens

Background Traditionally, gentamicin is given eight hourly, guided by drug levels. Several studies have shown that single-daily dosing of gentamicin offers an equal, if not improved, toxicity profile compared to traditional dosing. Single one-off dose gentamicin has been suggested as treatment for gonorrhoea, but its safety has not been reviewed. Aim Systematically review the frequency and type of adverse events associated with a single dose of intravenous or intramuscular gentamicin in adults, for any indication, in studies where a comparator was available. Methods A review protocol was developed and registered (PROSPERO: CRD42013003229). Studies were eligible for review if they; recruited participants ≥16 years old, used gentamicin intramuscularly or intravenously as a single one-off dose, compared gentamicin to another medication or placebo, and if adverse events were monitored. We searched MEDLINE, EMBASE and other relevant databases. Risk of bias was assessed in included studies. Results 12,116 records were identified. After removal of duplicates, screening of title/abstracts for relevance and independent selection of full texts by two reviewers, 20 studies were included. 3589 participants were analysed across all studies, 2042 received a single one-off dose of gentamicin (doses ranged from 1 mg/kg - 280 mg). Reversible nephrotoxicity/creatinine rise was reported in 37 cases, with one case of irreversible renal impairment. There were three cases of ototoxicity, with similar frequency reported in the comparator group. A meta-analysis was not possible due to heterogeneity. Reporting of adverse events was poor in the majority of studies. Discussion Adverse events with single dose gentamicin are infrequent.

The Role of Monitoring Gentamicin Levels in Patients with Gram-Negative Peritoneal Dialysis-Associated Peritonitis

There is limited available evidence regarding the role of monitoring serum gentamicin concentrations in peritoneal dialysis (PD) patients receiving this antimicrobial agent in gram-negative PD-associated peritonitis. Using data collected in all patients receiving PD at a single center who experienced a gram-negative peritonitis episode between 1 January 2005 and 31 December 2011, we investigated the relationship between measured serum gentamicin levels on day 2 following initial empiric antibiotic therapy and subsequent clinical outcomes of confirmed gram-negative peritonitis. Serum gentamicin levels were performed on day 2 in 51 (77%) of 66 first gram-negative peritonitis episodes. Average serum gentamicin levels on day 2 were 1.83 ± 0.84 mg/L with levels exceeding 2 mg/L in 22 (43%) cases. The overall cure rate was 64%. No cases of ototoxicity were observed. Day-2 gentamicin levels were not significantly different between patients who did and did not have a complication or cure. Using multivariable logistic regression analysis, failure to cure peritonitis was not associated with either day-2 gentamicin level (adjusted odds ratio (OR) 0.96, 95% confidence interval (CI) 0.25 - 3.73) or continuation of gentamicin therapy beyond day 2 (OR 0.28, 0.02 - 3.56). The only exception was polymicrobial peritonitis, where day-2 gentamicin levels were significantly higher in episodes that were cured (2.06 ± 0.41 vs 1.29 ± 0.71, p = 0.01). In 17 (26%) patients receiving extended gentamicin therapy, day-5 gentamicin levels were not significantly related to peritonitis cure. Day-2 gentamicin levels did not predict gentamicin-related harm or efficacy during short-course gentamicin therapy for gram-negative PD-related peritonitis, except in cases of polymicrobial peritonitis, where higher levels were associated with cure.

Pharmacokinetic Properties and Systemic Safety of Vancomycin-Impregnated Cancellous Bone Grafts in the Treatment of Spondylodiscitis

