Louis D. Saravolatz

Nitazoxanide: A New Thiazolide Antiparasitic Agent

Nitazoxanide is a new thiazolide antiparasitic agent that shows excellent in vitro activity against a wide variety of protozoa and helminths. It is given by the oral route with good bioavailability and is well tolerated, with primarily mild gastrointestinal side effects. At present, there are no documented drug-drug interactions. Nitazoxanide has been licensed for the treatment of Giardia intestinalis-induced diarrhea in patients >or=1 year of age and Cryptosporidum-induced diarrhea in children aged 1-11 years. At present, it is pending licensure for treatment of infection due to Cryptosporidium species in adults and for use in treating immunocompromised hosts. It represents an important addition to the antiparasitic arsenal.

Ceftaroline: A Novel Cephalosporin with Activity against Methicillin-resistant Staphylococcus aureus

Ceftaroline (PPI 0903, formerly TAK-599), the active metabolite of a N-phosphono prodrug, ceftaroline fosamil, has been approved by the US Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. This antimicrobial agent binds to penicillin binding proteins (PBP) inhibiting cell wall synthesis and has a high affinity for PBP2a, which is associated with methicillin resistance. Ceftaroline is consistently active against multidrug-resistant Streptococcus pneumoniae and Staphylococcus aureus, including methicillin-resistant, vancomycin-intermediate, linezolid-resistant, and daptomycin-nonsusceptible strains. It possesses variable activity against Enterobacteriaceae and good activity against oral anaerobes. The drug is usually administrated intravenously at 600 mg every 12 h. Ceftaroline has low protein binding and is excreted by the kidneys and thus requires dose adjustments in individuals with renal failure. Clinical trials have demonstrated noninferiority when compared with vancomycin in the treatment of acute bacterial skin and skin structure infections and noninferiority when compared with ceftriaxone in the treatment of community-acquired bacterial pneumonia. Ceftaroline demonstrated a safety profile similar to that of comparator drugs in clinical trials.

Broad-Range Bacterial Polymerase Chain Reaction for Early Detection of Bacterial Meningitis

The diagnosis of bacterial meningitis often depends on isolation of bacteria on culture, which may take 24-48 h. DNA amplification techniques could provide rapid diagnosis, which would guide the clinician in antimicrobial therapy decisions. This study determined the clinical utility of polymerase chain reaction (PCR) for the diagnosis of meningitis with use of a broad range of bacterial primers. Seventy-four cerebrospinal fluid specimens obtained from 70 patients were subjected to PCR with use of primers derived from conserved regions of the bacterial 16S RNA gene. The test characteristics for the broad-range bacterial PCR were as follows: sensitivity, 100%; specificity, 98.2%; positive predictive value, 94.4%; and negative predictive value, 100%. Broad-range bacterial PCR may be useful for excluding the diagnosis of meningitis, and the results may influence the decision to initiate or discontinue antimicrobial therapy.

Telavancin: A Novel Lipoglycopeptide

Telavancin, a derivative of vancomycin, is a lipoglycopeptide antibiotic that has been shown to be effective for the treatment of complicated skin and skin-structure infections. It has also been effective in the treatment of gram-positive pneumonia. This antibiotic has a dual mechanism of action by inhibiting peptidoglycan synthesis and causing membrane depolarization. Telavancin is consistently active against Staphylococcus aureus, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus, linezolid-resistant S. aureus, and daptomycin-nonsusceptible strains. The drug is usually administrated intravenously at 10 mg/kg every 24 h. Telavancin is excreted by the kidneys, and thus, dosage adjustments are required in cases of renal failure. Clinical trials have demonstrated non-inferiority, compared with vancomycin, in the treatment of complicated skin and skin-structure infections and pneumonia. Telavancin is associated with higher rates of renal events, altered taste, nausea, and vomiting but lesser rates of pruritus and infusion-related events, compared with vancomycin.

Gatifloxacin, Gemifloxacin, and Moxifloxacin: The Role of 3 Newer Fluoroquinolones

Gatifloxacin, gemifloxacin, and moxifloxacin are the newest fluoroquinolones and show excellent in vitro activity against a wide variety of respiratory tract pathogens, many gram-negative aerobic organisms, and Bacteroides fragilis. These agents may be administered as oral and/or intravenous formulations with excellent bioavailability. The pharmacodynamics of these 3 new fluoroquinolones is more favorable than that of levofloxacin or ciprofloxacin for Streptococcus pneumoniae. All 3 agents are approved for the treatment of acute exacerbation of chronic bronchitis and community-acquired pneumonia. In addition, gatifloxacin and moxifloxacin are approved for the treatment of sinusitis. The toxicity of these 3 agents appears to be similar to that of the other fluoroquinolones in terms of gastrointestinal and central nervous system disturbances. All 3 agents have a low risk of phototoxicity, but gemifloxacin is associated with an increased risk of skin rash that is not a photoreaction. These agents can be useful for treatment of bacterial respiratory tract infections in patients who are allergic to beta-lactams, but caution must be exercised to avoid the potential for selection of widespread resistance, which may occur with indiscriminate use.

Targeting STAT1 by myricetin and delphinidin provides efficient protection of the heart from ischemia/reperfusion-induced injury.

Flavonoids exhibit a variety of beneficial effects in cardiovascular diseases. Although their therapeutic properties have been attributed mainly to their antioxidant action, they have additional protective mechanisms such as inhibition of signal transducer and activator of transcription 1 (STAT1) activation. Here, we have investigated the cardioprotective mechanisms of strong antioxidant flavonoids such as quercetin, myricetin and delphinidin. Although all of them protect the heart from ischemia/reperfusion‐injury, myricetin and delphinidin exert a more pronounced protective action than quercetin by their capacity to inhibit STAT1 activation. Biochemical and computer modeling analysis indicated the direct interaction between STAT1 and flavonoids with anti‐STAT1 activity.

