Update on Treatment Options for Gonococcal Infections.

The incidence of Neisseria gonorrhoeae infections in the United States has grown over the past decade. The most recent data provided by the Centers for Disease Control and Prevention (CDC) indicate that reported cases have increased by almost 10% over the last 5 years. In conjunction with this rise, the presence of multidrug-resistant strains of N. gonorrhoeae has also emerged. The 2015 CDC guidelines recommend dual therapy with intramuscular ceftriaxone and oral azithromycin as first-line treatment, although components of this regimen are met with a high level of resistance. Although ceftriaxone resistance has not yet been reported in the United States, it is only a matter of time before such isolates are detected, thus ushering in a new era of difficult-to-manage uncomplicated gonococcal infection. The potential public health crisis and patient-associated sequelae (e.g., pelvic inflammatory disease, epididymitis, and human immunodeficiency virus infection) linked with untreatable gonorrhea are cause for great concern. To try to stem this tide, a number of new agents targeted against N. gonorrhoeae are being investigated in clinical trials. In this article, we review the various agents, both currently available and under clinical investigation, and provide recommendations for the management of gonococcal infections.

Comparison of serotonin toxicity with concomitant use of either linezolid or comparators and serotonergic agents: an analysis of Phase III and IV randomized clinical trial data.

OBJECTIVES AND METHODS: The present study's objective was to evaluate serotonin toxicity with concomitant use of linezolid or comparators and serotonergic agents from 20 Phase III and IV comparator-controlled clinical studies on treatment of various Gram-positive infections. All reported adverse events were evaluated for serotonin toxicity using exact and surrogate terms consistent with Sternbach Criteria and Hunter Serotonin Toxicity Criteria. RESULTS: Baseline demographics and co-morbidities were similar between linezolid and comparator groups. No patients in either group were reported to have adverse events identified as serotonin toxicity. Among the patients receiving at least one serotonergic agent, 9 of the 2208 (0.41%) linezolid patients and 3 of the 2057 (0.15%) comparator patients met the Sternbach Criteria [risk ratio (RR) 2.79; 95% confidence interval (95% CI) 0.76-10.31]; 3 (0.14%) of the linezolid patients and 1 (0.05%) of the comparator patients met the Hunter Serotonin Toxicity Criteria (RR 2.79; 95% CI 0.29-26.85). No patients met both criteria. Most patients meeting criteria for serotonin toxicity had past or present co-morbidities that may have contributed to or overlapped with reported adverse events. CONCLUSIONS: While the potential exists for serotonin toxicity to occur with concomitant use of linezolid and serotonergic agents, the risk appears to be low. Based on the large database of Phase III and IV studies included in our analysis, we did not find enough evidence to conclude that linezolid-induced serotonin toxicity was different from that of comparators.

The role of primary care prescribers in the diagnosis and management of community-associated methicillin-resistant Staphylococcus aureus skin and soft tissue infections.

Nosocomial infections caused by methicillin-resistant Staphylococcus aureus were first reported in the United States in the early 1960s. Beginning in the 1990s, healthy individuals from the community with no risk factors for resistant bacteria began presenting with methicillin-resistant Staphylococcus aureus infections, acquiring the name "community-associated methicillin-resistant Staphylococcus aureus" (CA-MRSA). CA-MRSA has a tendency to affect the skin and skin structures, generally in the form of abscesses and furuncles, carbuncles, and cellulitis. Cases of invasive infections including bacteremia, endocarditis, and necrotizing pneumonia have also been reported. A patient complaint of a "spider bite" is frequently associated with CA-MRSA. CA-MRSA and the traditional health care-associated methicillin-resistant Staphylococcus aureus are distinguished by their genetic composition, virulence factors, and susceptibility patterns to non-beta-lactam antibiotics. Appropriate management of CA-MRSA skin and skin structure infections includes incision and drainage of infected tissue and appropriate antimicrobial therapy. It has been suggested that when prevalence of CA-MRSA within a community eclipses 10%-15%, empiric use of non-beta-lactam antibiotics with in vitro activity against CA-MRSA be initiated when treating skin and skin structure infections. CA-MRSA retains susceptibility to a range of older antibiotics available in oral formulations such as minocycline, doxycycline, sulfamethoxazole-trimethoprim, moxifloxacin, levofloxacin, and clindamycin. Local susceptibility patterns and individual patient factors should guide the selection of antibiotics.

