Stan Deresinski

Posaconazole: A Broad-Spectrum Triazole Antifungal Agent

Posaconazole is a triazole antifungal agent with a spectrum of activity that includes Candida and Cryptococcus species, many molds, and some endemic fungi. Posaconazole has received US Food and Drug Administration approval for the treatment of oropharyngeal candidiasis, including infections refractory to itraconazole and/or fluconazole. It is also approved as prophylaxis for invasive Aspergillus and Candida infections in patients aged >or=13 years who are at high risk of developing these infections, in adult and adolescent hematopoietic stem cell transplant recipients with graft-versus-host disease, and in persons with hematologic malignancies and prolonged neutropenia due to chemotherapy, who are at high risk of developing these infections. Approval for additional indications is being sought. Limited clinical experience suggests efficacy for the treatment of infections due to Zygomycetes and as salvage therapy for patients with invasive aspergillosis and coccidioidomycosis. Currently available only as an oral suspension, posaconazole, which has been well tolerated, requires administration with food or a nutritional supplement to assure adequate bioavailability. Posaconazole is predominantly eliminated in the feces, where it appears as unchanged drug. Metabolism, mostly glucuronidation, plays only a minor role in its elimination, as does renal clearance; as a consequence, dose adjustment is not required in the presence of renal or hepatic insufficiency. Although not a substrate of hepatic CYP450 3A4, posaconazole inhibits this enzyme and thus has the potential for significant pharmacokinetic interactions with drugs metabolized by this isoform. Its use in combination with CYP450 substrates that prolong the QTc interval is contraindicated, as is its use with ergot alkaloids; administration of posaconazole with other substrates and/or inducers of this enzyme system requires caution. Posaconazole is both a substrate and inhibitor of P-glycoprotein. Currently, the major roles for posaconazole in clinical practice are as prophylaxis for neutropenic patients with significant risk of infection with filamentous fungi and as therapy for zygomycoses. It may also have a role in the treatment of other filamentous fungal and some yeast infections, but assessment of its overall place in antifungal therapy awaits the availability of further clinical experience.

Vancomycin in Combination with Other Antibiotics for the Treatment of Serious Methicillin-Resistant Staphylococcus aureus Infections

Vancomycin is often combined with a second antibiotic, most often rifampin or gentamicin, for the treatment of serious methicillin-resistant Staphylococcus aureus infections. Published data from experiments evaluating these and other vancomycin-based combinations, both in vitro and in animal models of infection, often yield inconsistent results, however. More importantly, no data are available from randomized clinical trials to support their use, and some regimens are known to have potential toxicities. Clinicians should carefully reconsider the use of vancomycin-based combination therapies for the treatment of infection due to methicillin-resistant S. aureus.

Norfloxacin for prevention of bacterial infections in granulocytopenic patients

The efficacy and safety of norfloxacin were compared with those of placebo, vancomycin-polymyxin, and trimethoprim-sulfamethoxazole (TMP/SMX) for prophylaxis of bacterial infections in granulocytopenic patients. The study results showed that norfloxacin treatment, which was well tolerated and not associated with any serious systemic adverse effects, prevented acquisition of gram-negative bacillary organisms. Fewer norfloxacin-treated patients (38 of 108 patients, or 35 percent) experienced microbiologically documented infections compared with patients receiving placebo (27 of 40 patients, or 68 percent), vancomycin-polymyxin (16 of 30 patients, or 53 percent), or TMP/SMX (14 of 28 patients, or 50 percent). Gram-negative bacteremia developed in five of 108 norfloxacin-treated patients (5 percent), compared with 17 of 40 placebo-treated patients (43 percent), five of 30 treated with vancomycin-polymyxin (17 percent), and one of 28 patients treated with TMP/SMX (4 percent). The incidence of gram-positive bacteremia was similar in all study groups and was not affected by norfloxacin or any other oral prophylactic antibiotics. These results suggest that norfloxacin is both safe and effective for the prevention of serious gram-negative bacillary infections in granulocytopenic patients. More effective prophylaxis of gram-positive bacterial infections, however, is needed.

Vancomycin: does it still have a role as an antistaphylococcal agent?

The recognition of the shortcomings of vancomycin as an antistaphylococcal agent, together with the burgeoning availability of alternative effective antistaphylococcal antibiotics, has led to a reassessment of the role of this glycopeptide antimicrobial in clinical therapeutics. Evidence indicates that vancomycin is inferior to semisynthetic penicillins in the treatment of infections due to methicillin-susceptible Staphylococcus aureus. Additional evidence suggests that vancomycin may be inferior to some comparator agents in the treatment of infections due to methicillin-resistant S. aureus (MRSA). While high-level resistance remains rare, data from some centers suggest an evolutionary change in S. aureus, evidenced by reduced susceptibility to vancomycin. This, together with the problem of heteroresistance to vancomycin, as well as poor tissue penetration after its systemic administration, presents potential obstacles to the successful therapy of S. aureus infections with this glycopeptide. While it has been suggested that these problems may be overcome by administration of vancomycin in much higher doses, the efficacy and safety of this approach remains to be determined and will require randomized clinical trials for its demonstration. A number of novel agents with activity against MRSA have been introduced to clinical practice in the last 2 years and others are still in the investigational stage. Despite the fact that these newer agents have been compared with vancomycin in trials only designed to demonstrate noninferiority, some potential evidence of superiority over vancomycin has emerged. While the relative roles of each of these newer agents and vancomycin can only be determined definitively by performance of adequately powered randomized clinical trials, current evidence suggests that vancomycin may be an inferior therapeutic agent.

