Cloxacillin-induced acute vanishing bile duct syndrome: A case study and literature review.

Ductopenia is often regarded as a chronic process where ≥50% of portal tracts lack bile ducts, which is also known as vanishing bile duct syndrome (VBDS). One aetiology is drug-induced liver injury. Cloxacillin, an antistaphylococcal penicillin, typically causes "bland" cholestasis. We present the first case of cloxacillin-induced acute ductopenia or VBDS and a review of published cloxacillin-induced liver injuries. A 66-year-old woman with no prior liver disease, but known penicillin allergy, was treated for postcarotid angioplasty staphylococcal infection with 6 weeks of cloxacillin. She presented with a 2-week history of weakness and jaundice. Laboratory work-up showed elevated liver enzymes with a cholestatic pattern, hyperbilirubinemia and eosinophilia. She required ICU transfer for hypotension and was started empirically on prednisone. Liver biopsy revealed severe centrilobular cholestasis, mild necroinflammation and ductopenia with epithelial injury, but no ductular reaction. Two months later she was discharged on hydrocortisone and ursodiol with persistently elevated alkaline phosphatase and bilirubin. She was considered for liver transplantation but died of liver failure 4 months later. Four additional articles were found with histopathologic descriptions of cloxacillin-related liver injury. These included portal inflammation, cholestasis and mild necroinflammation. Clinical features were reported in two cases; both had mild symptoms with cholestatic liver enzymes and hyperbilirubinemia. Both patients recovered completely within 10-60 days. Cloxacillin-induced cholestasis can be secondary to acute ductopenia, which can result in worse clinical outcomes than previously described "bland" cholestasis. Liver biopsy is recommended to identify cases with acute VBDS.

Intravenously administered cloxacillin-induced neutropenia with eosinophilia in a patient with infective endocarditis: a case report.

BACKGROUND: Bacteremia following Staphylococcus aureus is a serious clinical condition which is often associated with distant metastatic infections. One of the most dreaded complications of Staphylococcus aureus bacteremia is infective endocarditis. Cloxacillin is a common antibiotic prescribed for suspected staphylococcal infections and confirmed methicillin-sensitive Staphylococcus aureus infections. Prolonged use of cloxacillin may lead to neutropenia. CASE PRESENTATION: A 38-year-old Sinhalese man presented to Teaching Hospital Kurunegala, Sri Lanka, complaining of a 3-week history of fever; he was found to have a pansystolic murmur over the apex of his heart. He had leukocytosis with predominant neutrocytosis. His C-reactive protein was 231 mg/l and erythrocyte sedimentation rate was 100 mm/first hour. Transthoracic two-dimensional echocardiography revealed prolapsed mitral valve with 7 × 13 mm vegetation over the posterior mitral valve. On the following day, three blood cultures became positive and were subsequently identified as Staphylococcus aureus. Intravenously administered cloxacillin 3 g 6 hourly was started. Following day 24 of intravenously administered cloxacillin, our patient developed high spike fever. His total white blood cells were: 990/mm3 with 34% neutrophils and 22% eosinophils. His hemoglobin concentration was 9.5 g/dL and platelet count remained normal (202 × 106/mm3). His C-reactive protein was 78 mg/l, erythrocyte sedimentation rate was 95 mm/first hour, and he was otherwise comfortable, showing no signs of sepsis beside the high grade fever. His serum was negative for filarial and Toxoplasma antibodies while stool was negative for oocytes and amoebic cysts. Further, his serum was negative for dengue virus, Epstein-Barr virus, cytomegalovirus, and hepatitis B antibodies. He was clinically well on day 6 after stopping cloxacillin with 44% neutrophils and 18% eosinophils. His C-reactive protein and erythrocyte sedimentation rate became normal, and there was no further plan for cardiothoracic intervention or administration of antimicrobials. He was discharged from hospital and remained well 6 months later. CONCLUSION: This case report signifies the potential fatal adverse effect of cloxacillin in methicillin-sensitive Staphylococcus aureus infections. Leukopenia is associated with prolonged use of high doses of cloxacillin. In addition to transthoracic two-dimensional echocardiography and inflammatory markers, sequential white blood cells and differential counts would help clinicians to assess the prognosis of patients with infective endocarditis.