Comparison of dosing recommendations for antimicrobial drugs based on two methods for assessing kidney function: cockcroft-gault and modification of diet in renal disease.

STUDY OBJECTIVES: To quantify the difference between glomerular filtration rates (GFRs) estimated by using the Cockcroft-Gault and Modification of Diet in Renal Disease (MDRD) equations, and to determine whether dosing recommendations for four commonly prescribed antimicrobial agents are discordant when determined by using these equations. DESIGN: Prospective, observational study. SETTING: Tertiary-care medical center. PATIENTS: Two hundred seven consecutive adults without normal renal function but not receiving dialysis who were admitted to a non-intensive-care ward and had two consecutive serum creatinine concentration (S(cr)) values measured 20-24 hours apart. MEASUREMENTS AND MAIN RESULTS: The patients' mean +/- SD S(cr) was 1.41 +/- 0.95 mg/dl. Kidney function was estimated by using two versions of the four-variable MDRD equation and four versions of the Cockcroft-Gault equation. Mean estimated GFRs ranged from 52.3-73.1 ml/minute. Dosing for cefepime, levofloxacin, meropenem, and piperacillin-tazobactam was determined using the two equations that had the highest level of correlation; these were the MDRD equation unadjusted for body surface area and the Cockcroft-Gault equation adjusted for ideal body weight and S(cr). When the total daily doses based on these two equations for the four antimicrobials were compared, the discordance rate was 22.8-36.3%, and statistically significant differences were observed for most of the discordant doses. When discordance was present, the MDRD equation resulted in a higher dose of the drug. CONCLUSION: Discordance rates for drug dosing ranged from 22.8-36.3% between the MDRD and Cockcroft-Gault methods for estimating GFR. Although use of the MDRD equation is a well-accepted and accurate method of estimating GFR to stage chronic kidney disease, our results demonstrated a significant difference in drug dosing regimens between the MDRD method and the Cockcroft-Gault method.

Rifaximin for the treatment of hepatic encephalopathy.

OBJECTIVE: To review the effectiveness and safety of rifaximin for the treatment of hepatic encephalopathy. METHODS: A literature search was conducted of MEDLINE (1966-September 2007), the Cochrane Database of Systematic Reviews (1995-2007), and the Cochrane Hepato-Biliary Group Reviews (2003-2007). English-language articles identified from the data sources were evaluated. All available studies were reviewed, including placebo-controlled, treatment comparison, and open label. RESULTS: Rifaximin was effective in improving behavioral, laboratory, mental status, and intellectual abnormalities associated with hepatic encephalopathy. Some studies demonstrated superior and more rapid improvement in signs or symptoms of encephalopathy during treatment with rifaximin compared with nonabsorbable disaccharides (lactulose, lactitol). Patients treated with rifaximin also required less hospitalization, had shorter duration of hospitalization, and lower hospital charges compared with lactulose-treated patients. Adverse effects of rifaximin were mostly minor gastrointestinal complaints; however, rifaximin was better tolerated than other pharmacologic treatments. CONCLUSION: Rifaximin was at least equally effective as and in some studies superior to nonabsorbable disaccharides and antimicrobials in relieving signs or symptoms observed in patients with mild-to-moderately severe hepatic encephalopathy. Future clinical trials should focus on using standardized methods of evaluating mental status and limiting enrollment to patients with mild-to-moderate, episodic, persistent, or minimal hepatic encephalopathy. Well-designed studies are needed to fully delineate the efficacy of rifaximin and other pharmacologic treatments for patients with hepatic encephalopathy.

Impact of an institution-specific hospital-acquired pneumonia protocol on the appropriateness of antibiotic therapy and patient outcomes.

