Broad-spectrum Antimicrobial Therapy Research Articles

Determining duration of antibiotic use in children with complicated appendicitis.

The introduction of broad spectrum antibiotics has substantially decreased rates of mortality and morbidity associated with complicated appendicitis in children. The generally recommended therapy for children with complicated (gangrenous or perforated) appendicitis is administration of postoperative antibiotics for 3 to 14 days, but the decision as to the specific duration of treatment lies with the treating physician. This study evaluates whether the recommendation that the combination of the patient's being afebrile and eating and having a normal white blood cell (WBC) count and < or = 3% band forms can be used to decide when sufficient antibiotics have been given and can be safely discontinued. Thirty-three consecutive patients seen in the pediatric surgical service with perforated or gangrenous appendicitis were studied prospectively. All patients received a standard protocol of resuscitation, appendectomy and broad spectrum antimicrobial therapy to be continued until they were eating, afebrile and had normal white blood cell counts with < or = 3% immature neutrophils (band forms). Thirty-two children were treated until they met all criteria when antibiotics were stopped and the patients were discharged. Of these patients 31 had unremarkable courses of recovery with no development of intraabdominal abscess or wound infection [predictive value of criteria, 97% (31 of 32)]. The remaining patient who met the criteria required rehospitalization for treatment of intraabdominal abscess. Another patient was discharged prematurely when he failed to meet the criterion of afebrility. Although he was eating and his WBC count was normal, he had a temperature of 38.5 degrees C during the 24 h before discharge. He was readmitted for surgical drainage of an intraabdominal abscess, yielding a 100% predictive value for the criterion mismatch (1 of 1). Based on our observations, when a patient with complicated appendicitis is afebrile for 24 h (temperature < 38 degrees C), is eating and has a WBC count with < or = 3% band forms, antibiotics can be safely discontinued with small risk of recurrent intraabdominal abscess.

Contemporary antimicrobial susceptibility patterns of bacterial pathogens commonly associated with febrile patients with neutropenia.

One of the most challenging problems in antimicrobial chemotherapy is the effective empirical treatment of infection in patients with neutropenia. The rates of occurrence for pathogens have significantly changed (from predominance of gram-negative to gram-positive organisms) under selective pressure of broad-spectrum antimicrobial therapy or prophylaxis, and novel resistance mechanisms have emerged. To address the need for appropriate monotherapy or combination regimens for patients with neutropenia, physicians must prescribe agents with a spectrum of antimicrobial activity to inhibit the major, prevalent pathogens encountered in bloodstream infection and pneumonia; in addition, these selected agents must be active against recently described resistant organisms. Data from the SENTRY Antimicrobial Surveillance Program indicate that several broad-spectrum agents remain highly active and can be used alone or in combinations. In most cases, the newer compounds with increased activity and spectrum against gram-positive cocci (i.e., carbapenems, cefepime, levofloxacin, and trovafloxacin) offer a greater inhibitory potential for empirical therapy among patients with neutropenia and severe infections.

Fournier’s Gangrene: Risk Assessment and Enzymatic Debridement with Lyophilized Collagenase Application

Objectives: Fournier’s gangrene (FG) is an abrupt, rapidly progressive, gangrenous infection of the external genitalia, perineum or abdominal wall and is a real urologic emergency. In this study, the risk factors of FG and the effects of enzymatic debridements on wound healing were investigated. Patients and Methods: We reviewed the records of 34 patients with FG to investigate the possible correlation between clinical outcome and infection focus, patient age, number of types of bacteria cultured, delay until presentation, predisposing diseases or accompanying conditions such as diabetes, neurologic deficit, chronic alcoholism and renal failure. Broad-spectrum triple antimicrobial therapy, aggressive and frequent surgical debridement, and if necessary urinary and colonic diversions were performed to control the infection. The effects of enzymatic debridements with topical lyophilized collagenase applications on the wound healing after the control of active infection were evaluated. Results: The average age of the patients was 55 years. The sources of infections were urogenital in 12 (35.3%), anorectal in 10 (29.4%), dermal in 10 (29.4%) and undetermined in 2 (5.8%) of the patients. The average presentation time was 4.4 days and the number of isolated bacteria was 3.05 per case. The number of isolated bacteria and surgical debridements, the duration of hospital stay and the rate of mortality in patients with anorectal foci were higher than those of the patients with urogenital or dermal foci (p < 0.05). Diabetes, uremia and advanced age did not significantly affect the number of surgical debridements, the duration of hospital stay and control of active infection. Mortality was increased in chronic alcoholism, a finding of undetermined significance. Enzymatic debridements decreased the duration of hospital stay (p < 0.05). Five patients (14.7%) died despite prompt medical and surgical preventive measures. Conclusion: Chronic alcoholism, anorectal infection foci, neurological deficit and delayed presentation were found as risk factors in FG. Diabetes and advanced age did not affect the progression of disease in our cases. Enzymatic debridements decrease the number of surgical debridements and the duration of hospital stay.

