Burden of serious fungal infections in Guatemala.

Guatemala is a developing country in Central America with a high burden of HIV and endemic fungal infections; we attempted to estimate the burden of serious fungal infections for the country. A full literature search was done to identify epidemiology papers reporting fungal infections from Guatemala. We used specific populations at risk and fungal infection frequencies in the population to estimate national rates. The population of Guatemala in 2013 was 15.4 million; 40% were younger than 15 and 6.2% older than 60. There are an estimated 53,000 adults with HIV infection, in 2015, most presenting late. The estimated cases of opportunistic fungal infections were: 705 cases of disseminated histoplasmosis, 408 cases of cryptococcal meningitis, 816 cases of Pneumocystis pneumonia, 16,695 cases of oral candidiasis, and 4,505 cases of esophageal candidiasis. In the general population, an estimated 5,568 adult asthmatics have allergic bronchopulmonary aspergillosis (ABPA) based on a 2.42% prevalence of asthma and a 2.5% ABPA proportion. Amongst 2,452 pulmonary tuberculosis patients, we estimated a prevalence of 495 for chronic pulmonary aspergillosis in this group, and 1,484 for all conditions. An estimated 232,357 cases of recurrent vulvovaginal candidiasis is likely. Overall, 1.7% of the population are affected by these conditions. The true fungal infection burden in Guatemala is unknown. Tools and training for improved diagnosis are needed. Additional research on prevalence is needed to employ public health measures towards treatment and improving the reported data of fungal diseases.

The Diagnostic Laboratory Hub: A New Health Care System Reveals the Incidence and Mortality of Tuberculosis, Histoplasmosis, and Cryptococcosis of PWH in Guatemala.

BACKGROUND: A Diagnostic Laboratory Hub (DLH) was set up in Guatemala to provide opportunistic infection (OI) diagnosis for people with HIV (PWH). METHODS: Patients newly presenting for HIV, PWH not receiving antiretrovirals (ARVs) for >90 days but returned to care (Return/Restart), and PWH on ARVs with symptoms of OIs (ARV treatment) were prospectively included. Screening for tuberculosis, nontuberculous mycobacteria (NTM), histoplasmosis, and cryptococcosis was done. Samples were couriered to the DLH, and results were transmitted electronically. Demographic, diagnostic results, disease burden, treatment, and follow-up to 180 days were analyzed. RESULTS: In 2017, 1953 patients were included, 923 new HIV infections (an estimated 44% of all new HIV infections in Guatemala), 701 on ARV treatment, and 315 Return/Restart. Three hundred seventeen (16.2%) had an OI: 35.9% tuberculosis, 31.2% histoplasmosis, 18.6% cryptococcosis, 4.4% NTM, and 9.8% coinfections. Histoplasmosis was the most frequent AIDS-defining illness; 51.2% of new patients had <200 CD4 cells/mm3 with a 29.4% OI incidence; 14.3% of OIs in new HIV infections occurred with CD4 counts of 200-350 cells/mm3. OIs were the main risk factor for premature death for new HIV infections. At 180 days, patients with OIs and advanced HIV had 73-fold greater risk of death than those without advanced disease who were OI-free. CONCLUSIONS: The DLH OI screening approach provides adequate diagnostic services and obtains relevant data. We propose a CD4 screening threshold of <350 cells/mm3. Mortality remains high, and improved interventions are required, including expansion of the DLH and access to antifungal drugs, especially liposomal amphotericin B and flucytosine.

Can a clinical prediction tool guide HIV-testing decisions? Experience at a national hospital in Guatemala.

