Biomedical subjects
Publications and source records attributed to Robert C Owens.
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Until recently, cardiac toxicity manifesting in the form of arrhythmias related to QT interval prolongation was uncommonly appreciated within the antimicrobial class of drugs, but it was well described among antiarrhythmic agents. Antimicrobials that are associated with QT prolongation include the macrolides/ketolides, certain fluoroquinolones and antimalarials, pentamidine, and the azole antifungals. Although, in most cases, mild delays in ventricular repolarization caused by these drugs are clinically unnoticeable, they may serve to amplify the risk for torsades de pointes (TdP) when prescribed in the setting of other risk factors. Conditions or variables that influence proarrhythmic risk include sex, age, electrolyte derangements, structural heart disease, pharmacokinetic/pharmacodynamic interactions, and genetic predisposition. It is important that clinicians be knowledgeable about drugs with QT liability, as well as the risk factors that increase the probability of TdP. Additionally, because TdP remains a difficult-to-measure adverse event, we must rely upon multiple data sources to determine the risk versus the benefit for newly approved drugs.
The stabilities of cefepime and metronidazole were determined after preparation of a single admixture product in view of its potential use as a simple and cost-effective therapeutic alternative for infections caused by many aerobic and anaerobic pathogens. The stability of cefepime 1000 or 2000 mg mixed with metronidazole 500 or 1500 mg was evaluated via high-performance liquid chromatography after storage for up to 336 h at 4 or 23 degrees C. Cefepime was stable in all 4 degrees C samples for up to 336 h, retaining > or =95% of initial concentrations. Samples of cefepime 1000 and 2000 mg mixed with metronidazole 500 mg were stable at 23 degrees C for up to 48 h, whereas those mixed with metronidazole 1500 mg and cefepime controls were stable at 23 degrees C for up to 72 h. Metronidazole was stable in all samples for up to 336 h, retaining > or =94% of initial concentrations. These data suggest that therapeutic use of cefepime and metronidazole as a single intravenous admixture product is feasible and practical.
Selective pressures generated by the indiscriminate use of beta-lactam antibiotics have resulted in increased bacterial resistance across all beta-lactams classes. In particular, the use of third-generation cephalosporins has been associated with the emergence of extended-spectrum beta-lactamase-producing and AmpC beta-lactamase-producing Enterobacteriaceae and vancomycin-resistant enterococci. Conversely, beta-lactams (e.g., cefepime, piperacillin-tazobactam, and ampicillin-sulbactam) have not demonstrated such strong selective pressures. Chief among institutional strategies to control outbreaks of multidrug-resistant bacteria are infection-control measures and interventional programs designed to minimize the use of antimicrobial agents that are associated with strong relationships between use and resistance. Successful programs include antimicrobial stewardship programs (prospective audit and feedback), formulary interventions (therapeutic substitutions), formulary restrictions, and vigilant infection control. Fourth-generation cephalosporins, such as cefepime, have proven to be useful substitutes for third-generation cephalosporins, as a part of an overall strategy to minimize the selection and impact of antimicrobial-resistant organisms in hospital settings.
A formerly infrequently isolated strain of Clostridium difficile known as BI/NAP1 has resulted in geographically diverse outbreaks of C. difficile-associated disease. Such rapid dissemination and distribution of an outbreak strain of C. difficile are unprecedented, with many regions across North America, as well as several countries in Europe, being affected, all in such a short period of time. Also of note is that nontraditional hosts (e.g., otherwise healthy, noninstitutionalized persons residing in the community, some without antimicrobial exposure) have been reported to have severe disease. Data suggest that certain virulence characteristics may be responsible for more severe clinical presentations and poor outcomes. These factors (e.g., hypertoxin production, hypersporulation, antimicrobial resistance) possessed by a previously uncommon strain of C. difficile, in conjunction with particular host and environmental factors, may have precipitated the now widespread establishment of this pathogen. Antimicrobial intervention has traditionally been a mainstay of combating C. difficile-associated disease. Efforts to combat BI/NAP1 should include good antimicrobial stewardship in addition to effective infection control and environmental intervention.
