Immunomodulatory Agents as Adjunctive Therapy for the Treatment of Resistant Candida Species

Invasive Candida infections have increased fivefold over the past 20 years. During this time, the incidence of antifungal resistance and infection due to non-albicans species has risen with the increasing use of broad spectrum antifungals. As few new antifungal agents are in development, strategies to improve outcomes in the treatment of Candida infections are sorely needed. The use of immunotherapy to augment the host immune response as an adjunctive treatment for Candida infections is a potentially robust and promising approach. The purpose of this review is to focus on new developments in the use of adjunctive immunotherapy for the treatment of Candida infections, and discuss the potential impact of antifungal resistance on the host immune response.     

Medicinal plants used for the treatment of sexually transmitted infections by lay people in northern Maputaland,KwaZulu–Natal Province,South Africa

This ethnobotanical study on plants used for the treatment of sexually transmitted infections was undertaken to document the knowledge by lay people in a rural community in northern Maputaland, South Africa. The focus was on the medicinal plants which are growing in and around the immediate vicinity of the homesteads. Thirty three plant species were recorded as being used for the treatment of sexually transmitted infections such as gonorrhoea (drop or ugcusulu), external and internal sores caused by sexually transmitted infections, genital warts (cauliflower or umhluma) and syphilis. Nine plants (Bridelia cathartica subsp. cathartica, Cladostemon kirkii, Erianthemum dregei, Euphorbia hypericifolia, Ipomoea batatas, Krauseola mosambicina, Mimusops caffra, Opuntia stricta and Sarcophyte sanguinea subsp. sanguinea) were recorded for the first time in the literature world wide as a treatment for sexually transmitted infections. Five new vernacular names were documented for B. cathartica subsp. cathartica, Bryophyllum pinnatum, Clematis brachiata, E. hypericifolia and Pyrenacantha kaurabassana. The 33 plant species are used in 23 different combinations of two or more plants per herbal remedy. The three most frequently used plant species in the study area for the treatment of sexually transmitted infections are; Hypoxis hemerocallidia, Senecio serratuloides and Ranunculus multifidus. Roots are mostly prepared, as a decoction which is taken orally or used as an enema. All eighty of the interviewees preferred traditional medicine as the first therapeutic choice for treating sexually transmitted infections. The wide variety of plants that are used to treat sexually transmitted infections in this area emphasises the importance that medicinal plants can have in the primary health care system of the rural people in northern Maputaland (KwaZulu–Natal).     

Evaluation of Trimethoprim-sulphamethoxazole Compound in Treatment of Salmonella Infections

Fifty patients suffering from infections caused by various salmonella species were treated with trimethoprim-sulphamethoxazole compound. Twenty-three had enteric fever and two were biliary carriers of Salmonella typhi. The other 25 suffered from infections caused by salmonella species other than S. typhi or S. paratyphi B. Twenty-one of the patients with enteric fever responded clinically to the drug, one failed treatment, and one died. Two patients suffering from typhoid fever relapsed and three temporarily excreted S. typhi in stools following treatment. One of the typhoid carriers was successfully treated. All patients with infections caused by salmonella species other than S. typhi or S. paratyphi B responded to treatment but 17 continued to excrete the organism in their stools after the course of trimethoprim-sulphamethoxazole compound. Four patients developed rashes during therapy and two became anaemic.     

Bronchopulmonary Infection of Lophomonas blattarum: A Case and Literature Review

Human infections with Lophomonas blattarum are rare. However, the majority of the infections occurred in China, 94.4% (136 cases) of all cases in the world. This infection is difficult to differentiate from other pulmonary infections with similar symptoms. Here we reported a case of L. blattarum infection confirmed by bronchoalveolar lavage fluid smear on the microscopic observations. The patient was a 21-year-old female college student. The previous case which occurred in Chongqing was 20 years ago. We briefly reviewed on this infection reported in the world during the recent 20 years. The epidemiological characteristics, possible diagnostic basis, and treatment of this disease is discussed in order to provide a better understanding of recognition, diagnosis, and treatment of L. blattarum infection.     