The USA and international recommendations no longer emphasize using risk factors to target groups for HIV-testing. Using a Guatemalan database of HIV tests, we developed a clinical prediction rule to guide decisions on HIV-testing. Prior to HIV-testing, data were collected on demographics, risk factors and prior testing. Based on a theoretical construct incorporating demographics, known HIV risk factors and symptoms, we developed a logistic regression model to predict HIV seropositivity. Between 2000 and 2005, 16,471 tests were performed, of which 19.8% were positive. The algorithm successfully predicted 1883 of 2489 HIV-positive tests (sensitivity 76%, likelihood ratio [LR]-positive 2.45) and 6282 of 9086 HIV-negative tests (specificity 69%, LR-negative 0.35). Although the model indices are robust, applying the model in a clinical setting would have little impact on improving selective testing practices. Our findings support current recommendations for universal HIV-testing, not selective testing based on risk factors. Before these recommendations can be adopted widely in Guatemala, treatment access needs to be assured and protections put in place for people diagnosed with HIV infection.

Comparative studies of two-times-daily versus three-times-daily indinavir in combination with zidovudine and lamivudine.

OBJECTIVES: To compare the efficacy and safety of two-times-daily versus three-times-daily indinavir in combination with zidovudine and lamivudine. DESIGN: Two multicenter, open-label, randomized 24-week studies. METHODS: Adults HIV-1 infection, HIV-1 RNA greater than 10000 copies/ml, and no prior lamivudine or protease inhibitor therapy were eligible. In a pilot study (Study A), patients received indinavir at 800 mg every 8 h, 1000 mg every 12 h, or 1200 mg every 12 h. In a subsequent study (Study B), patients received indinavir at 800 mg every 8 h or 1200 mg every 12 h. All subjects received zidovudine (300 mg) and lamivudine (150 mg) every 12 h. An intent-to-treat analysis was used. RESULTS: In Study A, which enrolled 88 patients, neither HIV-1 RNA nor CD4 cell responses differed significantly between treatment groups at 24 weeks when corrected for multiple comparisons. Study B enrolled 433 patients, but was prematurely discontinued when interim analysis suggested greater efficacy of three-times-daily indinavir. Of the first 87 patients reaching week 24, HIV-1 RNA was less than 400 copies/ml in 91% receiving three-times-daily versus 64% receiving two-times-daily indinavir (P < 0.01). CONCLUSION: Three-times-daily indinavir appears more efficacious than two-times-daily dosing when administered with zidovudine and lamivudine. Two-times-daily indinavir dosing should only be considered in situations characterized by favorable pharmacokinetic drug-drug interactions.

Nosocomial infection due to Vibrio cholerae in two referral hospitals in Guatemala.

We report nosocomial infection with Vibrio cholerae 01, in four seriously ill individuals and one infant in Guatemala. Nosocomial cholera occurs in developing countries in Latin America and should be suspected in hospitalized patients with diarrhea, especially during community outbreaks, in order to institute appropriate diagnostic, therapeutic, and control measures.

Epidemic gram-negative bacteremia in a neonatal intensive care unit in Guatemala.

BACKGROUND: Nosocomial bloodstream infection is an important cause of morbidity and mortality among neonates. From September 1 through December 5, 1990 (epidemic period), gram-negative bacteremia developed in 26 neonates after their admission to the neonatal intensive care unit (NICU) of Hospital General, a 1000-bed public teaching hospital in Guatemala with a 16-bed NICU. Twenty-three of the 26 patients (88%) died. METHODS: To determine risk factors for and modes of transmission of gram-negative bacteremia in the NICU, we conducted a cohort study of NICU patients who had at least one blood culture drawn at least 24 hours after admission to the NICU and performed a microbiologic investigation in the NICU. RESULTS: The rate of gram-negative bacteremia was significantly higher among patients born at Hospital General, delivered by cesarian section, and exposed to selected intravenous medications and invasive procedures in the NICU during the 3 days before the referent blood culture was obtained. During the epidemic period, the hospital's chlorinated well-water system malfunctioned; chlorine levels were undetectable and tap water samples contained elevated microbial levels, including total and fecal coliform bacteria. Serratia marcescens was identified in 81% of case-patient blood cultures (13/16) available for testing and from 57% of NICU personnel handwashings (4/7). Most S. marcescens blood isolates were serotype O3:H12 (46%) or O14:H12 (31%) and were resistant to ampicillin (100%) and gentamicin (77%), the antimicrobials used routinely in the NICU. CONCLUSIONS: We hypothesize that gram-negative bacteremia occurred after invasive procedures were performed on neonates whose skin became colonized through bathing or from hands of NICU personnel.