Mycoses of the urogenital tract.

Mycotic infections of the urogenital tract are rarely caused by primary fungal pathogens, often however, by opportunistic fungi such as Candida species. Opportunistic fungi infect the urogenital tract either by haematogenous spread from a distant site, or a break of tissue integrity, or by retrograde ascension from the perianal region, or by wound contamination. After an initial polymorphonuclear reaction macrophages may invade giving rise to a granulomatous response. Risk factors for mycotic urogenital infections are extremes of age, long lasting and broad spectrum antimicrobial therapy, diabetes mellitus, immunosuppression, malignancy, x-ray therapy, contaminated i.-v. catheters, oral contraceptives, pregnancy, surgery, obstructive uropathy and indwelling urethral catheters.

Necrotizing Fasciitis After Cesarean Delivery

In Brief Objective To review our experience with the diagnosis and management of necrotizing fasciitis after cesarean delivery. Methods We reviewed medical records of women with serious post-cesarean wound infections at the University of Alabama at Birmingham between 1987 and 1994 to identify women with necrotizing fasciitis. The diagnosis of necrotizing fasciitis required intraoperative identification of necrotic fascia in febrile women undergoing post-cesarean wound debridement. Results During the study period, 5048 women had cesarean deliveries, nine of which were complicated by necrotizing fasciitis. The mean (± standard deviation) maternal age was 27 ± 6 years, and the mean maternal weight was 199 ± 64 Ib. None of the patients had insulin-dependent diabetes mellitus, and none had known peripheral vascular disease. There were no intraoperative complications at cesarean delivery. The mean time from cesarean delivery to the diagnosis of necrotizing fasciitis and reoperation was 10 ± 4 days (range 5–17). All patients had surgical debridement upon consideration of the diagnosis, and all received broad-spectrum antimicrobial therapy. Results of wound cultures were available in seven of the women, and all seven were found to have polymicrobial infections. There were two mortalities, one as a result of metastatic breast cancer and another with complications of sepsis. Conclusion Necrotizing fasciitis is infrequent (1.8 per 1000 women) after cesarean delivery at our institution, but it does result in appreciable morbidity and mortality. Necrotizing fascitis following cesarean delivery is uncommon but is associated with major morbidity and mortality.

Necrotizing fasciitis after cesarean delivery

To review our experience with the diagnosis and management of necrotizing fasciitis after cesarean delivery. We reviewed medical records of women with serious post-cesarean wound infections at the University of Alabama at Birmingham between 1987 and 1994 to identify women with necrotizing fasciitis. The diagnosis of necrotizing fasciitis required intraoperative identification of necrotic fascia in febrile women undergoing post-cesarean wound debridement. During the study period, 5048 women had cesarean deliveries, nine of which were complicated by necrotizing fasciitis. The mean (+/-standard deviation) maternal age was 27 +/- 6 years, and the mean maternal weight was 199 +/- 64 lb. None of the patients had insulin-dependent diabetes mellitus, and none had known peripheral vascular disease. There were no intraoperative complications at cesarean delivery. The mean time from cesarean delivery to the diagnosis of necrotizing fasciitis and reoperation was 10 +/- 4 days (range 5-17). All patients had surgical debridement upon consideration of the diagnosis, and all received broad-spectrum antimicrobial therapy. Results of wound cultures were available in seven of the women, and all seven were found to have polymicrobial infections. There were two mortalities, one as a result of metastatic breast cancer and another with complications of sepsis. Necrotizing fasciitis is infrequent (1.8 per 1000 women) after cesarean delivery at our institution, but it does result in appreciable morbidity and mortality.

