SESSION VIII. Infections Due to Gram-Negative Bacteria: An Overview

REVIEWS OF INFECTIOUS DISEASES. VOL. 7, SUPPLEMENT 4 NOVEMBER-DECEMBER 1985 1985 by The University of Chicago. All rights reserved. 0162-0886/85/0706-0033$02.00 SESSION VIII Infections Due to Gram-Negative Bacteria: An Overview Harold C. Neu From the Division of Infectious Disease, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York Infections caused by gram-negative bacteria have continued to be a major problem for hospitalized patients. Malignant necrotizing otitis due to Pseudomonas aeruginosa has been encountered with increasing frequency as the number of older diabetic patients has increased. Nosocomial sinusitis and bacteremia due to Escherichia coli, Klebsiella pneumoniae, Enterobacter species, or P. aeruginosa develop in hospitalized patients. Bacteremia due to E. coli, K. pneumoniae, or P. aeruginosa often follows instrumentation of the urinary, respiratory, or gastrointestinal tracts in the hospitalized patient. Mortality still is excessivelyhigh. Infections of skin structure, particularly decubitus ulcers in debilitated, bedridden patients, are due to a mixed gram-negative and anaerobic flora; frequently, P. aeruginosa and Enterobacteriaceae resistant to many older agents are the major pathogens. Similarly, osteomyelitis in patients who have undergone previous surgical procedures is caused by various multiply resistant Enterobacteriaceae and P. aeruginosa. In all of these situations, therapy has usually included an aminoglycoside. The availability of drugs such as aztreonam, which has activity directed at aerobic gram-negative bacilli, provides an alternative approach that has proved successful and can be evaluated in more detail in the coming years. It is only since the beginning of the 1960s that physicians have adequately appreciated the importance of gram-negative aerobic organisms as pathogens in a significant number of infections outside the urinary tract. The role of aerobic gram-negative bacilli in respiratory and urinary tract infections and in the neutropenic patient are discussed elsewhere in this issue. This overview will review other forms of infection in which aerobic gram-negative organisms have proven to be significant. Upper Respiratory Tract Infections External otitis, which is a superficial infection ofthe external auditory canal, is frequently caused by Pseudomonas aeruginosa. However, in the last decade and a half, a new and important form of external otitis, malignant external otitis, has been encountered with increased frequency [1, 2]. This severeform of external otitis is caused by R aeruginosa. Invasion ofthe cartilage and the external auditory canal Please address requests for reprints to Dr. Harold C. Neu, Department of Medicine, College of Physicians and Surgeons, Division of Infectious Disease, Columbia University, 630 West l68th Street, New York, New York 10032. produces osteomyelitis, which if not treated will lead to the developmentofcranial nerve palsies and even to death. Malignant external otitis occurs primarily in diabetic individuals older than 55 years of age. It produces severe pain and tenderness of the tissues around the ear and in the mastoid area of the skull. Successful treatment has involved aggressive surgical removal of devitalized tissue and the extended use of antipseudomonal penicillins - carbenicillin, ticarcillin, azlocillin, or piperacillin- in combination with an aminoglycoside [1-3]. Since the individuals who have this disease frequently have decreased renal function and may already have auditory problems, the use of aminoglycosides may present problems. Would aztreonam be suitable therapy for this disease? Treatment of invasive external otitis with cefsulodin, an antibiotic active primarily against R aeruginosa, has been successful provided thatthe disease has not progressed very far and that the antibiotic is used in conjunction with local debridement [4, 5]. It seems reasonable to suspect that in the future aztreonam will prove useful for treating this unusual infection. However, until a number of patients have been treated, such a statement is mere conjecture. Nosocomial sinusitis has been recognized with in- S778