A Clinical Trial of Cephaloridine

Cephaloridine, a cephalosporin derivative, was administered to 30 selected patients, including 19 with moderate to severe impairment of renal function. This antibiotic eradicated infections due to Staphylococcus pyogenes, and urinary tract infections due to a single member of the species Escherichia coli or Aerobacter aerogenes, which were sensitive to the drug on bacteriological testing. The drug failed in mixed urinary tract infections.No adverse effects were observed except for the development of superinfection in patients with urinary tract infections. No allergic reactions were noted in 10 patients who had reported previous reactions to penicillin.From these studies in patients with renal disease, approximations can be made concerning dose requirements in these special cases. Because of the apparent absence of dose-related toxic effects in humans, cephaloridine was particularly useful in the treatment of patients with renal disease and infections due to susceptible bacteria.     

Acremonium strictum: Report of a Rare Emerging Agent of Cutaneous Hyalohyphomycosis with Review of Literatures

We present a case of cutaneous hyalohyphomycosis due to Acremonium strictum in an immunocompetent individual along with an overview of fungal infections caused by A. strictum. The diagnosis was confirmed by the presence of hyphae in microscopic examination of cutaneous biopsy and discharge, positive culture for A. strictum and sequencing of the isolate at reference centre. The infection resolved with itraconazole and terbinafine. Cutaneous or subcutaneous infections of A. strictum have rarely been reported. Fungemia or disseminated infection often with fatal outcome in immunocompromised patients was the most common presentation of A. strictum infection found in the literatures. The studies also reveal worldwide variation in the treatment regime and outcome of the treatment.     

Infecciones por mohos en el trasplante pulmonar

Invasive infections by molds, mainly Aspergillus infections, account for more than 10% of infectious complications in lung transplant recipients. These infections have a bimodal presentation: an early one, mainly invading bronchial airways, and a late one, mostly focused on lung or disseminated. The Aspergillus colonization at any time in the post-transplant period is one of the major risk factors. Late colonization, together with chronic rejection, is one of the main causes of late invasive forms. A galactomannan value of 0.5 in bronchoalveolar lavage is currently considered a predictive factor of pulmonary invasive infection. There is no universal strategy in terms of prophylaxis. Targeted prophylaxis and preemptive treatment instead of universal prophylaxis, are gaining more followers. The therapeutic drug monitoring level of azoles is highly recommended in the treatment. Monotherapy with voriconazole is the treatment of choice in invasive aspergillosis; combined antifungal therapies are only recommended in severe, disseminated, and other infections due to non-Aspergillus molds.     

Hsp21 Potentiates Antifungal Drug Tolerance in Candida albicans

Systemic infections of humans with the fungal pathogen Candida albicans are associated with a high mortality rate. Currently, efficient treatment of these infections is hampered by the relatively low number of available antifungal drugs. We recently identified the small heat shock protein Hsp21 in C. albicans and demonstrated its fundamental role for environmental stress adaptation and fungal virulence. Hsp21 was found in several pathogenic Candida species but not in humans. This prompted us to investigate the effects of a broad range of different antifungal drugs on an Hsp21-null C. albicans mutant strain. Our results indicate that combinatorial therapy targeting Hsp21, together with specific antifungal drug targets, has strong synergistic potential. In addition, we demonstrate that Hsp21 is required for tolerance to ethanol-induced stress and induction of filamentation in response to pharmacological inhibition of Hsp90. These findings might pave the way for the development of new treatment strategies against Candida infections.     

Clearance of asymptomatic P. falciparum Infections Interacts with the number of clones to predict the risk of subsequent malaria in Kenyan children

Background

Protective immunity to malaria is acquired after repeated infections in endemic areas. Asymptomatic multiclonal P. falciparum infections are common and may predict host protection. Here, we have investigated the effect of clearing asymptomatic infections on the risk of clinical malaria.