The aim of the present study was to investigate the local pharmacokinetic properties and the systemic safety of vancomycin-impregnated cancellous bone grafts in the treatment of spondylodiscitis. Between 2010 and 2012, 8 patients (5 females, 3 males, mean age 68.75 y.) were treated with this method. Local vancomycin concentrations reached median values of 179 µg/mL (maximum 365 µg/mL) on day 1, decreasing to 98 µg/mL on day 3. The urine vancomycin concentrations showed similar pharmacokinetic properties as those locally determined. On day 1, median values were at 28.05 µg/mL (maximum 287 µg/mL). All serum vancomycin concentrations were in all cases and on every day below <2 µg/mL. The median serum creatinine values were preoperatively 0.87 mg/dL, followed by 0.625 mg/dL, 0.705 mg/dL, and 0.835 mg/dL on day 7, 14, and 28, respectively. No cases of ototoxicity could be observed. At a mean follow-up of 16.5 [4–36] months no cases of reinfections or persistent infections could be seen. In conclusion, the implantation of vancomycin-loaded cancellous bone grafts is an effective option in the treatment of spondylodiscitis with a high infection eradication rate and no risk of any systemic toxicity. The pharmacokinetic properties can be easily monitored locally, in the urine and the serum.

Toward safer practice in otology: A report on 15 years of clinical negligence claims

To determine the characteristics of medical negligence claims arising from otological practice. Retrospective analysis of medical negligence claims contained in the National Health Service Litigation Authority (NHSLA) database. Claims relating to otology and neurotology between 1995 and 2010 were obtained from the NHSLA database and analyzed for cause of injury, type of injury, outcome of claim and costs. Over 15 years there were 137 claims in otology, representing 26% of all the claims in otolaryngology. Of these, 116 have been closed, and 84% of closed claims resulted in payment. Of the 97 successful claims, 63 were related to operative complications. This included six cases of wrong side/site surgery, and 15 cases of inadequate informed consent. The most common injuries claimed were hearing loss, facial paralysis, and additional/unnecessary surgery. Middle ear ventilation and mastoid surgery were the procedures most commonly associated with a successful claim. There were 15 successful claims of misdiagnosis/delayed diagnosis, with chronic suppurative otitis media the condition most frequently missed. There were nine successful claims related to outpatient procedures, of which seven were for aural toilet and six claims of medical mismanagement, including three cases of ototoxicity from topical medications. There were also four successful claims for morbidity due to delayed surgery. This is the first study to report outcomes of negligence claims in otology. Claims in otology are associated with a high success rate. A significant proportion of claims are not related to surgery and represent areas where safety should also be addressed.

Outcome of Enterococcal Prosthetic Joint Infection: Is Combination Systemic Therapy Superior to Monotherapy?

The optimal medical or surgical therapy and outcome of enterococcal prosthetic joint infection are unknown. We performed a retrospective cohort study involving all patients with enterococcal total hip or knee arthroplasty infection treated at our institution from 1969 through 1999. The outcome for patients treated with combination systemic antimicrobial therapy (a cell wall-active agent and an aminoglycoside) versus monotherapy with a cell wall-active agent was analyzed. Fifty episodes of prosthetic joint infection due to enterococci occurred in 47 patients. The median duration of follow-up was 1253 days (range, 29-4610 days). The median age at the time of diagnosis was 70 years (range, 32-89 years). Fifty percent of episodes (25 of 50 episodes) occurred in male patients; 48% (24 of 50 episodes) involved total hip or knee arthroplasty. The estimate of 2-year survival free of treatment failure was 94% (95% confidence interval [CI], 83%-100%) for patients treated with 2-stage exchange, 76% (95% CI, 58%-100%) for patients treated with resection arthroplasty, and 80% (95% CI, 51.6%-100%) for patients treated with debridement and retention of the components (P=.9). The overall rate of 2-year survival free of treatment failure was 88% (95% CI, 77%-100%) for patients treated with monotherapy and 72% (95% CI, 54%-96%) for patients treated with combination therapy (P=.1). The development of cranial nerve VIII toxicity was significantly more common among patients receiving combination therapy (P=.002). Nephrotoxicity was more frequent in the combination therapy group (occurring in 26% of episodes; P=.09). Enterococcal prosthetic joint infection is uncommon at our institution. Patients receiving combination therapy and those receiving monotherapy did not differ with respect to outcome. There were more cases of ototoxicity in the combination therapy group than there were in the monotherapy group.

