Semi-mechanistic PK/PD modelling of combined polymyxin B and minocycline against a polymyxin-resistant strain of Acinetobacter baumannii.

OBJECTIVES: To expand on previous reports of synergy between polymyxin B (PMB) and minocycline (MIN) against Acinetobacter baumannii; and to gain insight into the qualitative and quantitative determinants of their synergy. METHODS: A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed on the basis of data from in vitro time-kill experiments with determination of resistant bacterial count to describe the effects of PMB and MIN alone and in combination. The model was enriched by complementary experiments providing information on the characteristics of the resistant subpopulation. RESULTS: The model successfully described the data and made possible quantification of the strength of interaction between the two drugs and formulation of hypotheses about the mechanisms of the observed interaction. The effect of the combination was driven by MIN, with PMB acting as an helper drug; simulations at clinically achievable concentrations showed that 1.5 mg/L MIN +0.2 mg/L PMB is expected to produce sustained killing over 30 hours, while 0.3 mg/L MIN +1 mg/L PMB is met by bacterial regrowth. Interaction equations showed that maximal synergy is reached for PMB concentrations ≥0.1 mg/L and MIN concentrations ≥1 mg/L. CONCLUSIONS: Semi-mechanistic PK/PD modelling was used to investigate the quantitative determinants of synergy between PMB and MIN on a PMB-resistant A. baumannii strain. The developed model, improving on usual study techniques, showed asymmetry in the drug interaction, as PMB acted mostly as a helper to MIN, and provided simulations as a tool for future studies.

[Pyomyositis caused by Staphylococcus aureus]. / Piomiositis por Staphylococcus aureus.

BACKGROUND: An evaluation of the clinical characteristics and profitability of the diagnostic methods of myositis by Staphylococcus aureus was undertaken in favor of earlier diagnosis and treatment. METHODS: Twenty-eight cases of pyomyositis by S. aureus attended over the last nine years were studied. Inclusion criteria were: 1) compatible clinical manifestations, 2) demonstration of an abscess in CT and/or surgery, 3) isolation of S. aureus in abscess, hemoculture and/or neighboring tissue. RESULTS: Age: 36 +/- 18 years (limits 9-70). Sex: 23 males (82%). Neighboring pathology existed in 11 cases (39%). 5 sacroiliitis (18%), 4 spondyliodiscitis, 2 osteomyelitis. Favoring/predisposing factors: intravenous drug addiction in 11, staphylococcal sepsis in 6, diabetes mellitus in 4, previous surgery in 3, penetrating muscle injury in 3, and parametritis in 1. Fourteen cases (50%) corresponded to primary pyomyositis. The muscle most frequently involved was the psoas/iliacpsoas, followed by near the forearm muscle, spinal, gluteal, and upper pectoral muscles. In 16 cases (57%), only one muscle was involved, in 10 two muscles, and in 2 three groups. The time of clinical manifestation prior to consultation oscillated between 1.5-30 days, being less in cases of primary pyomyositis (p less than 0.0005). All the patients referred fever and local pain, with functional impotence in 26 (93%), general involvement, shivering and perspiration in 24 (86%). All the patients presented pain upon palpation. In 19 (68%) there was an increase in local temperature and in 18 a palpable mass. S. aureus was isolated in 16 hemocultures (sensitivity 57%), in 12 of 13 cultures of neighboring tissue (92%) and in all those aspirated from abscesses (100%). CT demonstrated muscular (thickening and/or destructuration or abscess) and neighboring pathology (if existent) in all cases. All the patients received medical treatment. Evacuating puncture was carried out in 7 cases, and surgical drainage in 23 (82%). Two cases were cured exclusively with medical treatment. Complications were seen in 8 cases (29%) and two patients died of staphylococcal sepsis. CONCLUSIONS: 1) In myositis by Staphylococcus aureus the percentage of primary pyomyositis is considerable. 2) In secondary pyomyositis the most frequent neighboring processes were sacroiliitis and spondylitis. 3) intravenous drug addiction was the most frequent predisposing factor. 4) The time of clinical evolution is variable although less in case of primary pyomyositis. 5) The performance of hemocultures was found to be greater than described and even greater in primary pyomyositis. 6) Abscess cultures and CT are the most efficient microbiological and imaging techniques in the early diagnosis of myositis by S. aureus.

