Expert Review of Anti-infective Therapy

Published by Expert Reviews
Online ISSN: 1744-8336
Print ISSN: 1478-7210
Chronic lymphocytic leukemia (CLL) is the most prevalent type of leukemia and affects mostly the elderly. Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab is generally considered a standard treatment for younger fit patients with CLL. In a recent randomized Phase III study of patients with newly diagnosed CLL and coexisting conditions, obinutuzumab, a humanized anti-CD20 glycoengineered type 2 antibody, used in combination with chlorambucil, demonstrated significant improvement in progression-free survival and several other outcome parameters, in comparison to rituximab plus chlorambucil. Grade 3-4 infusion-related reactions and neutropenia occurred more frequently in patients who received obinutuzumab compared with those who received rituximab; however, the rate of serious infections was similar. Results of this trial clearly established that obinutuzumab in combination with chlorambucil represent the new first-line standard of treatment in this setting. A broad range of novel agents with different mechanisms of action have already proven their efficacy in CLL. New drugs targeting specific molecular features, such as ibrutinib, idelalisib or ABT-199, are being tested at present, and their advent is very likely to change the future treatment paradigm of CLL that relies today on chemoimmunotherapy for both fit and elderly/unfit patients.
Five main groups of commercial assays for the multiplex detection of alpha human papillomaviruses (HPVs) are currently available. DNA-based screening assays, which test for the presence of 13-14 HPVs without determination of HPV type, have been the standard for HPV detection in the last decade. Assays that combine testing for 14 HPVs and HPV-16 and HPV-18 genotyping are a potential future standard for HPV detection. The clinical value of HPV genotyping assays has still not been finally determined. Recently, one of the mRNA-based assays showed equal clinical sensitivity but higher clinical specificity for CIN2+/CIN3+ in comparison with the validated DNA-based assay. In situ hybridization assays are too laborious and have insufficient clinical sensitivity to be used in routine screening. Automation, price reduction and improvement of clinical specificity are the main goals for the future development of HPV assays.
The innate immune system is evolutionarily ancient and biologically primitive. Historically, it was first identified as an element of the immune system that provides the first-line response to pathogens, and increasingly it is recognized for its central housekeeping role and its essential functions in tissue homeostasis, including coagulation and inflammation, among others. A pivotal link between the innate immune system and other functions is mannose-binding lectin (MBL), a pattern recognition molecule. Multiple studies have demonstrated that MBL deficiency increases susceptibility to infection, and the mechanisms associated with this susceptibility to infection include reduced opsonophagocytic killing and reduced activation of the lectin complement pathway. Results from our laboratory have demonstrated that MBL and MBL-associated serine protease (MASP)-1/3 together mediate coagulation factor-like activities, including thrombin-like activity. MBL and/or MASP-1/3-deficient hosts demonstrate in vivo evidence that MBL and MASP-1/3 are involved with hemostasis following injury. Staphylococcus aureus-infected MBL null mice developed disseminated intravascular coagulation, which was associated with elevated blood IL-6 levels (but not TNF-α) and systemic inflammatory responses. Infected MBL null mice also develop liver injury. These findings suggest that MBL deficiency may manifest as disseminated intravascular coagulation and organ failure with infection. Beginning from these observations, this review focuses on the interaction of innate immunity and other homeostatic systems, the derangement of which may lead to complications in infection and other inflammatory states.
Crystal structures of protective antigen. (A) Monomeric structure of protective antigen (PA83) showing the four domains. Domain 1 docks to an enzyme component (edema or lethal factor), domain 2 forms a channel in lipid membranes and provides an accessory docking site for receptor, domain 3 facilitates oligomerization and domain 4 interacts with cell-surface receptor. (8) Heptameric form of PA63 solutionside view. Structures were derived from data from [53,69) provided by Entrez's 3D database and software for molecular modeling [184 ]. 
Model for the intracellular effects of lethal and edema toxins. After PA83-ANTXR interactions, PA83 is cleaved by a cell-surface protease (furin or furin-like) and PA20 subsequently released from the complex. Via lipid raft associations, PA63 forms homoheptamers that associate with three molecules of EF and/or LF. LF and EF are translocated with PA into the late endosome. LF is released into the cytosol, while EF remains associated to the late endosomal membrane. EF is a Ca 2 +-calmodulin-dependent adenylate cyclase that increases cAMP levels and induces cellular dysfunctions through PKA and CREB. Although LF cleaves all MKKs, MKK5 induces major cell dysfunction and death through MAPK pathway deregulation. NALPlb is another critical target for initiating cell death through caspase 1 and IL-l secretion. CREB: Cyclic AMP response-element binding protein; EF: Edema factor; LF: Lethal factor; MKK: Mitogen-activated protein kinase kinase; PA: Protective antigen; PKA: Protein kinase A. 