BACKGROUND: Recent reports suggest that the rate and severity of Clostridium difficile-associated disease in the United States are increasing and that the increase may be associated with the emergence of a new strain of C. difficile with increased virulence, resistance, or both. METHODS: A total of 187 C. difficile isolates were collected from eight health care facilities in six states (Georgia, Illinois, Maine, New Jersey, Oregon, and Pennsylvania) in which outbreaks of C. difficile-associated disease had occurred between 2000 and 2003. The isolates were characterized by restriction-endonuclease analysis (REA), pulsed-field gel electrophoresis (PFGE), and toxinotyping, and the results were compared with those from a database of more than 6000 isolates obtained before 2001. The polymerase chain reaction was used to detect the recently described binary toxin CDT and a deletion in the pathogenicity locus gene, tcdC, that might result in increased production of toxins A and B. RESULTS: Isolates that belonged to one REA group (BI) and had the same PFGE type (NAP1) were identified in specimens collected from patients at all eight facilities and accounted for at least half of the isolates from five facilities. REA group BI, which was first identified in 1984, was uncommon among isolates from the historic database (14 cases). Both historic and current (obtained since 2001) BI/NAP1 isolates were of toxinotype III, were positive for the binary toxin CDT, and contained an 18-bp tcdC deletion. Resistance to gatifloxacin and moxifloxacin was more common in current BI/NAP1 isolates than in non-BI/NAP1 isolates (100 percent vs. 42 percent, P<0.001), whereas the rate of resistance to clindamycin was the same in the two groups (79 percent). All of the current but none of the historic BI/NAP1 isolates were resistant to gatifloxacin and moxifloxacin (P<0.001). CONCLUSIONS: A previously uncommon strain of C. difficile with variations in toxin genes has become more resistant to fluoroquinolones and has emerged as a cause of geographically dispersed outbreaks of C. difficile-associated disease.
BACKGROUND/PURPOSE: Infrequent toxicities associated with certain drugs and drug classes have recently gained much attention from different health-care perspectives. To protect the patient, continued surveillance of safety and tolerability data is essential. Data from preclinical testing, phase 1-3 trials, and postmarketing surveillance may be used to objectively assess the risks associated with a specific drug or family of compounds. This review summarizes safety and tolerability data for the quinolones. MAIN FINDINGS: The most common adverse events associated with the quinolone class involve the gastrointestinal tract (nausea and diarrhea) and central nervous system (CNS) (headache and dizziness). These adverse events are usually mild and do not require discontinuation of therapy. Uncommon and potentially serious quinolone-related adverse events involve the cardiovascular system (rate-corrected electrocardiographic QT interval prolongation), musculoskeletal system (tendinitis and tendon rupture), endocrine system (glucose homeostasis dysregulation), renal system (crystalluria, interstitial nephritis, and acute renal failure), and the CNS (seizures). Severe idiosyncratic adverse events are specific to individual agents that may share some structural congruity, such as the 1-(2,4)-difluorophenyl group shared by trovafloxacin (associated with hepatitis), temafloxacin (associated with hemolytic-uremic syndrome), and tosufloxacin (associated with eosinophilic pneumonitis). Overall, discontinuation rates from clinical trials were <4% for the currently marketed quinolones. Quinolones with higher discontinuation rates, such as trovafloxacin (7.0%) and grepafloxacin (6.4%), are no longer available for general use. CONCLUSIONS: The currently marketed quinolones are well tolerated, with safety profiles similar to those of other antimicrobial classes. Although adverse effects are unusual, some, including tendinitis and CNS-related effects, are more common with quinolones than with other antimicrobial classes. Rare adverse effects attributed to some members of the quinolone family (e.g., Torsades de Pointes, hepatotoxicity, and dysglycemias) are more likely to occur in select "susceptible" populations. These adverse events can often be circumvented by avoiding exposure to the specific quinolone. In some cases, the therapeutic value offered by a quinolone may outweigh its potential risks.
The treatment of community-acquired respiratory tract infections has been complicated by the emergence of multidrug-resistant Streptococcus pneumoniae. Although traditionally rare, a growing concern for fluoroquinolone-resistant pneumococci has surfaced. More pharmacodynamically potent antimicrobial agents are clearly needed, as the use of such agents may further optimize clinical and microbiological outcomes for patients and slow the emergence of fluoroquinolone resistance. For fluoroquinolones, the ratio of the 24-h area under the concentration-time curve of the agent to the minimum inhibitory concentration of the agent against the pathogen for the fraction of unbound drug is the major pharmacokinetic-pharmacodynamic (PK-PD) measure correlating with efficacy in nonclinical models and infected patients. A 2500-patient Monte Carlo simulation, utilizing a patient-population pharmacokinetic model derived from phase 3 registration trials and the minimum inhibitory concentration distribution for gemifloxacin against 3117 clinical strains of S. pneumoniae, was carried out to estimate the probability of gemifloxacin attaining exposures associated with efficacy. The overall probability PK-PD target attainment for gemifloxacin was greater than 0.99. Gemifloxacin is among the most pharmacodynamically potent fluoroquinolones and is more potent than ciprofloxacin, ofloxacin, and levofloxacin. Preferential use of pharmacodynamically potent agents over other alternatives may lead to improved clinical outcomes and decreased selection of fluoroquinolone-resistant pneumococci.