Treatment of mycoses with itraconazole.

The efficacy of itraconazole, a new oral triazole, was evaluated at doses of 50-400 mg/day in 64 courses: 39 with coccidioidomycosis, and 25 with other mycoses. Among patients with coccidioidomycosis, 21 had pulmonary disease; 10, bone and joint; 8, lymphatic; 6, skin and soft tissue; 3, meningeal; and 1, urogenital. After a mean of 7.1 months of treatment, 17 of 27 evaluable courses (63%) have shown a full response; 8 (30%), a partial response; and 2 (7%), no response. Response to treatment was higher in patients with a shorter duration of illness and in patients with no previous treatment. After a mean of 12 months of treatment, two of five responders off therapy have relapsed. In patients with other mycoses, diagnoses include aspergillosis in six patients; histoplasmosis and tinea in three each; alternariosis, candidiasis, cryptococcosis, blastomycosis, and chromomycosis in two each; and pseudallescheriosis in one. After a mean of 9.4 months of treatment, 14 of 23 evaluable patients (61%) have shown a full response; 2 (8%), a partial response; and 7 (30%), no response. All patients with histoplasmosis and blastomycosis have responded to therapy. There are no relapses among five evaluable responders after a mean of 9.2 months off therapy. In 512 patient months of therapy, toxicity has been minimal. Mean serum levels in patients receiving 200 mg twice daily range from 3.9 to 5.9 micrograms/ml for 8 hr after dosing, with a peak at 7 hr and wide interpatient variability. Itraconazole is well tolerated and has continued to demonstrate efficacy in the treatment of a variety of systemic and superficial mycoses.

Effects of once-daily darunavir/ritonavir versus lopinavir/ritonavir on metabolic parameters in treatment-naive HIV-1-infected patients at week 96: ARTEMIS.

In the ARTEMIS trial, 689 treatment-naïve, HIV-1-infected adults received darunavir/ritonavir (DRV/r) 800/100 mg every day or lopinavir/ritonavir (LPV/r) 800/200 mg total daily dose plus fixed-dose tenofovir/emtricitabine. Week 96 metabolic parameters are reported. Adverse events (AEs) classed as metabolism/nutrition disorders were observed in 14% of DRV/r and 22% of LPV/r patients. Lipid-related AEs were reported in fewer DRV/r (8%) than LPV/r (16%) patients. A small increase in glucose and insulin levels was observed at week 96 in both groups. Lipoma was the only lipodystrophy-related AE reported in >1% of patients (DRV/r, n = 1; LPV/r, n = 4) and no grade 3 or 4 lipodystrophy-related AEs were reported. No clinically relevant changes from baseline were seen in anthropometric measurements in either group. Median mid-waist/hip ratio at week 96 was comparable to baseline in both arms. Over 96 weeks, DRV/r had a similar effect on glucose and insulin levels but a more favourable lipid profile than LPV/r in treatment-naïve, HIV-infected patients.

A cross-sectional study of risk factors for HIV among pregnant women in Guatemala City, Guatemala: lessons for prevention.