Outpatient Antimicrobial Protocol for Febrile Neutropenia: A Nonrandomized Prospective Trial Using Ceftriaxone, Amikacin, and Oral Adjuvant Agents

Broad-spectrum antimicrobial therapy has revolutionized the management of febrile neutropenia (FN) in cancer patients. In vogue is an effective therapy on an outpatient basis. One thousand three hundred episodes of FN observed in 70 pediatric solid tumors (STs) and 65 cases of hematomalignancy (HM) at a median age of 5.5 years were treated with a protocol using once-a-day injectable ceftriaxone plus amikacin and other oral adjuvant antimicrobial agents. The mean duration of FN in the ST group was 4.0 ± 1.2 days and in the HM group was 5.0 ± 2.5 days. The mean duration of antimicrobial cover in the ST group was 5.0 ± 1.75 days and in the HM group was 6.0 ± 1.5 days. The overall recrudescence rate was 6% and the mean duration to recrudescence was 4 ± 1.5 days (range 3-6 days). The objectives of this protocol were cost reduction and utilization of the available inpatient resources optimally by reducing the pressures of hospitalization for febrile neutropenia. We concluded that a selected group of patients with FN can be effectively managed with this regimen on an outpatient basis.

Descending Necrotizing Mediastinitis Causing Pleuroesophageal Fistula: Successful Treatment by Combined Transcervical and Pleural Drainage

Descending necrotizing mediastinitis (DNM) develops as a complication of an oropharyngeal infection and can be life-threatening. Aggressive therapy is generally advised; usually, treatment consists of cervicomediastinal and transthoracic drainage combined with broad-spectrum antimicrobial therapy, especially when the necrotizing process extends below the level of the fourth thoracic vertebra. A rare case of DNM secondary to a retropharyngeal abscess with fistula to both pleural cavities and to the hypopharynx is reported. The patient was successfully treated by cervicomediastinal surgical drainage and percutaneous drainage of both pleural cavities. In our opinion, even complicated DNM can be treated without aggressive surgery if the patient is in good condition.

Genital fournier's gangrene: experience with 38 patients

Objectives. Fournier's gangrene (FG) is an extensive fulminant infection of the genitals, perineum, or the abdominal wall. We report our experience with the management of this difficult infectious disease.Methods. Thirty-eight patients were admitted with the diagnosis of FG between May 1993 and May 1995. All patients were treated with broad-spectrum triple antimicrobial therapy, broad debridement, exhaustive cleaning, and application of unprocessed honey dressings. Patients then underwent split-thickness skin grafts or delayed closure as needed.Results. Patient ages ranged between 33 and 86 years (mean, 54) with a mean hospital stay of 17 days (range, 1 to 45). Sixty-six percent of the patients were diabetic, 16% had previous orchiepididymitis, and 5% had scrotal and urethral trauma. All the patients underwent surgical debridement and application of unprocessed honey to the wound. Cystostomy was performed in 60% of the patients and 21% underwent orchiectomy of the affected side. Free skin grafts were applied to 6 patients (16%) and the remaining wounds, once clean, were approximated. One patient died as a result of severe metabolic acidosis and sepsis.Conclusions. The management of this infectious entity should be aggressive. Patients with FG need extensive debridement and cystostomy or colostomy when necessary. Broad-spectrum triple antimicrobial regimen and aggressive debridement are mandatory. Topical application of unprocessed honey is beneficial to the healing process. A minority of patients require split-thickness skin grafts on denuded areas.

Group B Streptococcus and Pregnancy

Group B streptococcus is a significant pathogen for both mother and child. routine urine culture in pregnancy will identify and allow treatment of women with asymptomatic bacteriuria. An optimal protocol for the prevention of neonatal sepsis has not yet been developed. While intrapartum antimicrobial prophylaxis appears to provide the best potential, each of the currently suggested protocols has significant drawbacks. Drawbacks include the potential for missing high-risk carriers, failure to treat a significant proportion of those destined to deliver an affected infant because no risk factors are present, and empirical treatment of a large proportion of the population in order to present significant disease in a few. Until an effective program of immunization becomes available, intrapartum prophylaxis of group B streptococcal carriers appears to offer the best hope of reducing the incidence of neonatal disease. Caregivers should adopt a uniform practice with regard to screening and prophylaxis. It is essential that any broad-based screening program include an evaluation of efficacy as well as complications including the development of new etiologic agents as causes of neonatal sepsis and the emergence of resistant bacteria. Further, mothers and newborns should be evaluated for drug adverse reactions and the impact of intrapartum prophylaxis on the use of prolonged empirical broad-spectrum antimicrobial therapy on the asymptomatic infant. Additional research is necessary regarding the required duration of therapy for optimal effect of intrapartum prophylaxis, the need for postnatal prophylaxis of the asymptomatic neonate, and the optimal agent for neonatal prophylaxis (penicillin versus broad-spectrum agents) if neonatal therapy is necessary after intrapartum prophylaxis.