STUDY OBJECTIVE: To evaluate the impact of a hospital-acquired pneumonia (HAP) protocol on appropriateness of empiric antibiotic therapy, antibiotic deescalation, antibiotic duration, patient mortality, and length of stay. DESIGN: Before- and after-study of protocol implementation. SETTING: A 450-bed, academic medical center. PATIENTS: One hundred consecutive patients with proven or suspected HAP. INTERVENTION: Implementation of an HAP protocol that was based on the 2005 American Thoracic Society-Infectious Diseases Society of America guidelines and included extensive education of clinicians and monitoring by pharmacists. MEASUREMENTS AND MAIN RESULTS: Before protocol implementation, 50 patients with HAP were evaluated against protocol criteria. After protocol implementation, a second cohort of 50 patients with HAP was evaluated. Compared with the preprotocol group, implementation of the protocol led to an increase in both the proportion of patients who received appropriate empiric antibiotic coverage (17 [34%] vs 31 [62%] patients, p=0.005) and appropriate antibiotic deescalation (21 [42%] vs 36 [72%] patients, p=0.002) according to protocol recommendations but did not affect the appropriateness of empiric antibiotic therapy based on final lung culture data (34 [68%] vs 41 [82%] patients, p=0.11). Compared with the preprotocol group, use of the protocol decreased the duration of intravenous antibiotic therapy (median [range] 9 [2-21] vs 7 [1-16] days, p=0.024), was associated with a trend for a shorter duration of stay in the intensive care unit (median [range] 19 [2-57] vs 11 [3-76] days, p=0.065), and did not significantly affect mortality (5 [10%] vs 8 [16%] patients, p=0.37). Pharmacists performed 59 interventions to support the protocol in 29 patients in the postprotocol group, of which 48% were accepted. CONCLUSIONS: Implementation of an HAP protocol improved appropriate empiric antibiotic use and decreased the duration of antibiotic therapy without adversely affecting patient outcomes.

Antibiotic-lock therapy for long-term catheter-related bacteremia: a review of the current evidence.

Catheter-related bloodstream infections (CRBSIs) are a major cause of morbidity and mortality, especially among patients receiving hemodialysis, parenteral nutrition and chemotherapy. Antibiotic-lock therapy (ALT) represents a promising technique in the modern treatment of CRBSIs. In this review, we attempt to clarify the potential role of ALT in the treatment of long-term catheter-related bacteremia, based on the available evidence from published studies reporting on this issue. We identified 28 articles that were considered appropriate to be included in our review, only three of which were comparative studies. There is some evidence that ALT administered concurrently with systemic therapy may represent a significant therapeutic approach for CRBSIs involving long-term catheters. Prolonged infection-free catheter survival in the reported series is suggestive of sterilization of the catheters by ALT. The only reported comparison shows better outcome with ALT than with catheter exchange. Immunodeficient states, such as HIV, and the use of totally implanted devices instead of tunneled catheters may predispose to CRBSI treatment failure. No serious adverse effects, such as emergence of resistance or increased infectious complications, were found to be associated with the use of ALT in the reviewed studies. However, more comparative studies should be performed to examine this important therapeutic issue further.

Serotonin toxicity associated with the use of linezolid: a review of postmarketing data.