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Each year, approximately 2 million people in the United States contract an infection during a hospital stay. An increasing percentage of these institutionally acquired infections are attributed to antimicrobial-resistant organisms. At the same time, studies and surveys suggest that as much as half of all antimicrobial use is inappropriate. Recommendations for preventing and reducing antimicrobial resistance in hospitals stress the importance of improving antimicrobial use, referred to as antimicrobial stewardship, at the institutional level. Antimicrobial stewardship programs have served as wake-up calls to both clinicians and health care administrators. We review the more recent literature concerning the impact of antimicrobial stewardship programs on costs, outcomes, and resistance and summarize important considerations for implementation of these programs.
Cardiac toxicity has been relatively uncommon within the antimicrobial class of drugs, but well described for antiarrhythmic agents and certain antihistamines. Macrolides, pentamidine and certain antimalarials were traditionally known to cause QT-interval prolongation, and now azole antifungals, fluoroquinolones and ketolides can be added to the list. Over time, advances in preclinical testing methods for QT-interval prolongation and a better understanding of its sequelae, most notably torsades de pointes (TdP), have occurred. This, combined with the fact that five drugs have been removed from the market over the last several years, in part because of QT-interval prolongation-related toxicity, has elevated the urgency surrounding early detection and characterisation methods for evaluating non-antiarrhythmic drug classes. With technological advances and accumulating literature regarding QT prolongation, it is currently difficult or overwhelming for the practising clinician to interpret these data for purposes of formulary review or for individual patient treatment decisions. Certain patients are susceptible to the effects of QT-prolonging drugs. For example, co-variates such as gender, age, electrolyte derangements, structural heart disease, end organ impairment and, perhaps most important, genetic predisposition, underlie most if not all cases of TdP. Between and within classes of drugs there are important differences that contribute to delayed repolarisation (e.g. intrinsic potency to inhibit certain cardiac ion currents or channels, and pharmacokinetics). To this end, a risk stratification scheme may be useful to rank and compare the potential for cardiotoxicity of each drug. It appears that in most published cases of antimicrobial-associated TdP, multiple risk factors are present. Macrolides in general are associated with a greater potential than other antimicrobials for causing TdP from both a pharmacodynamic and pharmacokinetic perspective. The azole antifungal agents also can be viewed as drugs that must be weighed carefully before use since they also have both pharmacodynamic and pharmacokinetic characteristics that may trigger TdP. The fluoroquinolones appear less likely to be associated with TdP from a pharmacokinetic perspective since they do not rely on cytochrome P450 (CYP) metabolism nor do they inhibit CYP enzyme isoforms, with the exception of grepafloxacin and ciprofloxacin. Nonetheless, patient selection must be carefully made for all of these drugs. For clinicians, certain responsibilities are assumed when prescribing antimicrobial therapy: (i) appropriate use to minimise resistance; and (ii) appropriate patient and drug selection to minimise adverse event potential. Incorporating information learned regarding QT interval-related adverse effects into the drug selection process may serve to minimise collateral iatrogenic toxicity.
An understanding of fundamental PK-PD principles forms the basis for the rational use of antimicrobial agents. For quinolones, the fAUC24:MIC ratio is predictive of efficacy in animal and in vitro infection models, and in infected patients. The magnitude of the fAUC24:MIC ratio predictive of efficacy in animal and in vitro infection models has been shown to be concordant with those obtained from human data. By accounting for PK and microbiologic variability together with PK-PD targets associated with efficacy or resistance suppression by Monte Carlo simulation, it is possible to discriminate between therapeutic regimens and select those regimens likely to be of greater benefit to patients. The maturation of antimicrobial PK-PD as a scientific discipline continues to accelerate and currently impacts clinical practice, drug development, and regulatory decision making.