[Cryptococcosis of the central nervous system. Clinical and diagnostic characteristics]. / Criptococosis del sistema nervioso central. Características clínicas y diagnóstico.

BACKGROUND: Evaluation of the clinical features and diagnostic methods in the cryptococcosis of central nervous system (CNS), so as to facilitate a rapid recognition which may result in earlier diagnosis in view of the rapid increase in frequency shown in that condition. METHODS: A retrospective study of 13 patients with CNS cryptococcosis seen during the last 4 years. The isolation of C. neoformans in CSF, cerebral biopsy or other appropriate tissue was required for inclusion. The following were evaluated: 1) Age, sex, and underlying disease; 2) Clinical features; 3) Yield of biochemical, microbiological, pathological and imaging diagnostic procedures; 4) Treatment and evolution. RESULTS: Age (X +/- SD): 37 +/- 20 years (range: 15-81). Sex: 77% males. Underlying disease was identified in 10 cases (77%): HIV infection in 7 (54%), diabetes mellitus in 2, alcohol abuse in 2, systemic erythematous lupus on corticoid and immunosuppressant therapy in 1 and chronic liver disease in 1. Clinical features on admission: abnormal behaviour in 10 (77%), headache in 10, low/high grade fever in 9 (69%), abnormal consciousness in 7, respiratory features in 5 (38%); motor deficit, cranial nerve involvement and visual abnormalities in 4 (31%) each; and meningeal signs in 3. Investigation of CSF was carried out in 12 cases. The biochemical studies were normal in 5 (42%). China ink stain was positive in 55% of cases, and latex agglutination in 80%. CSF culture was diagnostic in 92% of cases and the culture for C. neoformans was positive in 2 cerebral and one pulmonary biopsies and in two urine cultures. All patients were treated with amphotericin B and flucytosine was associated in 9. Two patients were subsequently treated with fluconazole. The outcome was good in 8 patients, and 4 had sequelae. One case relapsed. CONCLUSIONS: 1) HIV infection is the most common underlying disease. 2) There is a high rate of CNS cryptococcosis with normal CSF or with mild biochemical abnormalities. 3) The yield of the microbiological studies of CSF is high, with diagnostic confirmation in 92% of cases. 4) Differences in CNS cryptococcosis were not found between cases with HIV infection and those with other underlying diseases.

[Cerebral hydatidosis. Analysis of a series of 23 cases]. / Hidatidosis cerebral. Análisis de una serie de 23 casos.

BACKGROUND: The aim of the present study was to contribute to the knowledge of cerebral hydatidosis so as to improve the prognosis of a benign condition with a malignant behavior, as it has a high relapse rate with a high morbidity. METHODS: A retrospective study of cerebral hydatidosis has been carried out in 23 patients, seen at the University Hospital Virgen del Rocío during the last 20 years. The following variables were recorded: 1) Sex and age at presentation; 2) epidemiological data; 3) number, size, localization and rate of growth of cysts; 4) latency period; 5) clinical features; 6) yield of imaging procedures; 7) surgical approaches and medical therapy; and 8) relapses and sequelae. A comparative study was made of patients aged 14 years or less and those above this age. RESULTS: The mean age of the patients was 15.1 +/- 10.3 years (65% were younger than 14 years). 24% were males. 65% came from Extremadura and 74% had a rural background. The latency period was 7.9 +/- 9.2 months (range 15 days-36 months), and it was shorter in children (4.2 +/- 3.8 vs 12.6 +/- 12.7 months) (p less than 0.05). 74% had a single cyst. The cyst size was greater in children (91 +/- 46 vs 67 +/- 35 mm), as it was the rate of growth, particularly in patients younger than 10 years (13.5 +/- 7 vs 9.2 +/- 2 mm/year) (p less than 0.001). 48% had intraparenchymal localization and 70% were in the right hemisphere. In two cases the localization was intraventricular and it was cerebellar in one. Cranial computed tomography was the imaging procedure with the highest yield. The diagnosis was confirmed with pathological examination. In 6 patients (26%) the Dowling and Orlando technique (hydatid delivery) was carried out without subsequent relapses. In 7 cases (30%), and owing to surgical technique difficulties or accidents, puncture and aspiration were carried out, with 4 relapses (57%). In 10 cases cyst rupture occurred, with 6 relapses (60%). The growth rate of the relapses was 9.4 +/- 6.5 mm/month. 87% had severe sequelae, associated with relapses and multiplicity, two patients died (9%). CONCLUSIONS: 1) Cerebral hydatidosis predominates in children and young adult males of a rural background; 2) usually there is a long latency period, which is shorter in children; 3) the size and the growth rate of the cysts is greater in children; 4) computed tomography is the imaging technique with the highest yield; 5) Dowling and Orlando technique is the most effective surgical procedure; 6) the incidence of relapses is high, depending on the type of surgical approach.

