Carbapenems and monobactams: imipenem, meropenem, and aztreonam.

Imipenem and meropenem, members of the carbapenem class of beta-lactam antibiotics, are among the most broadly active antibiotics available for systemic use in humans. They are active against streptococci, methicillin-sensitive staphylococci, Neisseria, Haemophilus, anaerobes, and the common aerobic gram-negative nosocomial pathogens including Pseudomonas. Resistance to imipenem and meropenem may emerge during treatment of P. aeruginosa infections, as has occurred with other beta-lactam agents; Stenotrophomonas maltophilia is typically resistant to both imipenem and meropenem. Like the penicillins, the carbapenems have inhibitory activity against enterococci. In general, the in vitro activity of imipenem against aerobic gram-positive cocci is somewhat greater than that of meropenem, whereas the in vitro activity of meropenem against aerobic gram-negative bacilli is somewhat greater than that of imipenem. Daily dosages may range from 0.5 to 1 g every 6 to 8 hours in patients with normal renal function; the daily dose of meropenem, however, can be safely increased to 6 g. Infusion-related nausea and vomiting, as well as seizures, which have been the main toxic effects of imipenem, occur no more frequently during treatment with meropenem than during treatment with other beta-lactam antibiotics. The carbapenems should be considered for treatment of mixed bacterial infections and aerobic gram-negative bacteria that are not susceptible to other beta-lactam agents. Indiscriminate use of these drugs will promote resistance to them. Aztreonam, the first marketed monobactam, has activity against most aerobic gram-negative bacilli including P. aeruginosa. The drug is not nephrotoxic, is weakly immunogenic, and has not been associated with disorders of coagulation. Aztreonam may be administered intramuscularly or intravenously; the primary route of elimination is urinary excretion. In patients with normal renal function, the recommended dosing interval is every 8 hours. Patients with renal impairment require dosage adjustment. Aztreonam is used primarily as an alternative to aminoglycosides and for the treatment of aerobic gram-negative infections. It is often used in combination therapy for mixed aerobic and anaerobic infections. Approved indications for its use include infections of the urinary tract or lower respiratory tract, intra-abdominal and gynecologic infections, septicemia, and cutaneous infections caused by susceptible organisms. Concurrent initial therapy with other antimicrobial agents is recommended before the causative organism has been determined in patients who are seriously ill or at risk for gram-positive or anaerobic infection.

Localized soft-tissue infections with Mycobacterium avium/Mycobacterium intracellulare complex in immunocompetent patients: granulomatous tenosynovitis of the hand or wrist.

In immunocompetent patients, Mycobacterium avium/Mycobacterium intracellulare complex (MAC) has been associated with pulmonary infection in adults, cervical lymphadenitis in children, and disseminated infection in children and adults. MAC rarely has been recognized as a cause of localized soft-tissue infection in immunocompetent hosts. Six cases of granulomatous tenosynovitis due to MAC are reported; five cases occurred after local surgical procedures, trauma, or corticosteroid injection. In four cases, cure was achieved with combined medical and surgical intervention. In these six cases and 11 previously reported cases, both males and females were affected equally, usually in the fifth to seventh decades of life, and the distal upper extremity was predominantly involved. Surgical debridement with appropriate culture was critical for diagnosis and management. Antimycobacterial chemotherapy seemed to be a beneficial adjunctive measure in most cases but was clearly necessary for cure in only a few cases.

The monobactams.

The monobactam antibiotics are synthetic compounds, although monocyclic beta-lactam compounds have been found in nature in various soil bacteria. Although additional orally and parenterally administered monobactams are under investigation, the first marketed monobactam was aztreonam. This agent has an antimicrobial spectrum similar to that of gentamicin and tobramycin, aminoglycoside antibiotics. Aztreonam, however, is not nephrotoxic, is weakly immunogenic, and has not been associated with disorders of coagulation. Aztreonam may be administered intramuscularly or intravenously; absorption after oral administration is poor. The primary route of elimination is the urine. The serum half-life of the drug in patients with normal renal function is 1.5 to 2.1 hours; the recommended dosing interval in patients with normal renal function is every 8 hours. Dosage adjustment is necessary in patients with renal impairment. The strictly gram-negative aerobic spectrum of aztreonam limits its use as a single empiric agent. Approved indications for its use include infections of the urinary tract or lower respiratory tract, intra-abdominal and gynecologic infections, septicemia, and cutaneous infections caused by susceptible organisms. Concurrent initial therapy with other antimicrobial agents is recommended before the causative organism (or organisms) has been determined in patients who are seriously ill and at risk for gram-positive or anaerobic infections.