Although the Central American HIV epidemic is concentrated in high-risk groups, HIV incidence is increasing in young women. From 2005 to 2007, we conducted a cross-sectional study of pregnant women in a large public hospital and an HIV clinic in Guatemala City to describe risk factors for HIV infection and inform prevention strategies. For 4629 consenting patients, HIV status was laboratory-confirmed and participant characteristics were assessed by interviewer-administered questionnaires. Lifetime number of sexual partners ranged from 1 to 99, with a median (interquartile range) of 1 (1, 2). 2.6% (120) reported exchanging sex for benefits; 0.1% (3) were sex workers, 2.3% (106) had used illegal drugs, 31.1% (1421) planned their pregnancy and 31.8% (1455) experienced abuse. In logistic regression analyses, HIV status was predicted by one variable describing women's behaviour (lifetime sexual partners) and three variables describing partner risks (partner HIV+, migrant worker or suspected unfaithful). Women in our sample exhibited few behavioural risks for HIV but significant vulnerability via partner behaviours. To stem feminization of the epidemic, health authorities should complement existing prevention interventions in high-risk populations with directed efforts towards bridging populations such as migrant workers. We identify four locally adapted HIV prevention strategies.

Clinical efficacy of echinocandin antifungals.

The prevalence of fungal infections has increased significantly over the past few decades. Candida and Aspergillus spp. are the most common fungal pathogens due to recent changes in medical technology. Amphotericin B continues to be the treatment of choice in many severe disseminated mycosis cases, but problems with toxicity, resistance and non-availability of an absorbable oral form are important drawbacks. The azoles offer a less toxic alternative but often they are not as effective as amphotericin B and resistance is an increasing problem. The echinocandins are new active antifungal agents with a novel mechanism of action. During the past year, one agent has been released and two others are undergoing advanced stages of investigation. Although these agents are not the ideal antifungal drug, they do offer new options of therapy.

Initial experience in therapy for progressive mycoses with itraconazole, the first clinically studied triazole.

The search for antifungal drugs, particularly oral agents with a broad spectrum of activity, led to the study of itraconazole, a triazole. In vitro susceptibility testing suggested activity against a variety of fungal pathogens affecting humans. Pharmacokinetic studies indicated absorption after oral administration to patients, with prolonged serum concentrations and peak levels exceeding the in vitro inhibitory concentrations for most pathogens. Twenty-four patients have been enrolled in efficacy studies; two-thirds of these individuals had experienced a relapse after apparently successful therapy with other drugs, had failed to respond to other drug therapy, and/or had experienced intolerable side effects with other drugs. Fourteen patients have thus far responded to treatment with itraconazole; this group includes two persons each with coccidioidal pneumonia and adenopathy, pulmonary coccidioidomycosis, and dermatophytosis plus onychomycosis as well as one person each with coccidioidal epididymitis, adrenal histoplasmosis, head and neck histoplasmosis, cutaneous blastomycosis, oral-sinonasal alternariosis, chromoblastomycosis, invasive pulmonary aspergillosis with fungus ball, and onychomycosis. Five other patients have had partial responses to therapy, three have failed to respond, and two have been deemed unassessable. Drug toxicity has been limited in 211.8 patient-months of therapy. The results are encouraging and indicate that more extensive studies are warranted.

Infections due to Achromobacter xylosoxidans. Case report and review of the literature.

Achromobacter xylosoxidans is an uncommon nosocomial pathogen known to cause many serious infections. A 69-year-old woman with diabetes mellitus and chronic renal failure was admitted with pulmonary edema. The patient developed fever and pulmonary infiltrate with bilateral pleural effusions while she was on a respirator in the intensive care unit. Culture of sputum, pleural fluid and blood grew A. xylosoxidans. Bilateral chest tubes were inserted and the patient was treated for one month with piperacillin and trimethoprim-sulfamethoxazole. Gradual response, both clinically and radiologically, was noted after prolonged therapy. A review of the literature on infections due to A. xylosoxidans, the unique susceptibility pattern of the organism to various antibiotics and the use of combination therapy in Achromobacter infections are discussed.

Efficacy of itraconazole in blastomycosis in a murine model and comparison with ketoconazole.