[Hydatidosis of the posterior fossa]. / Hidatidosis de fosa posterior.

The hydatid cyst is an endemic zoonosis in Spain. The central nervous system is seldom affected, the hydatid cyst in cerebellum being very rare. A patient with hydatid cyst affecting the vermis and right cerebellar hemisphere is presented. The case is described and discussed. The use of CT scan is encouraged as the most worthwhile election of diagnosis techniques. We highlight the need for very careful surgical treatment, preserving the hydatid cyst complete, to avoid relapses and to prevent the change of a benign disease to a chronic one with very high mortality.

[Arthritis and purulent pericarditis as presenting form of sepsis caused by serogroup C meningococcus]. / Artritis y pericarditis purulentas como forma de presentación de la sepsis por meningococo serogrupo C.

Meningococcal sepsis is usually a severe disease with very varied clinical manifestations. In our surrounding the most frequently appearing Neisseria meningitidis belongs to serogroup B, and only 10.2% belongs to group C. Both arthritis and exudative pericarditis are described as late, independent complications of N. Meningitidis C infections. The coexistence of both arthritis and suppurative pericarditis caused by this organism is extremely rare. A case of sepsis due to serogroup C N. Meningitidis in a patient who developed a right shoulder arthritis followed by septic shock and purulent pericarditis is presented. The characteristics of arthritis and pericarditis as complications of the acute meningococcal infection are analyzed, emphasizing the rareness of the coappearance of both as a form of clinical manifestation, as well as the purulent characteristic in order to keep them in mind and facilitate a prompt diagnosis and appropriate treatment.

[Curative treatment with fluconazole in 5 cases of invasive candidiasis]. / Tratamiento curativo con fluconazol en 5 casos de candidiasis invasiva.

BACKGROUND: Amphotericin B is the treatment of choice for invasive and disseminated Candida sp. infections. Fluconazole is an antifungal drug with less toxicity. Because of its pharmacokinetic properties, fluconazole can be specially useful in the treatment of invasive candidiasis. Although it is useful in several forms of candidiasis, its efficacy in deep-seated candidal infections is not totally proved due to the lack of comparative studies with amphotericin. In order to contribute new data about the usefulness of fluconazole in the treatment of invasive candidiasis, we report 5 patients which cured with this antifungal drug. METHODS: The clinical records of those patients with invasive candidiasis that cured with fluconazole were retrospectively reviewed. RESULTS: Fluconazole was used in 2 patients after detecting toxicity to amphotericin. Fluconazole was used from the beginning in the other 3 patients. None of the patients were neutropenic. All the patients cured without recurrence. CONCLUSIONS: In this series, the employment of fluconazole was a non-toxic and effective alternative to amphotericin B in nonneutropenic patients with invasive candidiasis.

Antibodies to antigen A60 in cerebrospinal fluid from patients with tuberculous meningitis.