OBJECTIVE: To report a case of successful meropenem desensitization in a patient with cystic fibrosis (CF) with documented hypersensitivity to multiple antibiotics including carbapenems. CASE SUMMARY: A 20-year-old white man with CF was admitted to the hospital for treatment of an acute pulmonary exacerbation caused by multidrug-resistant Burkholderia cepacia complex and methicillin-resistant Staphylococcus aureus (MRSA). Past treatments of his CF exacerbations were complicated by urticarial eruptions following administration of beta-lactams, including meropenem, and ototoxicity from aminoglycosides. Skin testing revealed hypersensitivity reactions to beta-lactam antibiotics including penicillin, piperacillin/tazobactam, ceftazidime, and imipenem. A literature review (MEDLINE, January 3, 2002) and communication with the manufacturer of meropenem revealed no specific information on desensitizing patients to this agent. Because of meropenem's activity against B. cepacia complex alone and in combination with other antimicrobials, a desensitization protocol was adapted and applied to meropenem in an effort to provide the most beneficial treatment available. A 12-dose escalation protocol was successfully employed without incident. DISCUSSION: Antimicrobial therapy is limited in CF patients by susceptibility profiles of common infecting organisms (e.g., Pseudomonas spp., B. cepacia complex, MRSA). Unfortunately, host responses may further reduce the utility of many effective antibiotic classes due to hypersensitivity and/or adverse reactions. Desensitization is a useful alternative that allows the administration of beneficial medications to patients with documented allergy histories. CONCLUSIONS: Meropenem is an important treatment option in the CF population, particularly due to its activity against B. cepacia complex. Successful desensitization using a dose-escalation protocol in patients with a documented carbapenem allergy will allow the most beneficial therapy to continue.
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Drugs not commonly considered to be cardioactive agents have been reported to cause prolongation of the corrected QT interval with resultant torsades de pointes or ventricular fibrillation. We report 4 cases of gatifloxacin-associated cardiac toxicity in patients with known risk factors for this adverse event.
Pseudomonas aeruginosa is one of the more common and clinically difficult-to-treat causes of hospital-acquired infections. Cefepime is a broad-spectrum cephalosporin with potent in vitro activity against Gram-positive cocci, enteric Gram-negative bacilli and Pseudomonas aeruginosa. Cephalosporins exhibit time-dependent bactericidal activity and lack prolonged post-antibiotic effects against Enterobacteriaceae and P. aeruginosa. In non-clinical models of infection against Enterobacteriaceae and P. aeruginosa, antibacterial effects are observed when serum levels are above the MIC for as little as 35% of the dosing interval and are maximized when levels exceed the MIC for 60-70% of the dosing interval. Based on the MIC distribution for P. aeruginosa and pharmacokinetic data obtained from patients with serious bacterial infections (including pneumonia and sepsis), time above MIC targets can be met in infected patients following 2 g doses of cefepime administered every 12 h. An understanding of the integration of target patient population pharmacokinetics and the MIC distribution is crucial for selecting effective dosage regimens, especially in the setting of empirical therapy. Moreover, sufficient clinical outcome data in infected patients exist and support these pharmacodynamic conclusions.
"We know everything about antibiotics except how much to give," Maxwell Finland once stated. Finally, with the proliferation of pharmacodynamics as a science, we are addressing the question of how much to give. We have moved from an era of more or less arbitrary antimicrobial dosage selection toward one characterized by evidence-based optimal dosing strategies. Optimizing antimicrobial therapy in critically ill patients is more than just the selection of a suitable dose for a particular patient. Optimizing therapy also involves the selection of an appropriate single or combination antibiotic regimen that is active against the suspected or documented pathogens at the site(s) of infection. The regimen should offer the fewest potential adverse events, and the duration of therapy should be the shortest possible so as not to encourage resistance. Dosing of the chosen regimen should reflect variables that are often ignored, such as the patient's weight and age. The new continuous renal replacement therapies are commonly used in the critical care unit and must be considered. Finally, the cost of the regimen should be considered, but not only the cost to purchase the chosen antimicrobial agent but the cost to administer it (, the cost of minibags or syringes, intravenous tubing, saline flushes [all multiplied by the number of times per day the drug is given]), and, most importantly, if the patient fails to respond to therapy, the cost necessary to re-treat the patient to bring about a cure. In this review, we discuss some of the principles required to optimize antimicrobial dosing and recently obtained data regarding its application to the critically ill patient.