Bacillus anthracis is the causative agent of anthrax, a disease that plagues both humans and various animal species. Effective vaccines are available, but those approved for human use are crude culture supernatants that require multiple injections and a yearly boost. Many experts agree that it is now time for the next generation of human vaccines against anthrax. Accordingly, this review will succinctly focus upon: pathogenesis of B. anthracis, with particular emphasis upon the immune system; the pertinent biophysical nature of protective antigen, which includes how the protein toxin component affords protection as a vaccine target; alternative methods for improving protective antigen as an immunogen; and additional B. anthracis antigens that might further sustain protective titers in humans. In addition to a better understanding of the disease process elicited by B. anthracis, which will logically lead to better vaccines (and therapeutics), there also needs to be the same level of open-mindedness applied to the politics of anthrax.
The tumor-suppressor miRNA 126 (miR-126) is downregulated in many tumors and has recently been placed at the heart of complex metastatic pathways. Hamada and colleagues have identified miR-126 as being downregulated in pancreatic ductal adenocarcinoma (PDAC) patient samples and cell lines. The protein ADAM9 has been implicated in the progression of various solid tumors including PDAC. ADAM9 is overexpressed in PDAC and also a direct target of miR-126. The miR-126/ADAM9 axis was subsequently established to control migration and invasion in PDAC, as well as reversal of epithelial-to-mesenchymal transition. miR-126 is also known to target other crucial oncogenes in PDAC such as KRAS and CRK. Replacing miR-126 in PDAC patients may be a novel strategy for preventing progression and metastasis.
Escherichia coli ST131 has emerged as a global epidemic, multidrug-resistant clone of E. coli causing extra-intestinal infections. It is now highly prevalent among fluoroquinolone-resistant and CTX-M ESBL-producing E. coli isolates worldwide. Humans are likely the primary reservoir of ST131. Factors associated with its acquisition include residence in long-term care facilities and recent receipt of antimicrobial agents. E. coli ST131 causes a wide array of infections ranging from cystitis to life-threatening sepsis. Fluoroquinolones and trimethoprim-sulfamethoxazole are no longer adequate options for empiric therapy when E. coli ST131 is suspected from risk factors and local epidemiology. Expanded-spectrum cephalosporins, piperacillin-tazobactam and carbapenems are options to treat serious non-ESBL-producing E. coli ST131 infections, while carbapenems are indicated for ESBL-producing infections. There is a growing interest in reevaluating oral agents including fosfomycin and pivmecillinam for less serious infections such as uncomplicated cystitis.
In the preantibiotic era, TB of the skin was treated successfully with UV light. By the 1920s, pulmonary TB was being treated with regular sun exposure. During the last decade, basic laboratory research into the antimicrobial actions of vitamin D has provided new insights into these historical observations. Vitamin D has a critical role in the innate immune system through the production of antimicrobial peptides - particularly cathelicidin. Vitamin D would appear to have an important role in respiratory tract, skin and potentially gut health. A number of autoimmune diseases, including multiple sclerosis, Type I diabetes, systemic lupus erythematosus and rheumatoid arthritis, are associated with vitamin D deficiency. Vitamin D could have an important role in the prevention and possible treatment of these conditions; however, much of the current evidence relates to basic science and epidemiological research. In many situations, appropriate double-blind, randomized controlled trial data to guide clinicians treating infectious and autoimmune disease is still lacking.
While amphotericin B deoxycholate (Fungizone, Apothecon Pharmaceuticals) has been considered by many to be the gold standard for the treatment for numerous invasive fungal infections for over 45 years, toxicities associated with its use often necessitate treatment modification or discontinuation. Lipid-based formulations, including liposomal amphotericin B (AmBisome, Fujisawa Healthcare, Inc.), were developed to decrease many of these toxicities while retaining broad antifungal spectrum and potency of amphotericin B. In clinical trials, liposomal amphotericin B has demonstrated efficacy comparable to that of amphotericin B deoxycholate while reducing the incidence of treatment-related nephrotoxicity, electrolyte-wasting, and infusion-related reactions. In addition, recent clinical trials have also compared liposomal amphotericin B with other antifungal classes. Acquisition costs of liposomal amphotericin B are substantially higher than those of amphotericin B deoxycholate and other antifungals. While pharmacoeconomic analyses consider outcomes and other treatment-related costs, they have yet to clearly demonstrate the cost-effectiveness of liposomal amphotericin B when compared with amphotericin B deoxycholate or other antifungal agents. This review will focus primarily on recent liposomal amphotericin B experience and attempt to put its use into perspective considering other available antifungal agents.