Rilpivirine: a new non-nucleoside reverse transcriptase inhibitor

Rilpivirine is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) that is approved for HIV-1 treatment-naive adult patients in combination with other antiretroviral agents. The recommended dose is a 25 mg tablet once daily taken orally with a meal. Due to cytochrome P450 3A4 enzyme induction or gastric pH increase, rilpivirine cannot be coadministered with a number of other drugs (anticonvulsants, rifabutin, rifampicin, rifapentine, proton pump inhibitors, systemic dexamethasone and St Johns wort). Rilpivirine should be used with caution when coadministered with a drug with a known risk for torsade de pointes. Rilpivirine has a better tolerability than a comparative NNRTI, efavirenz, in clinical trials, with fewer central nervous system adverse effects, rashes, lipid abnormalities and discontinuation rates. Virological failure occurs more commonly with higher baseline viral loads (>100,000 copies/mL) and lower baseline CD4 counts (<50 cells/mm(3)). Seventeen NNRTI mutations have been associated with decreased susceptibility to rilpivirine: K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, H221Y, F227C, M230I/L, Y188L and the combination L100I + K103N. Resistance to rilpivirine largely excludes future use of the NNRTI class.

Etravirine, a Next-Generation Nonnucleoside Reverse-Transcriptase Inhbitor

Etravirine is the first next-generation nonnucleoside reverse-transcriptase inhibitor (NNRTI) that is approved for the treatment of HIV infection in patients who have experienced virologic failure while receiving an NNRTI-containing regimen. The drug is taken as two 100-mg tablets twice daily after a meal. Because the drug is metabolized by cytochrome P450 isoenzymes, it cannot be coadministered with a number of other drugs (fosamprenavir, high-dose ritonavir, atazanavir, rifampin, and several antiepileptic medications). Etravirine demonstrates potent in vitro activity against wild-type and NNRTI-resistant strains of HIV. In vitro resistance and treatment failure is associated with the development of multiple NNRTI resistance mutations other than the K103N mutation. Several large clinical studies have documented the benefit of adding etravirine to an optimized background regimen in patients with virologic failure who are infected with multidrug-resistant HIV. The major adverse effects of etravirine therapy are nausea and rash, which are typically self-limiting and do not lead to treatment discontinuation.

Changing epidemiology of community-onset methicillin-resistant Staphylococcus aureus bacteremia

OBJECTIVESnTo review cases of community-onset Staphylococcus aureus bacteremia and to evaluate whether the risk factors and epidemiology of methicillin-resistant S. aureus (MRSA) bacteremia have changed from early reports.nnnDESIGNnRetrospective case-comparison study of community-onset MRSA (n = 26) and methicillin-susceptible S. aureus (MSSA) (n = 26) bacteremias at our institution.nnnSETTINGnA 600-bed urban academic medical center.nnnPATIENTSnTwenty-six patients with community-onset MRSA bacteremia were compared with 26 patients with community-onset MSSA bacteremia. Molecular analysis was performed on S. aureus isolates from the 26 MRSA cases as well as from 13 cases of community-onset S. aureus bacteremia from 1980 and 9 cases of nosocomial S. aureus bacteremia from 2001.nnnRESULTSnThe two groups were similar except that patients with MRSA bacteremia were more likely to have presented from a long-term-care facility (26.9% vs 4%; P = .05) and to have had multiple admissions within the preceding year (46% vs 15%; P = .03). Clamped homogeneous electric fields analysis of MRSA isolates from 1982 revealed predominantly that one clone was the epidemic strain, whereas there were 14 unique strains among current community-onset isolates. Among current nosocomial isolates, 3 patterns were identified, all of which were present in the community-onset cases.nnnCONCLUSIONSnPreviously described risk factors for MRSA acquisition may not be helpful in predicting disease due to the polyclonal spread of MRSA in the community. Unlike early outbreaks of MRSA in patients presenting from the community, current acquisition appears to be polyclonal and is usually related to contact with the healthcare system.

In Vitro Susceptibilities and Molecular Analysis of Vancomycin-Intermediate and Vancomycin-Resistant Staphylococcus aureus Isolates

BACKGROUNDnThere is increasing frequency of vancomycin-intermediate and -resistant Staphylococcus aureus (VISA and VRSA) isolates identified in clinical practice. There are limited reports evaluating susceptibility patterns and molecular characteristics of these strains.nnnMETHODSnLaboratory analysis was performed on 13 VRSA and 33 VISA isolates, including susceptibility testing by broth microdilution, detection of Panton-Valentine leukocidin (PVL) genes, arginine catabolic mobile element (ACME), and staphylococcal cassette chromosome mec typing using polymerase chain reaction. Strain typing using pulsed-field gel electrophoresis (PFGE) was performed on VRSA isolates.nnnRESULTSnTelavancin, linezolid, tigecycline, and minocycline were active against >90% of VISA isolates, while >90% of VRSA isolates were susceptible to ceftaroline, daptomycin, linezolid, minocyline, tigecycline, rifampin, and trimethoprim/sulfamethoxazole. There were no VISA or VRSA isolates that carried PVL genes or ACME, and most strains (69.8%) were staphylococcal cassette chromosome mec type II. VRSA isolates were predominantly related to USA100 (53.8%) and none were related to USA300 or USA400.nnnCONCLUSIONSnA large number of available antimicrobial agents retain very good in vitro activity against VRSA and VISA isolates. The present isolates appear to be derived from healthcare-associated strains based on the absence of features associated with community-associated strains, and VRSA isolates are polyclonal by PFGE.