Phase I Study of Weekly Oxaliplatin in Relapsed or Refractory Pediatric Solid Malignancies

To explore feasibility, maximum-tolerated dose (MTD), and recommended dose (RD) for phase II studies of weekly oxaliplatin for the treatment of relapsed or refractory pediatric solid malignancies. Eligible patients were 6 months to 21 years old, had a diagnosis of a solid malignancy, and had experienced treatment failure with at least two or more previous lines of therapy. The phase I study was multicentric, open-label, and nonrandomized. It foresaw two phases: a dose-escalation phase (comprising six levels) to find the RD and an extension at the RD to evaluate the cumulative toxicity. Oxaliplatin was administered intravenously over 2 hours on days 1, 8, and 15 of a 28-day cycle. Forty-five patients were enrolled: 29 patients in the dose-escalation phase and 16 patients in the extension at the RD. Median age was 9.5 years (range, 2.8 to 20.0 years) and 7.8 years (range, 1.8 to 19.2 years), respectively. The dose-limiting toxicities during the first treatment cycle were grade 3 (G3) sepsis at 50 mg/m(2), G3 dysesthesia at 90 mg/m(2), and G3 dysesthesia and G3 paresthesia at 110 mg/m(2), thus the MTD and RD was 90 mg/m(2). No case of ototoxicity was reported. Stable disease was reported in seven patients (16.3%), and confirmed partial response was observed in two patients (4.7%), one with neuroblastoma and one with osteosarcoma. Oxaliplatin administered in a weekly schedule has an acceptable safety profile, different from cisplatin and carboplatin, and shows activity in children with relapsed or refractory solid tumors, suggesting further investigation in pediatric malignancies.

Topical Antibiotics: Strategies for Avoiding Ototoxicity

As we continue to learn more about ototoxicity from ototopical drugs, there are several key points we must keep in mind: Aminoglycoside antibiotics used in ototopical agents do have ototoxic potential. Reported cases of ototoxicity are relatively uncommon, but the potential for serious complications does exist. Subclinical unilateral vestibular deficits do go unrecognized. Superior alternatives to aminoglycoside drops, particularly the quinolone drops, are readily available. The quinolones are superior to the aminoglycosides in terms of safety, bacterial eradication, and clinical cure and are therefore the drops of choice for treating otorrhea in an open infected ear.

Prediction of toxicity but not of clinical course by determining carboplatin exposure in patients with epithelial ovarian cancer treated with a combination of carboplatin and cisplatin.

We present the data from 105 patients with primary epithelial ovarian cancer, who received up to 6 cycles of carboplatin (300 mg/m2) and cisplatin (100 mg/m2) as one treatment arm of a prospective randomized trial. Values for first-course carboplatin area-under-the-curve (AUC) were determined retrospectively. WHO grade 3-4 thrombocytopenia was found in 10% of patients with low AUC (AUC <4 mg/ml x min), but in 44.6% of patients with high AUC (AUC 4 mg/ml x min) (chi-square p<0.0001). No single case of ototoxicity was found in the low AUC group but in 12% of patients in the high AUC group (chi-square p=0.003). Determination of carboplatin AUC may prevent ototoxicity and severe thrombocytopenia for the first cycle of combined treatment with carboplatin and cisplatin.

Audit of prescription and assay of aminoglycosides in a UK teaching hospital.

Despite potential nephrotoxicity and ototoxicity, aminoglycosides are widely used in the treatment of severe sepsis but monitoring of serum levels is necessary. The use and assay of aminoglycosides, together with microbiologists' and pharmacists' advice on dosage and potential toxicity were examined in a teaching hospital group during an eight week period. A total of 480 courses of aminoglycoside was recorded in 440 hospital in-patients and of these, 306 (64%) were for prophylaxis. For 79 (45%) of 174 therapeutic courses, bacteriological results were available at the start and the choice of antibiotic was appropriate in 69 cases. Serum aminoglycoside assays were performed in 86% (149/174) of therapeutic courses. Correct assay request forms were used in 79% of 473 assay requests, and the clinical diagnosis was given on 73% of forms. In so-called peak samples with a documented time of collection, this ranged from 5 min to over 9 h post dose. Potentially toxic concentrations were present in 56 (12%) serum samples from 50 courses, in ten of which there was a serum creatinine rise of > 40 microM. However, there were confounding factors in five cases. Probable nephrotoxicity was rare, although assays were not performed in 14% of therapeutic courses. There were no symptomatic cases of ototoxicity but audiometry and vestibular studies were not performed. Closer liaison between the microbiologists, pharmacists and clinical staff is essential to improve clinical practice. Computer notification of inadequately monitored courses would be helpful. The routine therapeutic use of aminoglycosides needs to be reviewed in the light of the rising costs of assay litigation and the increasing number of alternative antibiotics available.