Algorithm for the suggested initial antibiotic therapy of acute hematogenous osteomyelitis in children 3 months of age or older  
In children, osteomyelitis is primarily hematogenous in origin and acute in nature. The principal cause of osteomyelitis in children is Staphylococcus aureus, and both the epidemiology and pathogenesis of S. aureus infections, including osteomyelitis, have changed in recent years owing to the emergence of community-associated methicillin-resistant S. aureus. This review focuses on advances in the diagnosis and overall management of acute hematogenous osteomyelitis in children with these changes in mind.
The authors sought to evaluate whether sisomicin has a place in the current therapeutic armamentarium. PubMed and Scopus databases were systematically searched. Ten cohort studies and 11 case reports and case series were included evaluating, in total, 383 Gram-positive and 83 Gram-negative isolates. Sisomicin was active in vitro against 41% of Enterococcus spp., 97% of Staphylococcus spp. and was the most active in vitro (74%) aminoglycoside against Stenotrophomonas maltophilia isolates in one study. Regarding clinical effectiveness, sisomicin topical cream was effective in all 290 patients with pyoderma in one study, while the intravenous formulation of sisomicin was effective as prophylaxis for the development of postoperative pneumonia in 91% of lung surgery patients in another. In conclusion, sisomicin may be useful against certain pathogens; however, clinical data are scarce. Further studies are needed and may shed additional light in this area.
To assess 8-year antibiotic consumption and expenditure in all of the hospitals of Emilia Romagna. The analysis was based on the pharmacy records of each hospital. Antibiotic drug consumption was expressed as DDDs per 100 bed-days used (BDU) and data were analyzed according to ATC classification and to single wards. Expenditure was expressed as Euros per 100 BDU. In the 8-years considered, overall consumption increased by 27% and expenditure by only 3%. Consumption was higher in surgical wards than in medical ones. Penicillins and β-lactamase inhibitors ranked first, followed by fluoroquinolones and third generation cephalosporins. The results of the study strongly suggest that antibiotic use could be improved by educational interventions to improve clinical practice in hospitals, assessments of guidelines and monitoring of the outcomes of the interventions are needed.
Infection with HIV and subsequent development of AIDS is a pandemic. The Joint United Nations Program on HIV/AIDS together with the WHO and many relevant funding bodies demand that those infected should be reliably identified so that people who need, or will need, therapy may be provided for over time. This means that there is a renewed interest in testing for HIV and in laboratories' performances and quality. Whatever the conditions under which testing is performed, and whatever the levels of training, the tests and their outcomes must exhibit equivalent, high standards of performance and reliable results. This is regardless of whether testing is conducted in the most sophisticated laboratories (either diagnostic or transfusion screening) to voluntary testing and counseling centers where those conducting testing may not be technically trained. This is not currently the case, especially in some places where HIV is most prevalent. To achieve uniformly high performance standards, quality assurance programs are imperative, but currently not sufficiently valued to be well supported with adequate funding or human resources. Accurate HIV testing is a cornerstone of blood safety, diagnosis of infection, patient management and surveillance.
Inflammatory acne vulgaris remains one of the most common dermatologic disorders seen in clinical practice. Medical therapy remains the gold standard for therapy but recent advances have shown that a variety of lasers and light sources may be useful in the treatment of inflammatory acne vulgaris. In addition, the use of 20% 5-aminolevulinic acid has found a useful niche in the treatment of moderate-to-severe inflammatory acne vulgaris.
On 16-19 January 2008, the Third Advances Against Aspergillosis Meeting took place in Miami Beach, FL, USA. There were 351 registrants from 26 countries. The two earlier meetings had taken place in San Francisco, CA, 2004 and in Athens, Greece, 2006, and the series has become the place for scientists and clinicians to be updated on developments relevant to all aspects of this fungal genus.
During the 2010 HIV Diagnostics Conference, which took place in Orlando (FL, USA) between 24 and 26 March 2010, salient new data related to three aspects of HIV testing (rapid point-of-care testing, laboratory assays and new technologies) were presented and discussed. A conundrum central to HIV diagnostics in the USA for the last few years has resulted from technological developments in HIV testing that have outpaced recommendations for screening and confirmatory testing. Perhaps in response, one of the major outcomes of this 2010 meeting was the proposal of a novel laboratory testing algorithm. The proposed algorithm aims to take advantage of all of the capabilities of currently available tests (sensitivities for HIV-1 and HIV-2 IgG and IgM antibodies, and p24 antigen), while at the same time enhancing the turnaround time of results. This report will summarize the presentations at the meeting.