Daptomycin versus placebo as an adjunct to beta-lactam therapy in the treatment of Staphylococcus aureus bacteremia: study protocol for a randomized controlled trial.

BACKGROUND: Staphylococcus aureus bacteremia is associated with significant morbidity and mortality. To treat this infection, the current standard of care includes intravenous anti-staphylococcal beta-lactam antibiotics and obtaining adequate source control. Combination therapy with an aminoglycoside or rifampin, despite early promise, can no longer be routinely recommended due to an absence of proven benefit and risk of harm. Daptomycin is a rapidly acting bactericidal antibiotic that is approved for the treatment of Staphylococcus aureus bacteremia as monotherapy but has not been shown to be superior to the current standard of care. As demonstrated in vitro, the addition of daptomycin to beta-lactam therapy may result in enhanced anti-staphylococcal activity. Our objective is to assess the efficacy and safety of prescribing the combination of daptomycin with cefazolin or cloxacillin for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia in adults. We hypothesize that adjunctive therapy with daptomycin will reduce the duration of bacteremia in this population. METHODS: The DASH-RCT trial is a randomized, double blind, placebo-controlled trial designed per the Standard Protocol Items: Recommendation for Interventional Trials (SPIRIT) and Consolidated Standards of Reporting Trials (CONSORT) guidelines. We recruit adults with confirmed MSSA bacteremia, at the McGill University Health Center. Patients are eligible if they are 18 years or older, can receive cefazolin or cloxacillin monotherapy, and are enrolled within 72 h of the first blood culture being drawn. Exclusion criteria include anaphylaxis to study drugs, having polymicrobial bacteremia, anticipated hospital admission for < 5 days, and healthcare team refusal. While receiving standard of care, study patients are randomized to a 5-day course of adjunctive daptomycin or placebo. The trial began in December 2016 and is expected to end in December 2018, after recruiting an estimated 102 patients. DISCUSSION: The DASH-RCT will compare the use of daptomycin as an adjunct to an anti-staphylococcal beta-lactam versus placebo in the treatment of MSSA bacteremia. We believe that a short course of dual therapy will result in earlier eradication of bacteremia and that subsequent research could evaluate effects on metastatic infection, relapse, and/or mortality. Ongoing issues in the trial include a delay between presentation of infection, enrollment in the trial, and the potential for unrecognized deep foci of infection at diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02972983 . Registered on 25 November 2016. Trial protocol: http://individual.utoronto.ca/leet/dash/dashprotocol.pdf.

Reposicionando la cloxacilina como antibioticoterapia empírica inicial de la sepsis tardía neonatal / Reinstating cloxacilin for empiric antibiotic in late-onset sepsis

Vancomycin has been used for more than 50 years in neonatal intensive care units (NICUs) as the therapy of choice for late-onset sepsis, mainly because Coagulase negative Staphylococci (CoNS) are common and mostly resistant to oxacyllin despitelow virulence and unusual association with fulminant sepsis. CUs due to several factors including its high pharmacokinetic variability, difficulty in reaching therapeutic plasmatic drug concentrations and progressively increasing minimum inhibitory concentrations (MIC). The increase of CoNS with higher MICs as well as the rise of infections caused by resistant gram-negative bacilli and candida should move to reconsider Vancomycin as first line treatment. Infections in neonates have a different behavior than in other populations and we consoder of utmost importance to consider the use of oxacyllin as first line antimicrobial therapy for late-onset sepsis.