Gram-Negative Infections: An Overview S779 creasing frequency in the last several years [6]. This infection occurs in hospitalized patients who have had nasotracheal tubes or nasogastric tubes in place for a prolonged period. Gram-negative bacteriasuch as Escherichia coli, Klebsiella pneumoniae, or P. aeruginosa may be involved. Indeed, in a study by Kaplan [6], P. aeruginosa was the most frequently isolated pathogen (29070), and P. aeruginosa, Klebsiella species, and Enterobacter speciesaccounted for 63% of the isolates. Although resolution of the sinusitis frequently will follow removal of the nasal tube, in some situations antimicrobial therapy is necessary. An agent such as aztreonam, which would not alter the normal protective streptococcal flora of the oropharynx, may ultimately prove useful in treatment of this nosocomial infection affecting patients in intensive care and trauma units. Infections After Surgery of the Neck A possible use for an agent such as aztreonam would be as therapy for hospital-acquired, gram-negative infections that follow extensive surgery for malignancy of the oropharynx. K. pneumoniae and other Klebsiella species, E. coli, and particularly P. aeruginosa have been the most common pathogens in serious postoperative aerobic wound infections of the neck following cancersurgery [7, 8]. Although aminoglycosides have been used to treat such infections, in viewofthe debilitated state of these patients and the frequency of impaired renal function among them, an agent that would not be nephrotoxic and would not alter normal protective flora-thus decreasing the possibility of overgrowth of fungal and other gram-negative species- would be useful. Obviously, anaerobic bacteria could be involved in such infections, and agents active against grampositive or anaerobic organisms may also be necessary. Sepsis Due to Gram-Negative Bacilli Bacteremia due to gram-negative aerobic bacilli constitutes a major problemin medical and surgical servicesin hospitals throughout the world [9]. Although in some situations bacteremia can be self-limitingparticularly after urinary tract instrumentation in a healthy individual-in many patient populations mortality due to gram-negative bacteremia has remained high [9].Generally, E. coli has been the most common pathogen involved in gram-negative bac- teremia; K. pneumoniae is the next most common pathogen. In recent years, P. aeruginosa has become the third most commonly encountered organism, followed by Enterobacter species and Serratia marcescens [10]. Organisms such as Proteus mirabilis and Providencia (an indole-positive species previously classified as Proteus) are isolated less frequently. Most episodes of gram-negative bacteremia are the result ofdamage or infection in the integument, urinary tract, respiratory tract, or the mucous membranes ofthe gastrointestinal tract. Although many ofthe strains ofe. coli and K. pneumoniae thatproduce bacteremia in patients admitted to the hospital are susceptible to many of the currently available antimicrobial agents, it has become increasingly apparent that organisms which arise within the hospital frequently possess mechanisms that confer resistance to older antimicrobial agents [11]. Hospitalized patients frequently are treated prophylactically with antimicrobial agents or are treated for an infection with antimicrobial agents that alter the normal flora, situations that allow gram-negative bacteria to increase in number, particularly in the intestinal tract. During the past decade, a great deal of work has been devoted to the evaluation of new antimicrobial agents in the therapy for gram-negative bacteremia. The precise role of antimicrobial agents in the decrease in mortality among patients with gramnegative bacteremiaremains a moot question. There have been more aggressive approaches to the diagnosis and the rapid initiation of treatment as well as to the development of supportive and adjunctive measures, all of which contribute significantly to the survival of the patient with gram-negative bacteremia. Since the 1960s, aminoglycosides have been an integral part of the empiric therapy used to treat gram-negative bacteremia [12]. The advent of new cephalosporin antibiotics provided compounds that would yield levels of antibiotic in blood 100-fold or greater than the MIC 90 values for most strains of E. coli and K. pneumoniae and that frequently would yield equally high concentrations against S. marcescens, Proteus species, and Enterobacter species [13]. In this issue the role of aztreonam in therapy for gram-negative bacteremia is reviewed. When the bloodstream isolate is clearly derived from a urinary source, or when the organism has already been defined as gram-negative, the initiationof therapy with aztreonam would seem to be as appropriate as initi-