Clostridium tertium bacteremia: 2 cases and review

Clostridium tertium bacteremia is unusual, seen most often with gastrointestinal disease and/or neutropenia. Two cases are described. The first was a 19-yr-old female with acute leukemia, who developed gastrointestinal symptoms and C. tertium bacteremia while neutropenic. The second was a 57-yr-old female with quiescent ulcerative colitis, who presented with fever, rigors and epigastric pain. Four organisms including C. tertium were isolated from blood cultures. This patient responded to broad spectrum antimicrobial therapy, whereas the first patient required the addition of specific agents to recover. C. tertium is aerotolerant and thus can be misidentified as a Bacillus or Corynebacterium spp. Our isolates had a distinctive Gram stain morphology, were catalase negative and failed to sporulate aerobically--this aided in the recognition of this significant Gram-positive bacillus.

Nosocomial bacteremia due to Acinetobacter baumannii. Clinical features, epidemiology, and predictors of mortality.

To study the possible predisposing factors, clinical features, molecular epidemiology, and factors affecting mortality associated with bacteremia due to Acinetobacter baumannii, we reviewed 87 episodes of A. baumannii bacteremia occurring in 79 patients hospitalized at 2 university tertiary care centers and 4 community-based hospitals during a recent 18-month period. Plasmid DNA analysis and analysis of genomic DNA with pulsed-field gel electrophoresis was performed to investigate possible epidemiologic relationship. All patients acquired their infections in the hospital, and no seasonal variation was observed. Among patients with A. baumannii bacteremia, 91% were hospitalized in an intensive care unit, 99% had indwelling vascular catheters, 81% received prior broad spectrum antimicrobial therapy, 70% were mechanically ventilated, and 47% had major surgical procedures. In 39 cases (45%) the infection was related to indwelling vascular access devices. Other infections included pneumonia (9%), tracheobronchitis (22%), meningitis (2%), and burn wound infections (4%). Septic shock occurred in 30% of patients. All isolates were multidrug resistant. Polymicrobial bacteremia was observed in 35% of cases. The crude mortality rate was 44%. Death was considered attributable to A. baumannii bacteremia in 15 (19%) patients. All patients with pneumonia as the primary site of infection died. Using multivariate analysis, we identified 3 independent predictors of mortality: the presence of a rapidly or ultimately fatal underlying disease (p = 0.0009), septic shock at the onset of bacteremia (p = 0.0013), and mechanical ventilation (p = 0.016). Epidemiologic typing revealed that 82 episodes were associated with different hospital outbreaks of infection, and only 7 episodes were due to epidemiologically unrelated strains.

Randomized, Double‐blinded, Placebo‐controlled Trial of Amoxicillin/Clavulanic Acid to Prevent PretermDelivery in Twin Gestation

Objective: The objective of this study was to determine whether prophylactic treatment with oral broad-spectrum antimicrobial therapy improves pregnancy outcomes in twin gestations. Methods: Patients with twin gestations between 24 and 32 weeks were randomized to receive amoxicillin/clavulanic acid or placebo. Those patients randomized before 24 weeks received a 1-week course at 24 and at 28 weeks gestation. Those patients entered later than 24 weeks received a 1-week course either at 28 weeks or at enrollment (up to 32 weeks). Other than antibiotic use, the management of the groups was identical and unchanged from the routine care of twin gestations. Results: Of 149 twin pregnancies enrolled, 76 were randomized to the drug group and 73 to the placebo group. There was no significant difference in mean gestational age at delivery (35.9 vs. 35.7 weeks), birth weight (2,358 vs. 2,344 g), mean neonatal nursery stay (9.9 vs. 11.7 days), or respiratory distress syndrome (6/76 vs. 4/73) in the drug vs. placebo group, respectively. Conclusions: The addition of prophylactic oral broad-spectrum antimicrobial therapy to the standard antepartum management of twin gestations had no demonstrable effect on the gestational age at delivery, birth weight, or neonatal complications. There did not appear to be any beneficial effect of the prophylactic use of amoxicillin/clavulanic acid in this clinical setting.