8th World Congress of the World Society for Pediatric Infectious Diseases conference Cape Town, South Africa, 19-22 November 2013 The 8th World Congress of the World Society for Pediatric Infectious Diseases (WSPID) conference was held in Cape Town, South Africa in November 2013. This was the first WSPID conference to be held in Africa. The conference brought together 1368 delegates from 105 countries including many pediatric infectious diseases specialists from Africa. The conference explored a wide range of topics including childhood immunization, malaria, HIV infection, tuberculosis, gastroenteritis, sepsis, neonatal infections and arthropod-borne viral infections. This report largely covers developments regarding antimicrobial resistance, antibiotic stewardship, pneumonia and meningitis.
Direct-acting and host-targeting anti-HCV agents in Phase II or III clinical development. 
Baseline characteristics of patients enrolled in the STARTVerso4 trial. 
Interim safety and tolerability profile reported of STARTVerso4. 
Chronic HCV infection affects 130-170 million individuals worldwide and there are currently 34 million people living with HIV/AIDS. The aim of treatment of HCV is the elimination of the virus (sustained virological response). With development of drugs that specifically target HCV replication, direct-acting agents, sustained virological response rates have dramatically changed for genotype 1 infections. Challenges in the use of direct-acting agents in patients with HIV/HCV co-infection include the potential for drug-drug interactions between HIV and HCV drugs, additional drug toxicities and the need for therapy with IFN-α. Faldaprevir (FDV), previously known as BI 201335, is a second-wave HCV NS3/4A protease inhibitor with highly potent in vitro activity against HCV GT-1a/1b and improved pharmacokinetics suitable for once-daily dosing. FDV is currently in Phase III development. This article will review the pharmacology and pharmacodynamics of FDV, the efficacy and safety of the drug and explore possible future developments in the management of chronic hepatitis C infection, focusing on HIV/HCV co-infected patients.
Program steps taken by Global Program to Eliminate Lymphatic Filariasis to interrupt transmission of lymphatic filariasis. MDA; Mass drug administration; Mf: Microfilaremia; TAS: Transmission assessment survey. Adapted from [27]. 
Lymphatic filariasis (LF) is an important public health problem endemic in 73 countries, where it is a major cause of acute and chronic morbidity and a significant impediment to socioeconomic development. It is targeted for elimination by 2020, through preventive chemotherapy using albendazole in combination with either ivermectin or diethylcarbamazine citrate. Preventive chemotherapy enables the regular and coordinated administration of safe, single-dose medications delivered through mass drug administration (MDA). Many countries are now scaling down MDA activities after achieving 100% geographic coverage and instituting monitoring and evaluation procedures to establish the impact of several consecutive rounds of MDA and determine if transmission has been interrupted. At the same time, countries yet to initiate MDA for elimination of LF will adopt improved mapping and coverage assessment protocols to accelerate the efforts for achieving global elimination by 2020. This review provides an update on treatment for LF and describes the current global status of the elimination efforts, transmission control processes and strategies for measuring impact and continuing surveillance after MDA has ceased.
Respiratory syncytial virus (RSV) is a pathogen whose existence has been known for decades, causing mild-to-severe upper and lower respiratory tract infections that bear the risk of subsequent asthma and can even lead to a fatal outcome. RSV infects all groups of patients and is a major cause of hospitalization in children and in the elderly. This review briefly summarizes the current status of RSV drug development and clinical trials for drugs available for the treatment of RSV infections.
Data on the activity of chloramphenicol combinations with other antimicrobial agents. 
Summary of activity of chloramphenicol against ESKAPE organisms. 
The widespread use of antibiotics has been associated with the emergence of antimicrobial resistance among bacteria. 'ESKAPE' (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acintobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) pathogens play a major role in the rapidly changing scenario of antimicrobial resistance in the 21st century. Chloramphenicol is a broad spectrum antibiotic that was abandoned in developed countries due to its association with fatal aplastic anemia. However, it is still widely used in the developing world. In light of the emerging problem of multi-drug resistant pathogens, its role should be reassessed. Our paper reviews in vitro data on the activity of chloramphenicol against ESKAPE pathogens. Susceptibility patterns for Gram-positives were good, although less favorable for Gram-negatives. However, in combination with colistin, chloramphenicol was found to have synergistic activity. The risk-benefit related to chloramphenicol toxicity has not been analyzed. Therefore, extra precautions should be taken when prescribing this agent.
Number of citations found in the Pubmed database from 1960 to the middle of 2011 using either the term 'colistin' or 'colistin resistance'.  
Structure of polymyxin B and colistin. Polymyxin B and colistin (polymyxin E) share a similar primary sequence with the only difference being at position 6, which is replaced by D-Phe in polymyxin B and D-Leu in colistin.  
Results of in vitro studies carried out for synergy in combination of drugs with polymyxins. 