8780 Neu ation with other compounds. However, when the bacteremia may be caused by gram-positive organisms as wellas by gram-negative organisms, it seems appropriate to utilize another agent, which would provide coverage for gram-positive organisms, in combination with aztreonam. Indeed, bacteremia due to gram-positive organisms such as S. pneumoniae, Streptococcus pyogenes, and particularly Staphylococcus aureus can have a clinical presentation similar to that characteristically attributed to bacteremia due to gram-negativebacilli. There is clinical evidence supporting the use of a combination of an antipseudomonal f3-lactam agent with an aminoglycoside for bacteremia due to P. aeruginosa in the neutropenic patient [14]. Further studies will be necessary to clarify the place of aztreonam and aminoglycosides in therapy for such patients. However, the synergy of aztreonam and aminoglycosides against P. aeruginosa in vitro is well established. Biliary Tract Infections The organisms most frequently involvedin acute obstructive cholecystitis and in cholangitis are E. coli, K. pneumoniae, Enterobacter species, and Proteus species [15-17]. Pseudomonas is infrequently encountered, except in patients in whom a catheterhas been placed into the biliary tree to provide drainage and who have acquired a secondary infection. Anaerobic organisms such as Bacteroides, Clostridium, and Fusobacterium are present particularly in patients with chronic forms ofbiliary tract disease [15, 16].The treatment regimen that has been used most frequently in the past has been a combination of clindamycin or metronidazole and an aminoglycoside such as gentamicin or tobramycin. This antimicrobial program is directed primarily at the bacteremia that often complicates cholangitis. Since many of these patients are severely ill and elderly and have a poor fluid balance, it seems that the use of an agent such as aztreonam, which would provide the antibacterial spectrum of an amino glycoside without its associated toxicity, would be appropriate. Levelsof aztreonam in biliary fluid would be adequate to inhibit aerobic gram-negative organisms without causing marked distortion ofthe normal anaerobic flora of the small and large bowel. One must realize that enterococci complicate the tubes draining the biliary tree [17], and since these organisms are not inhibited by aztreonam, secondary infection could occur. Skin and Soft Tissue Infections Cellulitis due to gram-negative aerobic bacteria can occur in the immunocompromised host following trauma. Decubitus ulcers in the chronically debilitated, bedridden patient frequently are due to gramnegative organisms. It is important to realize, however, that anaerobic species probably playa very important role in most infections of the skin structure as well, and the pathologic process is the outcome of the synergistic action of the gram-negative aerobic species and gram-positive cocci and anaerobes [18]. Aminoglycoside antibiotics have characteristically been combined with other agents such as clindamycin or broad-spectrum f3-lactam antibiotics such as cefoxitin, which have activity against gramnegative anaerobes and aerobes, and have been used for treatment of hospital-acquired cellulitis. Such antimicrobial programs frequently result in an alteration in intestinal flora, with further perpetuation of the problem as a result of the selection of resistant microorganisms. It would seem that an agent such as aztreonam would be a possible replacement for the aminoglycoside that has been used in these programs. Obviously, proper care of wounds, including debridement ofdevitalized tissue, is critical and as important as or even more important than the use of antimicrobial agents. In recent years gram-negative aerobic organisms such as P. aeruginosa and various members of the Enterobacteriaceae have been important pathogens in burn-wound sepsis [19]. Although the use of topical silver sulfadiazine or mafenide has reduced the incidence of burn-wound sepsis, the frequent occurrence of severe infection due to gram-negative organisms in burned patients remains a significant problem. Aminoglycosides have been part of the therapeutic regimen for suspected sepsis in burned patients, but since excellentantipseudomonal agents that lack ototoxicity and nephrotoxicity- such as aztreonam - are available, it may be possible to replace the aminoglycoside component of the combination therapy used in these patients. However, it is important to realize that gram-positive infections, particularly those due to S. aureus, are still a problem in burned patients. Indeed, since methicillinresistant strains of S. aureus have become a problem in many burn centers [20], it would be inappropriate to utilize a compound such as aztreonam as a single initial therapeutic agent for the burned patient.