Cerebrospinal fluid (CSF) anti-mycobacterial antigen 60 (A60) IgM, IgG and IgA in patients affected by meningitis of different etiologies were assayed as a rapid diagnostic test in cases of tuberculous meningitis. A commercial EIA was used to test 127 CSF samples classified as follows: tuberculous meningitis (n = 27 CSF samples from 16 patients, 6 of them with AIDS), pyogenic meningitis (n = 13), non-tuberculous aseptic meningitis (n = 43) and 44 normal CSF samples (16 of them from HIV-positive patients, 8 of whom had extraneurological tuberculosis). Anti-A60 IgM was positive only in two cases (1 tuberculous meningitis and 1 self-resolving aseptic meningitis). Positive CSF anti-A60 IgG and IgA were observed in eight and nine out of 16 patients with tuberculous meningitis, but only in four and five out of 13 samples studied prior to or in the first ten days of treatment, respectively. Most of the patients with false-positive IgG and IgA (16%) had pyogenic meningitis, but without intrathecal synthesis of antibodies. In patients with aseptic meningitis, the finding of CSF anti-A60 IgG plus IgA, initially or during follow-up, can be used as a diagnostic criterion for tuberculous meningitis, with a specificity of 100%, a positive predictive value of 1, and a negative predictive value of 0.81. However, its sensitivity is only 50% in immunocompetent patients and 16% in patients with AIDS.

[Primary pyomyositis in mild climates. Presentation of 2 new cases]. / Piomiositis primaria en climas templados. Aportación de dos nuevos casos.

Pyomyositis is an acute bacterial infection which affects striated muscles. It is a relatively rare process in mild climates. Staphylococcus aureus is responsible for 90-95% of cases. Klebsiella pneumoniae pyomyositis is extremely rare with only one other case reported in a mild climate. Two new cases of pyomyositis are described one caused by K. pneumoniae, increasing thus the etiology spectrum in our country, and the other caused by S. aureus ending in fatality, with two focus of pyomyositis (one of which was chronic) and multisystemic secondary affectation. We highlight the appearance of this process in our environment and the necessity to keep it in mind when making a differential diagnosis in order to recognize it and treat it as soon as possible since its prognosis depends on the moment the diagnosis is made.

[Bacteremia caused by Stenotrophomonas maltophilia: epidemiology, clinical features, and prognosis factors]. / Bacteriemias por Stenotrophomonas maltophilia: epidemiología, características clínicas y factores pronósticos.

The epidemiologic, clinical and prognostic characteristics of Stenotrophomonas maltophilia bacteremias for a six-year period (January 1993 to December 1998) were reviewed. Twenty episodes of S. maltophilia bacteremia were include, which represented 0.62% of all bacteremias caused by gram-negative rods during that period. Seventy percent of bacteremias were clinically significant. The most common predisposing factors were the previous use of antimicrobial agents and the presence of vascular catheters. In most cases (57%), the origin of bacteremia was the intravascular catheter. The course of patients was favorable and all patients cured.

Computed tomographic brain scan findings in Q fever encephalitis.

Neurological involvement in Q Fever is unusual. We present a case of encephalitis due to Coxiella Burnetii with neuroradiologic findings on CT not described previously, consisting in areas of decreased absorption coefficient in the subcortical white matter of both hemispheres, predominantly in the right. Differential diagnosis must be established from viral encephalitis, of similar clinical presentation, which may show similar CT lesions to those in this case.

[Multicenter study of tuberculosis in clinical autopsies in Andalucia, in the 1973-1988 period]. / Estudio multicéntrico de la tuberculosis en autopsias clínicas en Andalucía, en el período 1973-88.

We revised 6,863 protocols of clinical autopsies in four hospitals of the Andalusian Health Service, from 1973 to 1988, out of which 2,814 were valid, and finding 81 active tuberculosis cases (TBC) (2.87%), in 53 males and 28 females, with mean age of 54.41 years. Milliar forms (44 cases) predominated over non-milliar (37), with a premortem diagnosis in 32 cases. TBC was considered as the principal disease in 65.43%, it directed contributed to death in 59.26% of cases, and was associated to other diseases in 79.01% of cases. The most frequent localizations were lung (80.25%), lymph nodes (43.20%) and liver (37.04%). We compared two similar periods of time: 1978-80 and 1986-88, observing an increase in TBC in the latter, 14:22, which can be attributed to HIV infection, since 6 of the 22 cases were associated to this pathology.