Imipenem.

Imipenem is the first of a new class of beta-lactam antibiotics, the carbapenems, to be released for clinical use. It has the broadest antibacterial activity of all antibiotics available for systemic use in humans. It is active against streptococci, methicillin-sensitive staphylococci, Neisseria, Haemophilus, anaerobes, and the common aerobic gram-negative nosocomial pathogens including Pseudomonas. Resistance to imipenem may emerge during treatment of P. aeruginosa infections, as has occurred with other beta-lactam agents; P. maltophilia and P. cepacia are typically resistant to it. Like the penicillins, imipenem has inhibitory activity against enterococci. Daily doses may range from 500 mg to 1 g, every 6 to 8 hours, in patients with normal renal function. The principal toxic effects have been nausea and vomiting, which occur during intravenous infusion, and seizures, which develop in 1 to 3% of treated patients and are likely to occur in the setting of renal insufficiency and underlying disease of the central nervous system. Imipenem should be considered for treatment of mixed bacterial infections and treatment of resistant aerobic gram-negative bacteria that are not susceptible to other beta-lactam agents. In addition to provoking unnecessary toxicity, indiscriminate use of this agent will promote dissemination of resistance against it.

Venous thromboembolism in patients with major trauma.

The risk of venous thromboembolism after trauma is thought to be high, but the specific risk factors and the incidence of venous thromboembolism in the trauma population are poorly defined. Between October 1, 1987, and March 1, 1988, 719 patients were evaluated; 542 had no risk factors and 177 had at least 1 risk factor. No venous thromboembolism occurred in any of the 542 patients without a risk factor, whereas 12 of 177 patients (7%) with at least 1 risk factor had a venous thromboembolism. Pneumatic compression hose was the most common form of prophylaxis used, but it could not be applied to 35% of limbs because of plaster immobilizers, external fixators, complex wounds, or traction. In the high-risk group, 25 patients (14%) received no prophylaxis because of a physical impediment to application of these hose and a contraindication to anticoagulation. Age greater than 45 years was the only risk factor predictive of venous thromboembolism by logistic regression analysis. Patients with more than one risk factor had a significantly higher incidence of venous thromboembolism than those with only one risk factor. We conclude that a selected subgroup of trauma patients appears to be at risk of venous thromboembolism and should receive prophylaxis. Approximately one in seven high-risk patients cannot receive anticoagulant or mechanical prophylaxis because of their injuries.

Patterns of pulmonary perfusion scans in normal subjects. IV. The prevalence of abnormal scans in smokers 30 to 49 years of age.

The usefulness of ventilation-perfusion scans in the diagnosis of pulmonary embolism is limited by the wide range of pulmonary diseases that are associated with abnormal scans, and by the largely undetermined prevalence of abnormal scans in persons without cardiopulmonary disease. In prior studies, we found perfusion defects to be rarely present in young persons and in older nonsmokers. To determine if normal older smokers have a higher prevalence of abnormal ventilation and perfusion scans, we performed six-view 99mTc perfusion (Q) scans and 133Xe ventilation (V) scans in 40 subjects 30 to 49 yr of age who had no known cardiopulmonary disease. Each subject had undergone a history, physical examination, electrocardiogram, spirometry, and posteroanterior chest roentgenogram prior to scanning. All V and Q scans were interpreted blindly and independently by two experienced readers. No subject demonstrated a lobar or segmental defect on two views. One subject had a matched subsegmental defect, and one subject had delayed washout from a subsegmental area of the right upper lobe during V scanning, with a normal Q scan. We conclude that abnormal V and Q scans are uncommon among normal smokers 30 to 49 yr of age.

Infection of pulmonary artery catheters in critically ill patients.

Bacteriologic cultures were performed on the tips of pulmonary artery catheters removed from 153 critically ill patients, who had required pulmonary artery catheterization for management of hypovolemic or septicemic shock or for hemodynamic monitoring during mechanical ventilation with positive end-expiratory pressure. Positive results were obtained in 29 (19%) of the cases. Infection of indwelling pulmonary artery catheters may result from contamination during placement or removal or from transient or persistent bacteremia. Colonization was probable in 17 cases, and contamination in 12. There were no instances of sepsis definitely attributable to the catheter. Positive catheter-tip culture was associated significantly with known presence of a focus of infection before catheter insertion and with periods exceeding four days that the catheter remained in place.