Gram-Negative Injections: An Overview S781 Bone and Joint Infections The role ofgram-negative bacteria in infectious arthritis has been recognized in the past few years [21]. Most patients with infectious arthritis due to gramnegative bacilli have had chronic debilitating disease or chronic arthritis in an infected joint and an associated urinary tract infection [22]. In general, infection with gram-negative bacteria has been associated with a poor outcome; and chronic flexion contractures, ankylosing joints, and chronic effusions havebeen a significant problem. Although aminoglycosides enter joint fluid, the activity of these agents at an acid ph in the presence of a large amount of cellular debris is markedly depressed. Therefore, {3-lactam compounds that have activity against gram-negative organisms have generated enthusiasm [23]. Althoughthe number of patients with infectious arthritis due to Enterobacteriaceae or Pseudomonas who have been treated with aztreonam is small, the results have been encouraging. The possibility that aztreonam can be used is particularly important since it can be administered without concern for the toxicity associated with use of the high doses of aminoglycosides that are necessary for clinical efficacy. Osteomyelitis due to gram-negative organisms is seen primarily in patients with underlying malignancy, alcoholism, or other diseases, all of which contribute to the susceptibility of the patient to such infections [24,25]. Surgery or the breach of integument by puncture wounds is frequently the cause of osteomyelitis due to Pseudomonas. Heroin addicts frequently have osteomyelitis due to gram-negative bacteria and S. marcescens [26]. In the majority of series evaluating the treatment ofgram-negative osteomyelitis, the results have been discouraging. The availability of agents such as third-generation cephalosporins or of compounds such as aztreonam provides alternatives to aminoglycoside therapy and its attendant toxicity. Eye Infections Fortunately, endophthalmitis due to gram-negative bacteria is exceedingly uncommon. P. aeruginosa is the organism involved most frequently in eye infections due to gram-negative bacteria; P. mirabilis and S. marcescens infections follow in frequency [28]. The most common organism of all types is S. aureus. Thus, any antibiotic therapy directed at en- dophthalmitis must be one that includes activity against this microorganism. The current data on the concentrations of aztreonam in vitreal fluid are still inadequate. Corneal ulcers caused by Pseudomonas have responded to therapy with gentamicin, and it would seem inappropriate to use aztreonam topically. Conclusions This discussion has been directed at those areas in which gram-negative aerobic bacteriaare important factors in infection. Aminoglycosides have been standard therapy for many of the gram-negative infections discussed in this brief overview. In this symposium, the experience with aztreonam as therapy for infections due to gram-negative bacteria is discussed. Aztreonam has been shown to be effective in many situations. It should be noted that in most trials aztreonam has been directly compared with an aminoglycoside. Are such comparisons trulynecessary? In the therapy for gram-negative bacteremia in the immunocompromised patient, such comparisons will be necessary. In many other areas, however, it seems that an agent with proven efficacy and low toxicity has much to recommend it over the agents currently used, which are known to have intrinsic toxicity. Clearly, the precise role of aztreonam in therapy for gram-negative infections will be established before the end of this