Antibioprophylaxie en chirurgie cardiaque

Cardiac surgery enters mainly into the class I of Altemeier (« clean surgery ). However, many factors may explain an intraoperative contamination : surgery of long duration, extra-corporeal circulation, aspiration of blood and air, immunodepression...). In fact, the infectious risk decreases from about 25 % with placebo to 5 % with prophylactic antibiotics. The staphylococcal infections are the most frequent (mediastinitis, endocarditis, parietal infections...). Cephalosporins, particularly of second-generation type (cefamandole, cefuroxime), perform better than antistaphylococcal penicillins. The combination with an aminoside may be used when Gram negative bacilli infection prevalence is high. Vancomycin is efficient but hypotension and renal impairment have been reported. Therefore, vancomycin is used in patients allergic to cephalosporins, when a high prevalence of methicillin-resistant Staphylococcus or enterococci infections is reported, or when the patient has recently received broad-spectrum antimicrobial therapy. The antibiotic doses must take into account the haemodilution due to extracorporeal circulation and the necessity to obtain sufficient serum concentrations throughout surgery. A prophylaxis of more than 48 hours is not associated with an improved outcome. In cardiac transplantation a prophylaxis is essential, but is still questionned during the insertion of pace-markers. In any case, the antibiotic prophylaxis must take into account the bacterial prevalence of each institution.

Verticillium Peritonitis in a Patient on Peritoneal Dialysis

We describe a case of peritonitis due to Verticillium spp. in a 33-year-old farmer on continuous ambulatory peritoneal dialysis (CAPD) for 3 months for end-stage renal failure due to chronic pyelonephritis. The etiologic agent was a hyaline hyphomycete which we report as a new human opportunistic pathogen. The fungus was isolated from the peritoneal fluid culture and from the tip of the catheter; identification was made on the basis of macroscopic and microscopic features. The patient had previously been admitted to our hospital for peritonitis caused by mixed enteric flora and treated for 8 days with intraperitoneal broad-spectrum antibiotic therapy. Five days after discharge he was readmitted for severe abdominal pain and cloudy drainage fluid. Two days of intraperitoneal broad-spectrum antimicrobial therapy produced no clinical improvement. Intravenous fluconazole and oral flucytosine were administered upon identifying the fungus. After another 2 days without improvement, peritoneal dialysis was discontinued and the catheter removed. Antimycotic therapy was continued for 4 days with complete resolution of the peritonitis. The patient chose to start hemodialysis and was discharged in good clinical condition.

Febrile neutropenia.

Fever is associated with malignancy and is a common problem in cancer patients. Fever in the cancer patients is closely linked with infection, especially when the patient is granulocytopenic. When fever appears, a series of diagnostic and therapeutic measures must be taken even if precise knowledge of the cause of the infection is lacking. Fever can be caused by infection or by the cancer itself through tumor-related necrosis, hemorrhage or pyrogens. Infection is the more common cause, however. Bacterial and fungal sepsis can coexist and the bacteremia can overshadow the more difficult to determine fungal infection. For this reason it has become accepted practice to administer amphotericin B to granulocytopenic patients who remain febrile after a few days of broad-spectrum antimicrobial therapy and in whom no bacteria can be documented. Viral infection is rarely diagnosed in neutropenic patients without concomitant immunosuppression.

Infections following cesarean section

Postpartum endomyometritis and abdominal wound infection remain the most common infectious complications following childbirth. New information now suggests that incipient infection of the myometrium explains why patients develop postpartum endometritis despite antibiotic prophylaxis. Clinical predictors of postpartum endometritis continue to suffer from low sensitivity. However, use of a Gram stain of the amniotic fluid may be helpful in identifying a subset of women that may benefit from a therapeutic course of antibiotics initiated immediately after cesarean section. Broad-spectrum antimicrobial therapy is the mainstay of therapy for postpartum endometritis. Two newer extended spectrum cephalosporins, cefotetan and ceftizoxime, appear to be as effective as cefoxitin in the treatment of these infections. Abdominal wound infection is a common cause of antimicrobial failure in patients treated for post-cesarean endomyometritis. The genital mycoplasmas, usually resistant to the penicillins and cephalosporins, are commonly isolated from infected wounds following cesarean section. Wound infection surveillance has been shown to decrease infection incidence rates by providing feedback to the operating surgeon.