Methods

Malaria episodes were continuously monitored in 405 children (1–6 years) in an area of moderate transmission, coastal Kenya. Blood samples collected on four occasions were assessed by genotyping the polymorphic P. falciparum merozoite surface protein 2 using fluorescent PCR and capillary electrophoresis. Following the second survey, asymptomatic infections were cleared with a full course of dihydroartemisinin.

Results

Children who were parasite negative by PCR had a lower risk of subsequent malaria regardless of whether treatment had been given. Children with ≥2 clones had a reduced risk of febrile malaria compared with 1 clone after clearance of asymptomatic infections, but not if asymptomatic infections were not cleared. Multiclonal infection was associated with an increased risk of re-infection after drug treatment. However, among the children who were re-infected, multiclonal infections were associated with a shift from clinical malaria to asymptomatic parasitaemia.

Conclusion

The number of clones was associated with exposure as well as blood stage immunity. These effects were distinguished by clearing asymptomatic infection with anti-malarials. Exposure to multiple P. falciparum infections is associated with protective immunity, but there appears to be an additional effect in untreated multiclonal infections that offsets this protective effect.     

Babesia hylomysci and Babesia microti: Dexamethasone treatment of infected mice

The effect of dexamethason on Babesia hylomysci and B. microti was investigated in LACA mice. The drug enhanced both infections by depressing the immune mechanisms of the host when treatment was initiated before parasite inoculation, but had no effects on established and subpatent infections. The degree of parasitemia in the treated mice seemed to depend on the tropism of either parasite toward mature erythrocytes or reticulocytes. B. hylomysci, which favors mature erythrocytes, produced fulminating infections in treated mice. B. microti, which prefers reticulocytes, produced similar parasitemia patterns in treated and untreated mice, but only the treated mice succumbed to the infection. The drug, which suppressed cellular proliferation in the spleens of infected animals, together with its direct lympholytic effects, drastically changed the architecture of the organ.     

Plasmodium vivax sub-patent infections after radical treatment are common in Peruvian patients: results of a 1-year prospective cohort study

Background

There is an increasing body of literature reporting treatment failure of the currently recommended radical treatment of Plasmodium vivax infections. As P. vivax is the main malaria species outside the African continent, emerging tolerance to its radical treatment regime could have major consequences in countries like Peru, where 80% of malaria cases are due to P. vivax. Here we describe the results of a 1-year longitudinal follow up of 51 confirmed P. vivax patients living around Iquitos, Peruvian Amazon, and treated according to the Peruvian national guidelines.

Methodology

Each month a blood sample for microscopy and later genotyping was systematically collected. Recent exposure to infection was estimated by detecting antibodies against the P. vivax circumsporozoite protein (CSP) and all PCR confirmed P. vivax infections were genotyped with 16 polymorphic microsatellites.

Results

During a 1-year period, 84 recurrent infections, 22 positive also by microscopy, were identified, with a median survival time to first recurrent infection of 203 days. Most of them (71%) were asymptomatic; in 13 patients the infection persisted undetected by microscopy for several consecutive months. The genotype of mostly recurrent infections differed from that at day 0 while fewer differences were seen between the recurrent infections. The average expected heterozygosity was 0.56. There was strong linkage disequilibrium (I_A^s = 0.29, p<1.10⁻⁴) that remained also when analyzing only the unique haplotypes, suggesting common inbreeding.

Conclusion

In Peru, the P. vivax recurrent infections were common and displayed a high turnover of parasite genotypes compared to day 0. Plasmodium vivax patients, even when treated according to the national guidelines, may still represent an important parasite reservoir that can maintain transmission. Any elimination effort should consider such a hidden reservoir.     

Experimental phage therapy against lethal lung-derived septicemia caused by Staphylococcus aureus in mice

Nosocomial respiratory infections caused by methicillin-resistant Staphylococcus aureus (MRSA) can progress to lethal systemic infections. Bacteriophage (phage) therapy is expected to be effective against these critical infections. Previously, phage S13′ was proposed as a potential therapeutic phage. We here examined phage treatment in a mouse model of lung-derived septicemia using phage S13′. Intraperitoneal phage administration at 6 h postinfection reduced the severity of infection and rescued the infected mice. Phage S13′ can efficiently lyse hospital-acquired MRSA strains causing pneumonia-associated bacteremia in vitro. Thus, phage therapy may be a possible therapeutic intervention in staphylococcal lung-derived septicemia.     