BACKGROUND: Linezolid is the first oxazolidinone antimicrobial marketed in the United States. It exhibits monoamine oxidase (MAO) type A and MAO type B inhibitory effects. The concomitant administration of nonselective MAO inhibitors or MAO-A inhibitors with drugs that increase serotonin concentrations is associated with serotonin toxicity. METHODS: We requested from the US Food and Drug Administration all postmarketing adverse event reports regarding linezolid that included serotonin toxicity or any report describing cognitive or behavioral symptoms and autonomic and neuromuscular excitability. We assessed the case summaries obtained from the Adverse Event Reporting System database for serotonin toxicity. A case of serotonin toxicity was defined as having the following: (1) linezolid as the primary suspect drug; (2) concurrent administration of > or =1 secondary suspect drug known to increase serotonin concentrations in the central nervous system; and (3) serotonin toxicity, as defined by the modified Hunter Serotonin Toxicity Criteria or by the reporter. RESULTS: Twenty-nine cases were classified as serotonin toxicity. Patients' ages ranged from 17-83 years, and the ratio of females to males was 1:1. The most common class of drugs received concurrently with linezolid was selective serotonin reuptake inhibitors (26 of 43 patients). Thirteen patients required an intervention to prevent permanent impairment or required hospitalization for the adverse event. CONCLUSION: The use of linezolid with medications that increase concentrations of serotonin in the central nervous system may result in serotonin toxicity. Prescribers must weigh risks and benefits of this combination. Patients and prescribers should be cognizant of signs and symptoms of serotonin toxicity and should initiate appropriate measures if such symptoms develop.

Hypoglycemia-induced anoxic brain injury possibly associated with levofloxacin.

Reports linking alterations in blood glucose concentrations with fluoroquinolones, mostly gatifloxacin and ciprofloxacin, have been published. We describe an elderly, non-diabetic patient with steroid-induced hyperglycemia prescribed glyburide who later developed severe hypoglycemia resulting in anoxic brain injury soon after initiating therapy with levofloxacin.

Continuous versus intermittent intravenous administration of antibacterials with time-dependent action: a systematic review of pharmacokinetic and pharmacodynamic parameters.

We performed a systematic review of randomised clinical trials to evaluate the comparative pharmacokinetic and pharmacodynamic properties of the continuous versus intermittent mode of intravenous administration of various antibacterials. Data were identified from PubMed (January 1950 to January 2005), Current Contents, the Cochrane central register of controlled trials, and references from relevant articles and reviews. Seventeen randomised clinical trials comparing continuous with intermittent intravenous administration of the same antibacterial regimen and examining the pharmacokinetic and pharmacodynamic properties were included in this systematic review. We reviewed data regarding the clinical setting, number of participants, antibacterial agents and dosages used, as well as maximum serum concentration (Cmax), trough serum concentration (Cmin), steady-state or plateau serum concentration (Css), area under the concentration-time curve (AUC), time above the minimum inhibitory concentration (MIC) [T>MIC], AUC: MIC, elimination rate constant, elimination half-life, volume of distribution and systematic clearance. The mean Cmax of the intermittently administered antibacterials was higher compared with Css achieved by the continuous infusion of the same antibacterial in all eligible studies (Cmax was on average 5.5 times higher than Css, range 1.9-11.2). Css was on average 5.8 times higher than the Cmin of the intermittently administered antibacterials (range 1.2-15.6). In three of six studies the length of time that the drug concentration was above the MIC of the responsible pathogens was longer in patients receiving the antibacterials continuously. In conclusion, the reviewed data suggest that the continuous intravenous infusion of antibacterials with time-dependent bacterial killing seems to be superior than the intermittent intravenous administration, from a pharmacodynamic point of view, at least when treating bacteria with high MIC values for the studied antibacterials.

Trimethoprim/sulfamethoxazole for treatment of severe Staphylococcus aureus infections.

OBJECTIVE: To evaluate the role of trimethoprim/sulfamethoxazole (TMP/SMX) as an alternative to vancomycin for the treatment of severe Staphylococcus aureus infections. DATA SOURCES: Clinical literature was accessed through MEDLINE (1966-February 2003) and EMBASE (1980-February 2003). Key search terms included trimethoprim/sulfamethoxazole combination and Staphylococcus aureus. DATA SYNTHESIS: An evaluation of case reports, case series, and clinical studies focusing on the use of TMP/SMX for treatment of severe S. aureus infections was conducted. The majority of the reports indicate that TMP/SMX may be effective for the treatment of infections due to low bacterial burdens of susceptible strains of S. aureus. CONCLUSIONS: In select infections, TMP/SMX may be a useful alternative to vancomycin for treatment of severe S. aureus infections. Additional randomized studies should be conducted comparing this agent with vancomycin and linezolid.