Toxic shock syndrome, a newly recognized disease entity. Report of 11 cases.

The toxic shock syndrome has only recently been described. Eleven female patients aged 13 to 43 years (median 17) with toxic shock syndrome have been seen at the Mayo Clinic since August 1975. One patient died. Seven patients had one or more recurrences. As previously described, the syndrome was often life-threatening, afflicted mostly menstruating females, and was characterized by a very brief prodromal illness consisting of high fever, vomiting, diarrhea, conjunctivitis, headache, irritability, sore throat, myalgias, abdominal tenderness, and erythematous rash. The disorder can progress to hypotension or prolonged refractory shock, adult respiratory distress syndrome, diffuse intravascular coagulation with severe thrombocytopenia, and renal failure. Pancreatitis was observed in two cases. During convalescence, pronounced desquamation and peeling of the skin occurred. Numerous laboratory abnormalities are observed. In 5 of the 11 patients, Staphylococcus aureus was isolated from conjunctiva, oral cavity or nares, vagina, or stool. A recently described pyrogenic exotoxin was identified in the isolates of three patients; its etiologic role remains speculative. Therapy is mainly supportive. Antistaphylococcal therapy for the acute illness and for prevention of recurrences has not yet proved to be of any benefit. The role of vaginal tampons, if any, in the pathogenesis of this disorder remains unclear.

Open-lung biopsy in the renal transplant recipient.

In 22 renal transplant recipients, 23 open-lung biopsy procedures were performed. There were two (8.7%) biopsy-related complications (hemorrhage and pneumothorax) and five deaths (22.7%), although the deaths could not be definitely related to the biopsy procedure itself. Seventeen biopsy specimens yielded specific diagnoses, and six were nonspecific. The mortality rate for the patients with specific diagnoses was not significantly different from that of patients with nonspecific diagnoses (25% vs. 16.7%). Other factors analyzed, such as age, diabetes, hypoxia, leukopenia, and donor source, did not affect the result of biopsy. We conclude that the patient's underlying disease and added immunosuppressive therapy are the factors most responsible for the clinical outcome. We suggest that without early treatment of the infectious agents, the mortality rate of the group with specific diagnoses would likely have been higher.

Infectious diseases of Indochinese refugees.

The recent Mayo Clinic experience in the diagnosis and treatment of infectious diseases in Indochinese refugees is discussed. One hundred patients from whom stool and blood specimens were submitted for parasitic examination showed a high percentage of parasitic infection, often with multiple agents. An outline for the initial medical examination and treatment of the parasitic agents found is presented.

Massive antigenemia during disseminated cryptococcosis.

Three cases of disseminated cryptococcosis associated with massive levels of cryptococcal antigen in the serum and cerebrospinal fluid are presented. These patients had antigen titers of at least 1:32,768. Titers of this magnitude have not previously been reported.

Trimethoprim with sulfamethoxazole for treatment of infection with Pneumocystis carinii in renal insufficiency.

Pneumonia due to Pneumocystis carinii developed in an immunosuppressed patient with a renal transplant who had substantial renal failure. Successful treatment was acheived with administration of trimethoprim plus sulfamethoxazole at a dosage adjusted to the degree of renal failure. There were no significant adverse effects from this therapy.

Disseminated Strongyloides stercoralis in an immunosuppressed host.

It is important that clinicians be aware that Strongyloides stercoralis can disseminate, because the helminth can exist as an asymptomatic infestation for years in a person from an endemic area and then become manifest when immunosuppressive therapy is given. A case of fatal strongyloidiasis is presented to emphasize this potential for causing serious infection in the compromised host.

Antimicrobial agents--Part II. The aminoglycosides: streptomycin, kanamycin, gentamicin, tobramycin, amikacin, neomycin.