Papel futuro de la micafungina en el tratamiento de las micosis invasoras por hongos filamentosos

BackgroundMicafungin is a echinocandin. It inhibits β-1,3-D-glucan synthesis, thus achieving fungicidal activity against virtually all Candida spp., including those resistant to fluconazole, and fungistatic activity against Aspergillus spp., as well as several but not all pathogenic molds. Results from in vitro studies, animal models, small clinical trials, hint at possible future indications such as invasive aspergillosis and empirical viantifungal therapy, although currently there is little information published.AimsTo describe published data of micafungin as treatment against invasive mold infections, specially analysing its role in the inmunodepressed host and critical care setting.MethodsA sistematic review of literature using the principal medical search engines was performed. Terms such as micafungin, aspergillosis, zygomycosis, invasive fungal infections, emerging fungal infections, antifungal treatment or therapy, antifungal prophylaxis, empiric or pre-emptive therapy were crossed. Febrile neutropenia patients were excluded.ResultsSeveral studies in these setting were identified and were described in this review. Although there were no blinded randomized clinical trials published, treatment or prophylaxis of invasive aspergillosis and other invasive mould infections with micafungin described in open clinical studies were analyzed.ConclusionsMicafungin could play a future important role as a primary or rescue therapy, alone or in combination, in the treatment or prophylaxis of invasive fungal infections caused by moulds. New randomized clinical trials are needed to confirm their efficacy.     

The influence of reduced susceptibility to fluoroquinolones in Salmonella enterica serovar Typhi on the clinical response to ofloxacin therapy

Background

Infection with Salmonella enterica serovar Typhi (S. Typhi) with reduced susceptibility to fluoroquinolones has been associated with fluoroquinolone treatment failure. We studied the relationship between ofloxacin treatment response and the ofloxacin minimum inhibitory concentration (MIC) of the infecting isolate. Individual patient data from seven randomised controlled trials of antimicrobial treatment in enteric fever conducted in Vietnam in which ofloxacin was used in at least one of the treatment arms was studied. Data from 540 patients randomised to ofloxacin treatment was analysed to identify an MIC of the infecting organism associated with treatment failure.

Principal Findings

The proportion of patients failing ofloxacin treatment was significantly higher in patients infected with S. Typhi isolates with an MIC≥0.25 µg/mL compared with those infections with an MIC of ≤0.125 µg/mL (p<0.001). Treatment success was 96% when the ofloxacin MIC was ≤0.125 µg/mL, 73% when the MIC was between 0.25 and 0.50 µg/mL and 53% when the MIC was 1.00 µg/mL. This was despite a longer duration of treatment at a higher dosage in patients infected with isolates with an MIC≥0.25 µg/mL compared with those infections with an MIC of ≤0.125 µg/mL.

Significance

There is a clear relationship between ofloxacin susceptibility and clinical outcome in ofloxacin treated patients with enteric fever. An ofloxacin MIC of ≥0.25 µg/mL, or the presence of nalidixic acid resistance, can be used to define S. Typhi infections in which the response to ofloxacin may be impaired.     

Submicroscopic Gametocytes and the Transmission of Antifolate-Resistant Plasmodium falciparum in Western Kenya

Background

Single nucleotide polymorphisms (SNPs) in the dhfr and dhps genes are associated with sulphadoxine-pyrimethamine (SP) treatment failure and gametocyte carriage. This may result in enhanced transmission of mutant malaria parasites, as previously shown for chloroquine resistant parasites. In the present study, we determine the association between parasite mutations, submicroscopic P. falciparum gametocytemia and malaria transmission to mosquitoes.