Rare and emerging viral infections in transplant recipients.

This review discusses the evolving field of viral discovery as well as emerging and reemerging viral pathogens that affect transplant recipients.

When sepsis persists: a review of MRSA bacteraemia salvage therapy

MRSA bacteraemia (MRSAB), including infective endocarditis, carries a high mortality rate, with up to 50% of patients failing initial therapy with vancomycin and requiring salvage therapy. Persistent MRSAB can be difficult to successfully eliminate, especially when source control is not possible due to an irremovable focus or the bacteraemia still persists despite surgical intervention. Although vancomycin and daptomycin are the only two antibiotics approved by the US FDA for the treatment of patients with MRSAB as monotherapy, the employment of novel strategies is required to effectively treat patients with persistent MRSAB and these may frequently involve combination drug therapy. Treatment strategies that are reviewed in this manuscript include vancomycin combined with a β-lactam, daptomycin-based therapy, ceftaroline-based therapy, linezolid-based therapy, quinupristin/dalfopristin, telavancin, trimethoprim/sulfamethoxazole-based therapy and fosfomycin-based therapy. We recommend that combination antibiotic therapy be considered for use in MRSAB salvage treatment.

Real-Time Electronic Tracking of Diarrheal Episodes and Laxative Therapy Enables Verification of Clostridium difficile Clinical Testing Criteria and Reduction of Clostridium difficile Infection Rates

ABSTRACT Health care-onset health care facility-associated Clostridium difficile infection (HO-CDI) is overdiagnosed for several reasons, including the high prevalence of C. difficile colonization and the inability of hospitals to limit testing to patients with clinically significant diarrhea. We conducted a quasiexperimental study from 22 June 2015 to 30 June 2016 on consecutive inpatients with C. difficile test orders at an academic hospital. Real-time electronic patient data tracking was used by the laboratory to enforce testing criteria (defined as the presence of diarrhea [≥3 unformed stools in 24 h] and absence of laxative intake in the prior 48 h). Outcome measures included C. difficile test utilization, HO-CDI incidence, oral vancomycin utilization, and clinical complications. During the intervention, 7.1% (164) and 9.1% (211) of 2,321 C. difficile test orders were canceled due to absence of diarrhea and receipt of laxative therapy, respectively. C. difficile test utilization decreased upon implementation from an average of 208.8 tests to 143.0 tests per 10,000 patient-days (P < 0.001). HO-CDI incidence rate decreased from an average of 13.0 cases to 9.7 cases per 10,000 patient-days (P = 0.008). Oral vancomycin days of therapy decreased from an average of 13.8 days to 9.4 days per 1,000 patient-days (P = 0.009). Clinical complication rates were not significantly different in patients with 375 canceled orders compared with 869 episodes with diarrhea but negative C. difficile results. Real-time electronic clinical data tracking is an effective tool for verification of C. difficile clinical testing criteria and safe reduction of inflated HO-CDI rates.

Antistaphylococcal vaccines and immunoglobulins : Current status and future prospects

Staphylococci are among the most frequently encountered pathogens in both the inpatient and the outpatient setting. Management of infections caused by these organisms is complicated by the increasingly common resistance of staphylococcal pathogens to commonly used antibacterials. As a consequence, novel approaches to prevention and treatment are urgently required. Such approaches include the development of vaccines and immunoglobulin preparations targeted at virulence factors expressed in vivo by staphylococci. This article reviews the biopharmaceutical progress made to date in this field and suggests approaches to further progress.

Mycotic Infections Acquired outside Areas of Known Endemicity, United States.

ncreased awareness that mycoses can be acquired in unusual geographic locations is needed to promote early diagnosis and treatment.

Carbapenemase-producing Klebsiella pneumoniae.

The continuing emergence of infections due to multidrug resistant bacteria is a serious public health problem. Klebsiella pneumoniae, which commonly acquires resistance encoded on mobile genetic elements, including ones that encode carbapenemases, is a prime example. K. pneumoniae carrying such genetic material, including both blaKPC and genes encoding metallo-β-lactamases, have spread globally. Many carbapenemase-producing K. pneumoniae are resistant to multiple antibiotic classes beyond β-lactams, including tetracyclines, aminoglycosides, and fluoroquinolones. The optimal treatment, if any, for infections due to these organisms is unclear but, paradoxically, appears to often require the inclusion of an optimally administered carbapenem.