Does administration of an aminoglycoside in a single daily dose affect its efficacy and toxicity?

Treatment efficacy, oto- and nephrotoxicity, and aminoglycoside pharmacokinetics were evaluated in a prospective, comparative, randomized clinical study of aminoglycosides given once a day or three times a day for severe infections. Sixty patients were treated with netilmicin or gentamicin 4.5 mg/kg bodyweight/day, either once a day or divided into three doses a day. The patients were allocated randomly to the different groups. The clinical effect was difficult to compare in the different groups, because of the small numbers of patients. Therapeutic failures were seen in seven patients (three after one and four after three doses per day). Two patients, one with Staphylococcus aureus endocarditis and one with streptococcal endocarditis, on netilmicin once daily and conventional high-dose therapy with a penicillin had positive blood cultures after five and seven days of treatment, respectively. Vestibular function and hearing acuity were examined by serial audiograms and electronystagmograms. In spite of extensive diagnostic evaluation, only two cases of ototoxicity were detected. One patient treated with gentamicin three times a day developed vertigo and a severe abnormality of her electronystagmogram. One young patient treated with gentamicin once daily had a slight bilateral reduction of hearing. Nephrotoxicity was mild and did not differ in the four treatment groups. This was the first investigation of a once-daily dosing regimen conducted in seriously ill patients with systemic infections. We could not demonstrate any evidence that aminoglycoside treatment once daily has greater oto- or nephrotoxicity than the traditional three times daily regimen.

Drug-induced ototoxicity. Pathogenesis and prevention.

Ototoxicity is a disabling adverse effect of several widely used classes of drugs, such as diuretics, anti-inflammatory agents, antineoplastic agents and aminoglycoside antibiotics. High-dose therapy with either diuretics or anti-inflammatory agents is primarily associated with acute and transient impairment of hearing or tinnitus. In contrast, long term treatment with antineoplastic agents or aminoglycoside antibiotics is typically associated with delayed and irreversible loss of hearing; lesion in the organ of Corti include the destruction of auditory sensory cells. Vestibular function can also be compromised by ototoxic drugs. Occasional cases of ototoxicity have been reported for a variety of other therapeutic compounds and environmental toxins. In addition, the simultaneous administration of multiple agents which are potentially ototoxic can lead to synergistic loss of hearing. Exposure to loud noise may also potentiate the hearing loss due to cochleotoxic drugs. Ototoxic agents can impair the sensory processing of sound at many cellular or subcellular sites. However, the molecular mechanisms of ototoxicity have not been established for most of these drugs, and structure-toxicity relationships have not been determined. It has therefore been difficult to predict the ototoxic potential of new drugs, and rational approaches to the prevention of ototoxicity are still lacking. The clinical and experimental features of ototoxicity are reviewed for several classes of drugs, with an emphasis on current knowledge of the mechanism and the possibilities for the prevention of ototoxicity for each.

The Furosemide Myth

<h3>To the Editor.</h3> —In light of the interesting article by Drs Gerlag and van Meijel in the February 1988 issue of theArchives,¹we would like to raise the possibility that the maximum recommended daily orally administered dose of furosemide is too low and should be raised. A quick review of the medical literature concerning the use of high doses of furosemide demonstrates that its use has been beneficial in various studies other than those of Gerlag and van Meijel.^2-5These studies treated 105,²28,³6,⁴and 36⁵patients (respectively) with doses of furosemide, generally over 2 g/d and up to 4 g/d (administered either intravenously or orally). In these studies, there were a total of two cases of ototoxicity observed, with one condition being permanent. No other serious side effects were reported. It is noted that the two cases of ototoxicity that did