Methodology/Principal Findings

Samples from children treated with SP alone or in combination with artesunate (AS) or amodiaquine were genotyped for SNPs in the dhfr and dhps genes. Gametocytemia was determined by microscopy and Pfs25 RNA–based quantitative nucleic acid sequence–based amplification (Pfs25 QT-NASBA). Transmission was determined by membrane-feeding assays. We observed no wild type infections, 66.5% (127/191) of the infections expressed mutations at all three dhfr codons prior to treatment. The presence of all three mutations was not related to higher Pfs25 QT-NASBA gametocyte prevalence or density during follow-up, compared to double mutant infections. The proportion of infected mosquitoes or oocyst burden was also not related to the number of mutations. Addition of AS to SP reduced gametocytemia and malaria transmission during follow-up.

Conclusions/Significance

In our study population where all infections had at least a double mutation in the dhfr gene, additional mutations were not related to increased submicroscopic gametocytemia or enhanced malaria transmission. The absence of wild-type infections is likely to have reduced our power to detect differences. Our data further support the use of ACT to reduce the transmission of drug-resistant malaria parasites.     

Haloprogin: a Topical Antifungal Agent

Haloprogin was shown to be a highly effective agent for the treatment of experimentally induced topical mycotic infections in guinea pigs. Its in vitro spectrum of activity also includes yeasts, yeastlike fungi (Candida species), and certain gram-positive bacteria. The in vitro and in vivo antifungal activity of haloprogin against dermatophytes was equal to that observed with tolnaftate. The striking differences between the two agents were the marked antimonilial and selective antibacterial activities shown by haloprogin, contrasted with the negligible activities found with tolnaftate. Addition of serum decreased the in vitro antifungal activity of haloprogin to a greater extent than that of tolnaftate; however, diminished antifungal activity was not observed when haloprogin was applied topically to experimental dermatophytic infections. Based on its broad spectrum of antimicrobial activity, haloprogin may prove to be a superior topical agent in the treatment of dermatophytic and monilial infections in man.     

Influence of Schistosoma mansoni and Hookworm Infection Intensities on Anaemia in Ugandan Villages

BackgroundThe association of anaemia with intestinal schistosomiasis and hookworm infections are poorly explored in populations that are not limited to children or pregnant women.MethodsWe sampled 1,832 individuals aged 5–90 years from 30 communities in Mayuge District, Uganda. Demographic, village, and parasitological data were collected. Infection risk factors were compared in ordinal logistic regressions. Anaemia and infection intensities were analyzed in multilevel models, and population attributable fractions were estimated.FindingsHousehold and village-level predictors of Schistosoma mansoni and hookworm were opposite in direction or significant for single infections. S. mansoni was found primarily in children, whereas hookworm was prevalent amongst the elderly. Anaemia was more prevalent in individuals with S. mansoni and increased by 2.86 fold (p-value<0.001) with heavy S. mansoni infection intensity. Individuals with heavy hookworm were 1.65 times (p-value = 0.008) more likely to have anaemia than uninfected participants. Amongst individuals with heavy S. mansoni infection intensity, 32.0% (p-value<0.001) of anaemia could be attributed to S. mansoni. For people with heavy hookworm infections, 23.7% (p-value = 0.002) of anaemia could be attributed to hookworm. A greater fraction of anaemia (24.9%, p-value = 0.002) was attributable to heavy hookworm infections in adults (excluding pregnant women) as opposed to heavy hookworm infections in school-aged children and pregnant women (20.2%, p-value = 0.001).ConclusionCommunity-based surveys captured anaemia in children and adults affected by S. mansoni and hookworm infections. For areas endemic with schistosomiasis or hookworm infections, WHO guidelines should include adults for treatment in helminth control programmes.     