Antimicrobial mode of action of polymyxin against Gram-negative bacterial membranes. LPS: Lipopolysaccharide.
The emergence of multidrug-resistant Gram-negative bacteria that cause nosocomial infections is a growing problem worldwide. Colistin was first introduced in 1952 and was used until the early 1980s for the treatment of infections caused by Gram-negative bacilli. In vitro, colistin has demonstrated excellent activity against various Gram-negative rod-shaped bacteria, including multidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. Recent clinical findings regarding colistin activity, pharmacokinetic properties, clinical uses, emerging resistance, toxicities and combination therapy have been reviewed. Recent approaches to the use of colistin in combination with other antibiotics hold promise for increased antibacterial efficacy. It is probable that colistin will be the 'last-line' therapeutic drug against multidrug-resistant Gram-negative pathogens in the 21st century.
Since its discovery as an agent of mycetoma nearly a century ago, Pseudallescheria boydii with its asexual (synanamorphic) form, Scedosporium apiospermum, is now recognized as an important emerging opportunistic pathogen causing invasive mycosis in immunocompromised patients. The clinical spectrum of pseudallescheriasis is wide. Invasive disease of the lung, CNS and dissemination are serious manifestations in immunocompromised patients. This organism responds poorly to amphotericin B, and its histopathologic resemblance to aspergillosis often results in a delay in diagnosis. In vitro data, animal models and accumulating clinical experience support the use of voriconazole as a primary treatment for pseudallescheriasis. This paper reviews the microbiology, ecology, epidemiologic trends, clinical manifestations and current treatment options of pseudallescheriasis.
Radionuclides have been widely used for cancer treatment. Recently, new research about radium-223 dichloride has been conducted in prostate cancer, which reveals that it is the first radiopharmaceutical to demonstrate an improvement in overall survival and time to first symptomatic skeletal event in patients with castration resistant prostate cancer with symptomatic bone metastases. This fact has created a new paradigm in the treatment of prostate cancer landscape, where only chemotherapy and hormone therapy had a role, while β-emitters had been confined exclusively to the role of pain relief with no impact on survival. The aim of this review is to outline current treatment approaches for advanced prostate cancer with a focus on the role of radium-223 dichloride, reviewing patients' profile that make them suitable to therapy and chances for further studies.
The annual meeting of the European Society for Paediatric Infectious Diseases (ESPID) was recently held in Brussels, Belgium, and gathered world experts in pediatric infectious diseases, vaccinology, epidemiology, microbiology and public health, among others. Among nonvaccine related topics that were discussed, emphasis was given to the continuous surveillance of the most common pathogens causing noninvasive and invasive infectious diseases, other organisms that cause disease, and nosocomial outbreaks by resistant organisms. However, despite the availability of newer antimicrobial therapies for fighting infections in childhood, effective common-sense preventive measures such as hand hygiene can impact positively on the decrease of incidence, and spread of drug- and multidrug-resistant organisms.
Infection with Toxoplasma gondii is transmitted to man by infected meat or meat products and by contact with soil or surface water. In theory, prevention by hygienic measures is possible, but this has never been proved to work in practice. Therefore, pre- and postnatal screening has been implemented in several countries aiming at early diagnosis. However, data on the effect of treatment are limited and no randomized, controlled trials have been performed. The risk of T. gondii infection in Europe is declining and studies using historical controls from earlier decades cannot be used for decision making. The screening of pregnant women or neonates makes the assumption that any children diagnosed can be offered an effective treatment. There is an urgent need to test new drugs and demonstrate, using randomized, controlled trials, that the currently used drugs are effective.
The success rate in HCV treatment of HIV/HCV-coinfected patients is still unsatisfactory and new strategies are required to improve the effectiveness of current regimens and eventually optimize the oncoming new antiviral drugs. This article assesses the findings of a recently published paper comparing pharmacokinetics, pharmacodynamics and HCV decay with twice-weekly dosing of pegylated IFN-α-2a versus the standard weekly dosing, and weight-based ribavirin. A more rapid HCV-RNA decline was observed in the twice-weekly pegylated interferon arm and associated with a higher induction of interferon-stimulated genes, despite a similar pharmacokynetic profile between the two dosing schedules. This promising novel therapeutic approach to improve sustained virologic response in difficult-to-treat populations is discussed in relation to the key findings of the article.