Vancomicina se utiliza hace más de 50 años en unidades de cuidados intensivos neonatales (UCIN) como terapia de elección en sospecha de sepsis neonatal tardía; su principal indicación se fundamenta en que Staphylococcus coagulasa negativa (SCN) es el principal microorganismo que ocasiona sepsis tardía y éste es habitualmente resistente a cloxacilina; sin embargo, su virulencia es baja y la sepsis fulminante es inusual. Lamentablemente la prescripción de vancomicina se ha convertido en un grave problema en las UCIN, debido a diversas razones incluyendo: alta variabilidad farmacocinética del fármaco, dificultad en alcanzar concentraciones plasmáticas apropiadas y aumento de la concentración inhibitoria mínima (CIM), implicando además una mayor probabilidad de seleccionar cepas resistentes y aumento de otro tipo de infecciones ocasionadas por bacilos gramnegativos resistentes y candidiasis invasora. Considerando lo anteriormente señalado y a lo publicado en la literatura médica con respecto a las infecciones en neonatología, debido a su comportamiento clínico diferente a hospederos en otras etapas de la vida, resulta de suma importancia replantear el uso de vancomicina basado en fundamentos teóricos que avalen la seguridad de no utilizar este antimicrobiano como primera línea en sepsis neonatal tardía.

A probable clinically significant interaction between warfarin and cloxacillin: three case reports.

CASES: Three patients were admitted to the Imam Hospital, Tehran, Iran with a diagnosis of bacterial endocarditis. The patients had indications for valve replacement surgery and anticoagulant therapy. The administration of cloxacillin reduced the effect of warfarin, and subsequent increases in warfarin doses were unable to overcome this effect. CONCLUSION: A decrease in warfarin anticoagulation effects was detected in our three patients following cloxacillin therapy for infective endocarditis. Penicillinase-resistant penicillins remain essential antibiotics in the treatment of severe infections caused by Staphylococcus aureus due to their bactericidal activity, safety, and cost. Thus, in situations where anticoagulants are indicated in patients with infective endocarditis, it would be better to replace warfarin with low-molecular-weight or unfractionated heparin.

Reacciones adversas medicamentosas mucocutáneas en pacientes hospitalizados en servicio de medicina interna / Mucocutaneous adverse reactions to drugs in hospitalized patients of internal medicine service

Las reacciones adversas medicamentosas mucocutáneas (RAMM) son una de las manifestaciones más frecuentes de reacción adversa a medicamentos. Su incidencia según datos internacionales alcanza un 2 por ciento a 3 por ciento en pacientes hospitalizados. Nosotros investigamos la incidencia de RAMM en el Servicio de Medicina Interna del Hospital Base de la ciudad de Los Ángeles. En el período junio-septiembre de 2006 se hospitalizaron 1.052 pacientes, diagnosticándose 3 casos de RAMM que representan un 0,3 por ciento. Se identificaron los fármacos atribuibles a las RAMM, correspondiendo a cloxacilina, toxoide tetánico y drogas antituberculosas; éstas se compararon posteriormente con un grupo control. Los casos identificados fueron un rash morbiliforme, una reacción inflamatoria local tipo celulitis y un rash urticariforme. La incidencia obtenida fue más baja de lo esperado, atribuyéndose a las características de atención del centro estudiado.

Mucocutaneous adverse reactions to drugs (MCRD) are one of the most frequent manifestations of adverse drug reaction. Its incidence, according to international data, reaches 2 to 3 percent in hospitalized patients. We studied the incidence of MCRD in the Internal Medicine Service of the Base Hospital, located in the city of Los Angeles, Chile. 1,052 patients were hospitalized during the June-September 2006 period, and three cases of MCRD were diagnosed, representing 0.3 percent. The drugs causing to MCRD were cloxacilin, tetanic toxoid and antituberculosis drugs; these were later compared to a control group. The identified cases were morbiliform rash, a cellulitis-type local inflammatory reaction, and urticariform rash. The obtained incidence was lower than expected, attributed to the characteristics of the studied center.

Antibiotic associated diarrhoea: a controlled study comparing plain antibiotic with those containing protected lactobacilli.

Antibiotic associated diarrhoea is known to occur with broad spectrum antibiotics. Lactobacillus has been used for prophylaxis and therapy of this condition. In a double blind controlled study, the antibiotic containing ampicillin (250 mg) and cloxacillin (250 mg) with or without protected lactobacilli was evaluated in 740 patients undergoing cataract surgery. The incidence of diarrhoea in patients receiving plain antibiotic was 13.3% compared to 0.0% in patients receiving antibiotic with protected lactobacilli (p<0.001). The study demonstrates that antibiotic formulations containing protected lactobacilli maintain prophylactic effect of lactobacilli.