Antibiotics delivered by an implantable drug pump: A new application for treating osteomyelitis

Osteomyelitis is usually treated with wide surgical debridement and prolonged intravenous antibiotics. The advent of the implantable drug pump has led us to evaluate this therapeutic modality for the treatment of osteomyelitis. We have previously shown that amikacin retains microbiologic activity in an implantable drug pump over a six-week period when incubated at 37°C. We have also demonstrated in rabbits that high local levels and low systemic levels of antibiotic can be achieved using an implantable drug pump as a delivery system and that this method can be used to sterilize infected wounds. This method was applied in the treatment of osteomyelitis in 14 patients whose duration of symptoms ranged from one month to 22 years. In 13 patients, active drainage had been present for more than six months, and all patients had undergone one or more attempts at eradication of their infection. Prior therapy included surgical debridement alone (one patient), one or more attempts at debridement and extended intravenous antibiotic therapy (13 patients), debridement and local flap procedures (four patients), and extended oral antibiotic therapy (two patients). The bones involved were the tibia (six patients), femur (four patients), and elbow, shoulder, hip, and radius (one patient each). Intra-operative cultures indicated that the infecting organism was Staphylococcus aureus alone (seven patients), S. aureus in combination with gram-negative bacteria (five patients), or gram-negative organisms alone (two patients). Debridement and pump implantation were performed in one stage. On an outpatient basis, the pumps were filled with amikacin in a concentration determined by each patient's serum level. Duration of therapy was based upon cessation of drainage and erythrocyte sedimentation rate. During therapy, serum amikacin levels ranged from less than 2.5 μg/ml to 8.2 μg/ml. The amikacin concentration in the wound drainage was always greater than the upper limits of what could be measured (greater than 55 μg/ml to greater than 5,000 μg/ml). There were no cases of ototoxicity and one case of minimal renal toxicity (posttreatment creatinine clearance of 66 ml per minute; normal equal to 70 ml per minute). Length of therapy ranged from 32 to 140 days (mean equal to 63 days). Length of hospitalization ranged from five to 52 days (mean equal to 24 days). Drainage in all patients stopped during therapy, but resumed in three patients after pump removal—in two patients, for brief periods of time, and in one patient, it continues. Twelve patients have posttreatment erythrocyte sedimentation rates less than or equal to 20 mm per hour. This is a potentially important method of treating patients with osteomyelitis. It offers the advantages of extremely high local and low systemic levels of antibiotic, a low incidence of side effects, a decreased length of hospitalization, and a high rate of suppression of infection.

Systematically individualizing tobramycin dosage regimens.

Tobramycin dosage regimens were individually calculated from serum concentration-time data in 64 patients. Tobramycin pharmacokinetic parameters and dosage requirements demonstrated wide interpatient variation. The tobramycin half-life varied from 0.5 to 8.6 hours in patients with normal serum creatinines. The mean (+/- S.D.) distribution volume was 0.22 (+/- 0.09) liter/kg for all patients. Dosage requirements were higher for the younger patients, however, considerable variability existed within age groups. In patients with normal serum creatinines, an 8-hour dosing interval was optimal in only 17 of the 46 patients. A multiple regression model using age, weight, and creatinine clearance could explain only 44.2% of the variance in tobramycin clearance. Measured steady-state peak and trough concentrations compared favorably with desired peak and trough concentrations. The mean (+/- S.D.) desired peak was 7.2 (+/- 1.8) microgram/ml, and the mean (+/- S.D.) measured peak was 7.1 (+/- 2.0) microgram/ml. The mean (+/- S.D.) desired trough was 1.1 (+/- 0.9) microgram/ml, and the mean (+/- S.D.) measured trough was 1.3 (+/- 0.8) microgram/ml. Many patients required dosage regimens exceeding those commonly recommended; however, no cases of ototoxicity or nephrotoxicity were encountered. This model proved successful in calculating dosage regimens of tobramycin to obtain optimal serum concentrations.