Mice were infected intranasally with B. dermatitidis yeasts, and after infection treated orally. Itraconazole 50-150 mg/kg/day was protective (prolonged survival) against lethal infection, although the infection was not sterilized. Itraconazole was approximately 3 times as potent as ketoconazole. These results suggest advantages for itraconazole therapy clinically.

The epidemiologic patterns of drug-resistant Mycobacterium tuberculosis infections: a community-based study.

A community-based study of tuberculosis in Santa Clara County, California was conducted in order to identify community-specific determinants of drug-resistant Mycobacterium tuberculosis infections. From January 1984 through December 1986, 517 verified cases of tuberculosis were reported from the county. Drug susceptibility test results to isoniazid, streptomycin, ethambutol, and rifampin were available for 256 of the 517 cases. The frequency of resistance of M. tuberculosis isolates to one or more drugs was 27% for all cases and 25% for those who had had no previous antituberculosis treatment. Isolates from Asian immigrants had the highest frequencies of resistance (33 to 45%), and the Southeast Asian immigrants had a drug-resistant tuberculosis case rate greater than 30/100,000 population per year. In patients who had cavitary lung disease and who had a previous history of tuberculosis, drug-resistant tuberculosis was 3.5 times as likely to occur than in persons who had neither of these characteristics (p less than 0.001). For such patients, the positive predictive value of isolating resistant M. tuberculosis approached 90%. We believe these community-based findings will guide clinical and public health interventions specifically appropriate for the community.

[Women of Guatemala City: facilitating AIDS prevention in a vulnerable group]. / Mujeres de la Ciudad de Guatemala: facultando a un grupo vulnerable para la prevencion del SIDA.

PIP: Despite the mistaken belief in Central America that AIDS is primarily a disease of male homosexuals, some 21% of reported cases in Guatemala have been women 15-44 years old. Many Guatemalan women are at risk of AIDS and other sexually transmitted diseases (STDs) because of their lack of sexual bargaining power and negotiating skills, the widespread acceptance of male infidelity in marriage, tolerance of bisexual relations and frequenting of prostitutes, and ignorance of women about sexuality. Condom use is infrequent in Guatemala. Most men and women lack knowledge of AIDS and other STDs and have no perception of their own vulnerability. Male alcohol use and violence against women diminishes the ability of women to protect themselves. Sex education and information about STDs should be provided for both men and women to slow the spread of AIDS. AIDS educators should direct their messages to women toward promoting condom use, increasing knowledge of AIDS and STDs, providing basic sex education, questioning stereotypes of AIDS patients as persons with disordered lifestyles, encouraging realistic assessment of risks, and assisting women to increase their negotiating ability in sexual relations. Three crucial ways of helping women protect themselves are by making them aware of the influence of gender roles in their reproductive lives, teaching them communication and negotiating skills, and providing strategies for them to confront alcohol abuse and gender violence. Survey results indicate that Guatemalan women were extremely motivated to protect their children and secondarily to maintain their homes and be good wives. Motivational messages for AIDS prevention should be related to children and the family. Men were found to be concerned about their families as well and to fear the stigma of HIV infection. Educational techniques for AIDS prevention should be accessible to the illiterate and should focus on life stories or similar methods that make AIDS seem less abstract to those who have had no direct experience with the disease.^ieng