Histopathologic findings in drug-induced pemphigus.

Drug-induced pemphigus represents a diagnostic challenge, as usually no clinical feature differentiates it from its idiopathic counterpart. It was suggested recently that some histologic features may assist in diagnosing drug-associated diseases. The purpose of the study was to determine whether the histologic criteria suggested in the literature are specific enough to arouse suspicion of drug-induced pemphigus. Biopsy specimens of drug-induced and idiopathic pemphigus were reviewed by five dermatologists with no clinical data available about the patients. The sections were assessed to the presence of spongiosis with eosinophils, vacuolar degeneration, and the degree of acantholysis and cleavage level. Using the suggested criteria, the reviewers were unable to confirm a diagnosis of drug-induced pemphigus. It is advisable to consider drug etiology in every case of newly diagnosed pemphigus based on clinical criteria an detailed drug consumption history, as histologic features do not differentiate between drug-associated and idiopathic disease.

Isquemia aguda de la mano secundaria a la admmnistración intraarterial de cloxacilina / Hand acute ischemia secondary to the intraarterial administration of cloxaciline

La isquemia aguda de la mano, luego de la inyección intraarterial de medicamentoses un problema frecuente, de difícil manejo, y que requiere tratamiento médico urgente. Este reporte describe un caso de inyección inadvertido de cloxacilina en arteria humeral, con isquemia grave de mano, que llegó a la amputación digital. Se discute patogénesis y opciones de tratamiento

Estudio clínico comparativo de mupirocine tópico y cloxacilina oral en el tratamiento de infecciones cutáneas / Comparative clinique study of topical mupirocine and oral cloxacillin in the treatment of skin infections

Comparamos en un estudio randomizado la efectividad en el tratamiento de enfermedades cutáneas superficiales con mupirocine tópico y cloxacilina oral. Los resultados demostraron un a mejor respuesta con mupirocine, con 85,7 por ciento de eliminación bacteriana a la semana post-tratamiento versus un 54,5 por ciento con cloxacilina. No se reportaron efectos sistémicos colaterales con mupirocine excepto prurito y sensación de ardor

Cloxacillin-induced acute tubulo interstitial nephritis.

OBJECTIVE: To report a case of possible cloxacillin-induced acute tubulo interstitial nephritis (AIN). CASE SUMMARY: A 15-year-old male patient presented with hypertension, edema, lumbar pain, sterile pyuria, eosinophiluria (ten percent), and severe renal dysfunction three months after the ingestion of cloxacillin. A renal biopsy revealed diffuse edema and inflammatory infiltrate of the interstitium (five percent eosinophils). He received four sessions of peritoneal dialysis with dramatic improvement in urinary output and renal function. His biochemical parameters returned to normal values 21 days after admission, without the use of glucocorticosteroids. DISCUSSION: Published case reports on AIN induced by penicillin and related drugs are reviewed and compared. The role of interstitial edema in acute renal failure associated with drug-induced AIN is mentioned. CONCLUSIONS: AIN is a rare but significant complication of therapy with penicillin and related drugs. The clinical picture is similar for all of these drugs, but skin rash and fever are absent in AIN induced by cloxacillin and cloxacillin-related drugs. Dialysis improved the patient's urinary output and renal function. Beta-lactam antibiotics should be avoided in patients with cloxacillin-induced AIN.

Nephrotoxicity in isoxazolylpenicillin prophylaxis in hip surgery.