Chronic hepatitis C is the leading cause of liver disease and liver-related mortality in the western world. Treatment of this chronic viral infection has considerably improved with the introduction of ribavirin-interferon combination therapy. Ribavirin (Copegus, Rebetol) is a synthetic nucleoside analogue with broad antiviral effects. It is absorbed readily upon oral administration with meals. Daily doses of up to 1200 mg are usually well-tolerated, causing dose-dependent haemolysis, reversible with dose reduction in most patients, in particular in those with renal insufficiency. In the circulation it is bound to erythrocytes, and eliminated by phosphorylation and deribolysation. The drug accumulates in blood with renal insufficiency. Impairment of hepatic function does not influence drug levels in the circulation. In animal studies, teratogenic and reproductive toxicity was shown. In chronic hepatitis C virus infection, monotherapy with ribavirin has no effect on concentrations of viral RNA or liver histology. Combination therapy with pegylated interferon-alpha2a (40 kDa) (Pegasys) produces significantly higher sustained virological response rates in infections with all viral genotypes, even in advanced stages of liver disease compared pegylated interferon-alpha2a monotherapy, adverse effects and quality of life are not significantly different.
Hepatitis C virus infection is among the leading causes of chronic liver disease in the USA and has a worldwide prevalence of approximately 300 million people. Chronic hepatitis C virus is the most common indication for liver transplantation in the USA. Due to the chronic nature of hepatitis C virus infection, these numbers are expected to grow fourfold in the next decade. Interferon-alpha(2b) monotherapy followed by combination therapy with ribavirin have been used to treat chronic hepatitis C virus with limited success. The development of pegylated interferon-alpha(2b), (Peg-intron, Schering-Plough) instituted the next chapter in hepatitis C virus therapy. The demonstration of its safety and efficacy led to a major trial studying coadministration with ribavirin for compensated chronic hepatitis C virus infection. Pegylated interferon combination therapy has improved efficacy over standard interferon combination therapy without an increase in adverse effects. This article reviews the data regarding pegylated interferon-alpha(2b) with ribavirin therapy. The pharmacokinetics and pharmacodynamics of combination therapy will be presented along with clinical trial data. The efficacy and ease of usage of Pegintron and ribavirin support its use for chronic hepatitis C virus infection.
Prior to 1981, treatment options for invasive fungal infections were limited and associated with significant toxicities. The introduction of ketoconazole marked the beginning of an era of dramatic improvements over previous therapies for non-life-threatening mycosis. After nearly a decade of use, ketoconazole was quickly replaced by the triazoles fluconazole and itraconazole due to significant improvements in pharmacokinetic profile, spectrum of activity and safety. The triazoles posaconazole and voriconazole followed, and were better known for their further extended spectrum, specifically against emerging mold infections. With the exception of fluconazole, the triazoles have been plagued with significant inter- and intrapatient pharmacokinetic variability and all possess significant drug interactions. Azoles currently in development appear to combine an in vitro spectrum of activity comparable to voriconazole and posaconazole with more predictable pharmacokinetics and fewer adverse effects.
Segmentation. The figure illustrates a step-wise segmentation of a liver tumor. The baseline image (A) is a contrast-enhanced portal-venous phase T1 MRI. The lesion demonstrates central necrosis and rim enhancement. The semi-automated segmentation process starts from a central seed point (B), which is being expanded (C-E) to include the entire lesion (E). The segmentation results in a 3D mask which encompasses the entire tumor volume (F). 
Comparison of tumor assessment techniques. This figure illustrates different techniques of tumor assessment. The upper row shows measurements of the overall tumor size (1D: Response Evaluation Criteria in Solid Tumors [RECIST], 2D: World Health Organization [WHO], 3D: volumetric Response Evaluation Criteria in Solid Tumors [vRECIST]). The lower row illustrates enhancement-based techniques (1D: modified Response Evaluation Criteria in Solid Tumors [mRECIST], 2D: European Association for the Study of the Liver [EASL], 3D: quantitative European Association for the Study of the Liver [qEASL]). 
Assessing the tumor response of liver cancer lesions after intraarterial therapies is of major clinical interest. Over the last two decades, tumor response criteria have come a long way from purely size-based, anatomic methods such as the Response Evaluation Criteria in Solid Tumors towards more functional, enhancement- and diffusion-based parameters with a strong emphasis on MRI as the ultimate imaging modality. However, the relatively low reproducibility of those one- and 2D techniques (modified Response Evaluation Criteria in Solid Tumors and the European Association for the Study of the Liver criteria) provided the rationale for the development of new, 3D quantitative assessment techniques. This review will summarize and compare the existing methodologies used for 3D quantitative tumor analysis and provide an overview of the published clinical evidence for the benefits of 3D quantitative tumor response assessment techniques.