Efficacy of short courses of oral novobiocin-rifampin in eradicating carrier state of methicillin-resistant Staphylococcus aureus and in vitro killing studies of clinical isolates.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important nosocomial infection problem. Colonization appears to be more common than invasive disease is. Eradication of colonization or the carrier state could limit the spread of MRSA, thus reducing the potential for mortality and morbidity in other patients. The detection of patients with MRSA infection in a rehabilitation ward led to a study of the combination of novobiocin-rifampin in vivo and in vitro. We found that 300 mg of rifampin plus 500 mg of novobiocin orally twice daily for 5 days, in 18 courses of treatment given to 12 patients, resulted in the clearing of MRSA in 79% of the evaluable courses and 81% of the evaluable sites. A second course cleared MRSA from one of the patients with a treatment failure. Side effects were not noted. All 18 pretherapy isolates were susceptible to either drug in vitro, but 1 of 2 posttherapy isolates was rifampin resistant. Timed-kill studies demonstrated that the rate of killing was the same with either drug alone or both drugs together. Pretherapy isolates from treatment successes or failure were killed at the same rate by the drug combination. However, with the rifampin-resistant isolate killing ceased after 48 h. Results of this study suggest that previously untreated patients are likely to have isolates that are susceptible to the combination of drugs and that the combination is commonly effective in eradicating MRSA carriage. Since the regimen is orally administered, and thus convenient, in conjunction with other measures it has the promise of reducing the spread of MRSA in hospitals.

A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis.

Caspofungin is a new broad-spectrum antifungal drug. A multicenter, double-blind, randomized trial was conducted to assess the efficacy, safety, and tolerability of caspofungin relative to amphotericin B in adults with endoscopically documented symptomatic Candida esophagitis. By use of a modified intent-to-treat analysis, endoscopically verified clinical success was achieved in 74% (95% confidence interval [CI], 59%-86%) and 89% (95% CI, 72%-98%) of patients receiving caspofungin at 50 and 70 mg/day, respectively, and in 63% (95% CI, 49%-76%) of patients given amphotericin B at 0.5 mg/kg/day. Therapy was stopped because of drug-related adverse events in 24% of patients in the amphotericin B group and 4% and 7%, respectively, for the caspofungin groups. This report provides the first demonstration of clinical utility for an echinocandin compound. Caspofungin appeared in this study to be as effective as and better tolerated than amphotericin B for the treatment of esophageal candidiasis.

Itraconazole therapy for nonmeningeal coccidioidomycosis: clinical and laboratory observations.

Itraconazole, a new oral triazole antifungal agent, was administered in 75 courses to patients with chronic coccidioidomycosis at dosages of 50 to 400 mg/day for a median duration of 10 months. Assessment of efficacy was made with a standardized scoring system. Responses were seen in 42 of 58 assessable courses (72%). Nonresponse occurred exclusively in patients who had failed previous therapy and was most common in pulmonary disease. Toxicity was minimal at the doses studied. Pharmacokinetic analysis of itraconazole in serum at steady state showed negligible circadian variation; differences in serum concentrations among patients were large. Clinical isolates of Coccidioides immitis showed uniform in vitro susceptibility to itraconazole. Itraconazole shows impressive activity in this series of patients with refractory coccidioidomycosis. Further evaluation of itraconazole in this and in other systemic mycoses is in order.

New targets and delivery systems for antifungal therapy.

Development of new approaches for treatment of invasive fungal infections encompasses new delivery systems for approved and investigational compounds, as well as exploiting the cell membrane, cell wall and virulence factors as putative antifungal targets. Novel delivery systems consisting of cyclodextrins, cochleates, nanoparticles/nanospheres and long circulating ('stealth') liposomes, substantially modulate the pharmacokinetics of existing compounds, and may also be useful to enhance the delivery of antifungal agents to sites of infection. Further insights into the structure-activity relationship of the antifungal triazoles that target the biosynthesis of ergosterol in the fungal cell membrane have led to the development of highly potent broad spectrum agents, including posaconazole, ravuconazole and voriconazole. Similarly, a novel generation of cell-wall active semisynthetic echinocandin 1,3 beta-glucan inhibitors (caspofungin, FK463, and VER-002) has entered clinical development. These agents have potent and broad-spectrum activity against Candida spp, and potentially useful activity against Aspergillus spp. and Pneumocystis carinii. The ongoing convergence of the fields of molecular pathogenesis, antifungal pharmacology and vaccine development will afford the opportunity to develop novel targets to complement the existing antifungal armamentarium.