In 789 courses of antibiotic prophylaxis in hip arthroplasty surgery, either dicloxacillin (Diclocil) or cloxacillin (Ekvacillin) was used during two different time periods. The surgical methods, anesthesia, preoperative and postoperative care of the patients, and laboratory procedures were the same all the time. Changes in creatinine values were used as a method for evaluating the impact on renal function. When using dicloxacillin, a pathologic increase of creatinine was noted in 12 and 13 percent by two different calculation methods. Sixteen patients (4.2 percent) had a severe creatinine increase during the first postoperative week after dicloxacillin prophylaxis, requiring dialysis in 2 patients. Cloxacillin had only a marginal impact on renal function. Patients above aged 70 years were more vulnerable as regards renal function than younger persons, and the impairment was slightly dose related in all ages. In the dicloxacillin group, preoperative use of antiphlogistic drugs was correlated with reduced postoperative renal function.

Cefamandole and isoxazolyl penicillins in antibiotic prophylaxis of patients undergoing total hip or knee-joint arthroplasty.

In a prospective comparative clinical efficacy and safety study, 58 patients undergoing total hip or knee arthroplasty were randomly allocated to two groups; one received 29 cefamandole intravenously before operation and then 1 g every 6 h parenterally for 3 days and the other received 29 cloxacillin i.v. every 8 h for 1 day and 29 dicloxacillin perorally every 8 h for 2 days. Concentrations of cefamandole and cloxacillin were measured in the serum of all patients and in the synovial fluid of 28 patients. The serum C-reactive protein (CRP) level was measured in 16 randomly allocated patients preoperatively and daily for 8 days. In serum the concentrations of cefamandole and cloxacillin were high. The great variation in cloxacillin concentration can be due in part to its strong affinity for blood proteins. Cefamandole entered the synovial fluid of the knee joint at high concentrations in 5-15 min; similar concentrations of cloxacillin were measured after 16-30 min. Thus, cefamandole seems to be more recommendable as antibiotic prophylaxis in total hip and knee replacements. The CRP level decreased to below 60 mg/l in all 16 patients on the 6th postoperative day.

Henoch-Schönlein purpura complicating staphylococcal endocarditis in a heroin addict.

A 21-year-old heroin addict with right-sided staphylococcal endocarditis developed skin purpura, abdominal pain, bloody diarrhea, proteinuria and microscopic hematuria. Skin biopsy showed leukocytoclastic vasculitis with IgA deposits in dermal vessels and renal biopsy disclosed proliferative glomerulonephritis with granular mesangial IgA and fibrinogen deposition. These features are typical of Henoch-Schönlein purpura. Symptoms abated spontaneously. Since the syndrome appeared during cloxacillin therapy, both this drug or the infectious disease itself could have triggered the immune response. Henoch-Schönlein purpura is a distinct clinical entity that can complicate the course of staphylococcal endocarditis.

Use of macrophage inhibition factor and mast-cell degranulation tests for diagnosis of cloxacillin-induced cholestasis.

Cloxacillin-induced cholestasis was diagnosed with the help of the macrophage inhibition factor and mast-cell degranulation tests. The simultaneous occurrence of both immediate type as well as cell-mediated hypersensitivity to the drug suggested that a defect in the histamine-induced suppressor cells may underly this cloxacillin-induced allergic reaction.

Effect of high-dose ampicillin and cloxacillin on bleeding time and bleeding in open-heart surgery.

To determine if platelet dysfunction caused by high doses of penicillin compounds is of practical importance in patients with additional haemostatic defects perioperatively, a study was made of patients undergoing open-heart surgery. They were randomly assigned to prophylactic treatment with ampicillin 8 g plus cloxacillin 4 g daily for three days, or with cephalothin 8 g daily for three days. Fifty patients in each group were evaluated. The median bleeding time preoperatively and on days 1 and 4 postoperatively did not differ between the groups. The bleeding time was prolonged beyond the normal range in eight patients of the ampicillin/cloxacillin group and in three of the cephalothin group (p less than 0.05). Prolonged bleeding time was not associated with lower platelet count or greater blood loss. The total blood loss and the amounts of transfused blood, platelets and cryoprecipitate were all greater in the ampicillin/cloxacillin group, but the difference was not statistically significant. Combined use of ampicillin and cloxacillin in open-heart surgery is associated with increased bleeding, but the increase is without practical importance.