Enterovirus 71 (EV71) has emerged as a major cause of neurological threat in the world following the eradication of poliovirus. Most EV71 infections commonly result in hand-foot-mouth disease or herpangina, and some cases are associated with brainstem encephalitis and acute flaccid paralysis. Mortality was high in EV71 brainstem encephalitis complicated with pulmonary edema, particularly in children below 5 years of age. Destruction of vasomotor in the brainstem by EV71 produces autonomic nervous system dysregulation prior to the pulmonary edema. The pulmonary edema is the result of increased pulmonary vascular permeability caused by the direct brainstem lesions and/or a systemic inflammatory response syndrome produced by the release of cytokines and chemokines. There is currently no specific antiviral agent to treat or vaccine to prevent EV71 diseases. Treating severe EV71 brainstem encephalitis patients with intravenous IgG and milrinone is associated with significantly decreased mortality by attenuated sympathetic activity and cytokine production.
The meeting of the American Society of Microbiology was recently held in San Francisco, CA, USA - a gathering of experts in the fields of infectious diseases, microbiology and the pharmaceutical industry, among others. Owing to this large attendance and extensive coverage of many infectious disease topics, we focus on the optimization of anti-infective use in the clinical setting. We will cover antimicrobial stewardship, drugs with Gram-positive activity, and antifungal and antiretroviral agents.
This review focuses on chemotherapies used against the parasite, Cryptosporidium parvum, the causative agent of cryptosporidiosis. Populations at risk from severe morbidity or mortality from cryptosporidiosis are discussed with particular reference to those infected with HIV. The review then examines chemotherapies used in the clinical setting, as well as a number of in vitro and in vivo experimental studies. It begins with a discussion of the targets within Cryptosporidium that have been the foci of past treatments and then examines novel target sites that may present an exploitable alternative. Some of the novel target sites discussed include the recently discovered apicomplexan plastid and its associated pathways. Lastly, the review examines tubulin as a potential anticryptosporidial target in view of the fact that it has been exploited successfully for almost 50 years for the treatment of helminthiasis. The review concludes with a five-year outlook on the future of anticryptosporidial drug design.
Infection with HIV is independently associated with an increased risk for clinical heart failure, cardiomyopathies and premature atherosclerosis, including stroke and myocardial infarction in both the pre-HAART and HAART eras. HAART is also associated with clinical cardiovascular concerns. In HIV-infected individuals, HAART may cause adverse lipid profiles and increased risk for cardiovascular events. Its effects on the developing heart remain unclear. Although in utero HAART exposure may improve cardiac function in the first 2 years of life, it may also inhibit myocardial growth. Additional potentially damaging cardiovascular effects of HAART are present, and continuing cardiovascular risk evaluations, screening and follow-up of treated patients is necessary. Here, we review available research in this field and highlight the importance of understanding known complications and their mechanisms.
The 6th World Congress of the World Society for Pediatric Infectious Diseases (WSPID), which was recently held in Buenos Aires, Argentina, between 18 and 22 November 2009, attracted 2401 attendees from 90 countries representing six continents. The WSPID, founded in 1994 by Professor Saldana Gonzalez of the Mexican Pediatric Infectious Diseases Society, is a network of pediatric infectious diseases societies dedicated to the treatment and prevention of pediatric infectious diseases. All the regional societies from Europe, North America, Latin America, Asia, Australasia and Africa have participated in the WSPID.
Enterovirus 71 (EV71) is a neurotropic human pathogen that is the causative agent of hand foot and mouth disease (HFMD), herpangina and brain stem encephalitis. Recurrent EV71 epidemics of various scales have occurred in the Asia-Pacific region. Several specific cell surface molecules serve as the receptors for EV71. Identification of the receptors is an important step to understand EV71 disease. Cytokines, lymphocytes and monocytes contribute significantly to EV71 pathogenesis. The interaction of EV71 and receptors may be associated with the cytokines immunopathogenesis. Some animal models have been established and aim to explore the pathogenesis of EV71 infections. EV71 antibodies can neutralize or enhance infection at subneutralizing levels. These results are important for EV71 vaccine and therapeutics design. Several clinical trials of human inactivated EV71 vaccine have recently been completed. The purpose of this review is to summarize recent discoveries about the epidemiology and pathogenesis of EV71 and provide insights into human vaccine development.
The incidence of Clostridium difficile has doubled over the past 15 years, and rising mortality rates associated with this infection have followed in its wake. C. difficile infection (CDI) has supplanted methicillin-resistant Staphylococcus aureus as the major cause of nosocomial infection. An insufficient response rate to currently available CDI therapies has prompted the search for new and alternative treatment modalities for this disease. The investigational pipeline includes evaluation of new antimicrobial agents that exhibit good activity against C. difficile without altering normal gut flora, C. difficile toxin-absorbing compounds, and preformed antibodies and vaccines against C. difficile toxin. In two robust clinical trials comparing fidaxomicin to vancomycin in the treatment of CDI, treatment with fidaxomicin demonstrated a superior global cure (cure without recurrence) rate compared with the current gold standard, vancomycin. Fidaxomicin, the first of a new class of macrocyclic antimicrobial agents, represents an advance in the management of CDI.