Vaginal versus Obstetric Infection Escherichia coli Isolates among Pregnant Women: Antimicrobial Resistance and Genetic Virulence Profile

Vaginal Escherichia coli colonization is related to obstetric infections and the consequent development of infections in newborns. Ampicillin resistance among E. coli strains is increasing, which is the main choice for treating empirically many obstetric and neonatal infections. Vaginal E. coli strains are very similar to extraintestinal pathogenic E. coli with regards to the virulence factors and the belonging to phylogroup B2. We studied the antimicrobial resistance and the genetic virulence profile of 82 E. coli isolates from 638 vaginal samples and 63 isolated from endometrial aspirate, placental and amniotic fluid samples from pregnant women with obstetric infections. The prevalence of E. coli in the vaginal samples was 13%, which was significant among women with associated risk factors during pregnancy, especially premature preterm rupture of membranes (p<0.0001). Sixty-five percent of the strains were ampicillin-resistant. The E. coli isolates causing obstetric infections showed higher resistance levels than vaginal isolates, particularly for gentamicin (p = 0.001). The most prevalent virulence factor genes were those related to the iron uptake systems revealing clear targets for interventions. More than 50% of the isolates belonged to the virulent B2 group possessing the highest number of virulence factor genes. The ampicillin-resistant isolates had high number of virulence factors primarily related to pathogenicity islands, and the remarkable gentamicin resistance in E. coli isolates from women presenting obstetric infections, the choice of the most appropriate empiric treatment and clinical management of pregnant women and neonates should be carefully made. Taking into account host-susceptibility, the heterogeneity of E. coli due to evolution over time and the geographical area, characterization of E. coli isolates colonizing the vagina and causing obstetric infections in different regions may help to develop interventions and avoid the aetiological link between maternal carriage and obstetric and subsequent puerperal infections.     

Invasive Fungal Infections in the Child with Chronic Granulomatous Disease

Invasive fungal infections (IFI) are a major threat for patients with chronic granulomatous disease (CGD) which is an inherited disorder of NADPH oxidase. The absence of a functional NADPH oxidase complex affects the display of an efficient antimicrobial effect as well as a controlled inflammatory response. Invasive aspergillosis caused by either Aspergillus fumigatus or A. nidulans is the most common IFI. Aspergillus nidulans infections seem to display a unique interaction with the CGD host and are seldom reported in other immunocompromised hosts. The occurrence of mucormycosis in the CGD host is mainly noted in the setting of treatment of inflammatory complications with immunosuppressive drugs. Candida infections are infrequently seen and show an age-dependent clinical presentation mainly affecting infants and young children. Furthermore, the child with CGD is susceptible to a wide range of fungal pathogens, indicating the need to determine the causative fungus, often by invasive diagnostic approaches, to guide optimal and rational treatment. Currently, it is becoming more and more clear that the exaggerated inflammatory response to fungal infection in the CGD host is leading in the pathogenesis, and antiinflammatory treatment might become as important as antifungal treatment in this specific host.     

‘Berenil’ and nitroimidazole combinations in the treatment of Trypanosoma brucei infection with central nervous system involvement

Three nitroimidazole compounds were tested for trypanocidal activity against early (3-day) T. brucei TREU 667 infections. Compound 1 (1-methyl-2-carbamoyl-oxy-methyl-5-nitroimidazole) at both 5 and 20 mg/kg given as four daily doses was ineffective, while Compound 2 (3-(1-methyl-5-nitroimidazole-2-yl)-3α, 4,5,6,7, 7α-hexahydro-1, 2-benz-isoxazole) at 4 × 80 mg/kg and Compound 3 (3-(1-methyl-5-nitroimidazole-2-yl)-4, 5-hexamethylene-Δ²-isoxazoline) at 4 × 20 mg/kg both elicited a permanent cure. When tested against late (21-day) infections of T. brucei 667 neither Compound 2 nor Compound 3 given singly, or in various combinations was effective in that parasitaemias returned rapidly in nearly all mice.When the trypanocidal drug ‘Berenil’ was administered followed by the Compound 3, the majority of the mice with a 21-day infection of T. brucei TREU 667 or T. brucei LUMP 1001 were cured permanently. When ‘Berenil’ alone was used the mice usually relapsed within a few weeks of treatment. The isolate used affected the outcome of the treatment. Higher dosages of ‘Berenil’ followed by Compound 3 were required to cure infections with T. brucei LUMP 1001 than with T. brucei TREU 667.The importance of these findings in the treatment of human sleeping sickness with central nervous system involvement is discussed.