Aminoglycoside antibiotics are poorly absorbed from the gastrointestinal tract, do not penetrate well into the cerebrospinal fluid, are minimally bound to plasma proteins, and are rapidly excreted by the normal kidney. Neomycin is limited by its toxicity to irrigating and topical preparations or to oral medication for surgical bowel preparations or hepatic coma. Streptomycin has only a few specific indications, because newer agents are available that have broader spectrums of activity. Kanamycin is indicated in serious gram-negative infections in which Pseudomonas aeruginosa is not a likely causative agent. Gentamicin, tobramycin, and amikacin are effective against a broad spectrum of gram-negative organisms including P. aeruginosa. In general, both gentamicin and tobramycin are more active in vitro than amikacin on a weight basis; however, higher serum levels are achievable with amikacin than with the two others. Amikacin is probably the aminoglycoside of first choice when gentamicin resistance is strongly suspected.

Cryptococcosis, with emphasis on the significance of isolation of Cryptococcus neoformans from the respiratory tract.

Cryptococcus neoformans was isolated from 65 patients: 11 had meningitis, 11 had disseminated cryptococcosis without meningitis, and 43 had C neoformans isolated from the respiratory tract. Predisposing conditions and the diagnostic value of cultures from various sites and of the latex agglutination test on cerebrospinal fluid and serum are analyzed for patients with extrapulmonary disease. Nine patients had pleural effusions; the effusion was cultured in six and yielded C neoformans in four. None of 11 deaths among 43 patients with respiratory tract isolates could be attributed to cryptococosis. The 32 survivors were nor treated with antifungal agents. Twenty-six of 43 patients with respiratory isolates had various bronchopulmonary disorders, with chronic obstructive pulmonary diseases and asthma the most common (28 percent). Seven of 28 patients (25 percent) with roentgenographically detected lung lesions had carcinoma of the lung. Roentgenographic evidence of a lung lesion and C neoformans grown from the respiratory tract warrant a further search for carcinoma of the lung.

Sporotrichosis arthritis: clinical features in seven patients.

A review of the clinical features of seven patients with sporotrichosis arthritis showed that six had joint infection without previous skin or lung involvement and that one with myelofibrosis had joint and skin infection. The average time from onset of joint symptoms to diagnosis was 25 months, resulting in joint damage that required arthrodesis in four patients. Tissue from open synovial biopsy was superior to synovial fluid for obtaining a positive culture; concomitant synovial fluid and synovial tissue cultures were superior to either one alone. Granulomatous inflammation was seen in synovial tissue in six patients biopsied. Amphotericin B with surgical debridement of the affected joint was successful treatment in four patients. Although an uncommon cause of joint disease, sporotrichosis arthritis may go unrecognized and mimic other forms of arthritis, resulting in irreparable damage in an otherwise curable form of arthritis.

Squamous-cell carcinoma complicating chronic osteomyelitis.

Treatment of carcinomatous degeneration in patients with chronic osteomyelitis requires differentiation between benign, penetrating epithelioma and invading, low-grade squamous-cell carcinoma. Although most lesions are low grade, analysis of the case histories of twenty-three patients treated at the Mayo Clinic indicates that these tumors do metastasize. When malignant-appearing epithelium invading bone is identified, ablative surgery is indicated. Inadequate surgical treatment resulted in the deaths of two patients in our series. Routine regional lymphadenectomy at the time of amputation seems unnecessary. Regional lymphadenopathy persisting for six to twelve weeks after amputation warrants surgical intervention. With prompt, aggressive surgical treatment, the prognosis for patients with squamous-cell carcinoma in an osteomyelitic cavity is good.

Diagnostic tissue microbiology methods.

Tissue specimens, when processed properly, may yield important microbiologic information. Various techniques have evolved for specimen collection and transport, processing of tissue specimens, and demonstration of organisms by staining histologic material that enhance the identification of infectious agents. Careful attention to these details may yield diagnostic information that might otherwise be missed.

Brain abscess: a review of recent experience.

From 1961 through 1973, 60 patients with brain abscess were treated at the Mayo Clinic by surgical excision and antimicrobial therapy. The operative mortality was 17%, which was identical to a similar series reported in 1959. The patients who had the diagnosis of brain abscess confirmed at autopsy and who never underwent operation (24 patients) were more elderly than the group operated on, and a higher percentage had multiple brain abscess. Severe systemic disease or multisystem disease, or both, usually precluded a vigorous surgical approach among the nonsurgical group. Etiologic, diagnostic, and microbiologic factors were examined to develop an approach to antimicrobial therapy.