Given the global importance of chronic HCV infection as a major health burden, there is still a need for developing treatment options that are more efficient, safer, simpler, more convenient and preferably interferon-free. Sofosbuvir (GS-7977; formerly PSI-7977) is a direct-acting antiviral agent that has met many of these attributes. This novel nucleotide analogue has demonstrated a consistently potent antiviral activity across several HCV genotypes, and has been found to be safe and well tolerated when administered alone or with ribavirin (RBV) +/- pegylated interferon (Peg-IFN). The clinical data of sofosbuvir evaluating the safety, tolerability and antiviral activity in various treatment regimens are presented in this article. Sofosbuvir is a major breakthrough in the care of HCV infection, making possible that thousands of HCV infected patients around the world cures, and preventing HCV associated morbidity and mortality.
With a broad-spectrum of activity, fluoroquinolones have been widely and successfully used for decades for the treatment of and prophylaxis against various bacterial infections, including community-acquired pneumonia (CAP). However, the use of fluoroquinolones has been compromised by the emergence and spreading of bacterial resistance and the potential for adverse effects. Therefore, there is an unmet need for newer compounds that have a broader spectrum of activity to overcome existing bacterial resistance as well as the potential to minimize the risk of adverse effects. Nemonoxacin (TG-873870), a newly developed quinolone, has demonstrated broad-spectrum activity against Gram-positive, Gram-negative and atypical pathogens, including drug-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus. Results from Phases I and II studies of treatment of CAP are encouraging. This article reviews the updated data on nemonoxacin, including the bacterial susceptibility, the pharmacologic characteristics, and toxicities, and clinical trials using nemonoxacin for treatment of CAP.
Currently available drugs for the treatment of visceral leishmaniasis. 
Completed, ongoing and planned clinical studies. 
Human visceral leishmaniasis (VL), a potentially fatal disease, is most prevalent in the Indian subcontinent, East Africa and South America. Definite diagnosis and effective treatment are the primary needs for the control of VL. Diagnosis of VL has typically relied on microscopic examination of bone marrow/splenic aspirate, but serology and molecular methods are now better alternatives. The conventional drugs for treatment of VL have limitations including unresponsiveness, relapse, specific toxicities and parenteral administration lasting for long durations. Moreover, they are less effective in HIV-VL-coinfected patients. Registration of miltefosine and paromomycin, and preferential pricing of AmBisome has offered more choices for monotherapy and combination therapy for VL. Combination therapy will increase treatment efficacy and prevent the development of resistance. In addition, active case finding and vector control strategies will also have a positive impact in the control of VL. This article critically addresses the currently available diagnostic and treatment regimens for the control of VL.
The fixed dose combination of abacavir with lamivudine represents a new treatment option for patients infected with HIV. Fixed dose combination abacavir/lamivudine has the convenience of one pill and once-daily dosing. It achieves comparable suppression of plasma HIV RNA with the pill's individual components dosed twice daily and with thymidine analogs combined with lamivudine. The combination is well tolerated, with the potential advantages of less lipoatrophy and fewer metabolic perturbations. However, the abacavir component may cause hypersensitivity reactions, which are reported in up to 8% of patients, and are potentially life threatening. Fixed dose combination abacavir/lamivudine should be considered as a viable treatment option for HIV-infected patients, particularly for those who have otherwise limited nucleoside reverse transcriptase inhibitor choices.
The biomarker procalcitonin (PCT) has been used to diagnose and monitor a number of clinically significant infections. Serum levels of PCT are often increased in the presence of bacterial and fungal infections but not viral infections or noninfectious inflammation. Intra-abdominal infections (IAIs) are serious conditions that pose difficult challenges to physicians and the healthcare system. Researchers have evaluated PCT in the management of IAIs, both for diagnosis and for guiding antibiotic therapy. The studies have produced mixed results, leading to controversy on the utility of PCT in IAIs. PCT appears to be most useful in diagnosing postoperative infections and necrotizing pancreatitis. This review aims to summarize these data, explore the pathophysiology of PCT in sepsis from IAIs, discuss the strengths and weaknesses of PCT monitoring in IAIs, and provide guidance for the interpretation of PCT levels.
Top-cited authors
Michael Hamblin
  • University of Johannesburg
Tianhong Dai
  • Harvard Medical School
Brendan Gilmore
  • Queen's University Belfast
Sean P Gorman
  • Queen's University Belfast
Ying-Ying Huang
  • Massachusetts General Hospital