Progress in the management of tuboovarian abscesses.

The last 20 years have witnessed remarkable improvements in the treatment of tuboovarian abscesses. Gone are the days of significant mortality associated with ruptured and unruptured TOAs. Broad-spectrum antibiotics have enabled patients to be treated solely with medical therapy, avoiding the need for surgery. Operative intervention is still necessary in 25% of cases of unruptured TOAs, but the combination of conservative surgical procedures, such as unilateral salpingo-oophorectomy, and broad-spectrum antimicrobial agent therapy have reduced the need for total abdominal hysterectomy with bilateral salpingo-oophorectomy greatly. Although fertility after TOAs is compromised significantly, new advances in reproductive technology, including in vitro fertilization and donor egg transplantation, represent reproductive options for these women. Percutaneous drainage and laparoscopic treatment of TOAs are becoming popular treatment options, but prospective studies urgently are needed to assess their efficacy.

RESPIRATORY INFECTIONS IN IMMUNOCOMPROMISED PATIENTS

Respiratory infections in immunocompromised patients cause significant morbidity and mortality. After initial broad-spectrum antimicrobial therapy has been instituted, an early, aggressive diagnostic approach is usually appropriate. The initial diagnostic procedure is often flexible fiberoptic bronchoscopy with BAL and transbronchial lung biopsy. Bacteria, CMV and other viral pathogens, and several fungi including Aspergillus and Candida species are the most common respiratory pathogens isolated in bone marrow and solid organ transplant recipients. The spectrum of respiratory pathogens in patients who have not undergone transplantation is dependent on the type of immune defect.

Comparative study of cefazolin, cefamandole, and vancomycin for surgical prophylaxis in cardiac and vascular operations: A double-blind randomized trial

Three-hundred twenty-one adults undergoing cardiac or major vascular operations were randomized to receive intravenous cefazolin, cefamandole, or vancomycin for prophylaxis against surgical infection in a double-blind trial. All three regimens provided therapeutic blood levels throughout operation in patients studied undergoing cardiopulmonary bypass. The prevalence of surgical wound infection was lowest with vancomycin (4 infections [3.7%] versus 14 [12.3%] and 13 [11.5%] in the cefazolin and cefamandole groups, respectively; p = 0.05); there were no thoracic wound infections in cardiac operations in the vancomycin group (p = 0.04). The mean duration of postoperative hospitalization was lowest in the vancomycin group (10.1 days; p < 0.01) and highest in the cefazolin group (12.9 days). Prophylaxis with vancomycin or cefamandole, compared with cefazolin, did not prevent nosocomial cutaneous colonization by methicillin-resistant coagulase-negative staphylococci; colonization or infection with vancomycin-resistant staphylococci or enterococci was not detected. Adverse effects attributable to the prophylactic regimen were infrequent in all three groups. Eight patients given vancomycin became hypotensive during administration of a dose, despite infusion during a 1-hour period; however, slowing the rate of administration and pretreating with diphenhydramine allowed vancomycin to be resumed and prophylaxis completed uneventfully in five of the patients. We conclude that administration of vancomycin (approximately 15 mg/kg), immediately preoperatively, provides therapeutic blood levels for surgical prophylaxis throughout most cardiac and vascular operations, resulting in protection against postoperative infection superior to that obtained with cefazolin or cefamandole. Vancomycin deserves consideration for inclusion in the prophylactic regimen (1) for prosthetic valve replacement and prosthetic vascular graft implantation, to reduce the risk of implant infection by methicillin-resistant coagulase-negative staphylococci and enterococci; (2) for any cardiovascular operation if the patient has recently received broad-spectrum antimicrobial therapy; and (3) for all cardiovascular operations in centers with a high prevalence of surgical infection with methicillin-resistant staphylococci or enterococci. Guidelines for dosing and administration of vancomycin for cardiovascular surgical prophylaxis are provided.