decade. References 1. Chandler JR. Malignant external otitis. Laryngoscope 1968; 78:1257-94 2. Doroghazi RM, Nadol JB Jr, Hyslop NE Jr, Baker AS, Axelrod L. Invasive external otitis: report of 21 cases and review of the literature. Am J Med 1981;71:603-14 3. Strauss M, Aber RC, Conner GH, Baum S. Malignant external otitis: long-term (months) antimicrobial therapy. Laryngoscope 1982;92:397-405 4. Scully B, Prince A, Ores C, Neu HC. Cefsulodin therapy of Pseudomonas aeruginosa infections: pulmonary and osteomyelitis [abstract no. 69]. In: Program and abstracts of the 22nd Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1982 5. Mendelson MH, Meyers BR, Hirschman SZ, Shapiro ER, Parisier SC. Treatment of invasive external otitis with cefsulodin. Rev Infect Dis 1984;6(Suppl 3):S698-704 6. Caplan ES, Hoyt NJ. Nosocomial sinusitis. JAMA 1982; 247:639-41 7. JaneckaIP. Maxillofacial infections. Clin Plastic Surg 1979; 6:553-73 8. Becker GO, Parell GJ, Busch OF, Finegold SM, AcquareIIi

S782 Neu MJ. Anaerobic and aerobic bacteriology in head and neck cancer surgery. Arch Otolaryngol 1978;104:591-4 9. Bryan CS, Reynolds KL, Brenner ER. Analysis of 1,186episodes of gram-negative bacteremia in non-university hospitals: the effects of antimicrobial therapy. Rev Infect Dis 1983;5:629-38 10. Allen JR, Hightower AW, Martin SM, Dixon RE. Secular trends in nosocomial infections: 1970-1979. Am J Med 1981;70:389-92 11. Neu HC. Current mechanisms of resistance to antimicrobial agents in microorganisms causing infection in the patient at risk for infection. Am J Med 1984;76(Suppl 5A):11-27 12. Neu HC. Clinical use of aminoglycosides. In: Whelton A, Neu HC, eds. Aminoglycosides: microbiology, clinical use and toxicology. New York: Marcel Dekker, 1982: 611-28 13. Neu HC. Do we need the third-generation cephalosporins? J Antimicrob Chemother 1984;14(Suppl B):1-12 14. Young LS. Combination or single drug therapy for gramnegative sepsis. In: Remington JS, Swartz MN, eds. Current clinical topics in infectious disease. Vol. 3. New York: McGraw-Hill, 1982:177-205 15. Lou MA, Mandell AK, Alexander JL, Thadepalli H. Bacteriology of the human biliary tract and the duodenum. Arch Surg 1977;112:965-7 16. Pitt HA, Postier RG, Cameron JL. Biliary bacteria: significance and alterations after antibiotic therapy. Arch Surg 1982;117:445-9 17. Macfarlane JR, BrowneMK. Cholecystectomy wounds: source of infection. J Hosp Infect 1982;3:49-54 18. Stone HH, Martin JD Jr. Synergistic necrotizing cellulitis. Ann Surg 1972;175:702-10 19. Pruitt BA Jr. Burn wound care. Current Problems in Surgery 1979;16(5):6-10 20. Locksley RM, Cohen ML, Quinn TC, Tompkins LS, Coyle MB, Kirihara JM, Counts Gw. Multiply antibiotic-resistant Staphylococcus aureus: introduction, transmission and evolution of nosocomial infection. Ann Intern Med 1982;97:317-24 21. Goldenberg DL, Cohen AS. A review of patients with nongonococcal joint infections (with emphasis on therapy and prognosis). Acute infectious arthritis. Am J Med 1976; 60:369-77 22. Goldenberg DL, Brandt KD, Cathcart ES, Cohen AS. Acute arthritis caused by gram-negative bacilli: a clinical characterization. Medicine 1974;53:197-208 23. LeFrock JL, Carr BB. Clinical experience with cefotaxime in the treatment of serious bone and joint infections. Rev Infect Dis 1982;4(Suppl):S465-71 24. Meyers BR, Berson BL, Gilbert M, Hirschman SZ. Clinical patterns of osteomyelitis due to gram-negative bacteria. Arch Intern Med 1973;131:228-33 25. Waldvogel FA, VaseyH. Osteomyelitis: the past decade. N Engl J Med 1980;303:360-70 26. Kido D, Bryan D, Halpern M. Haematogenous osteomyelitis in drug addicts. AJR 1973;118:356-63 27. Sapico FL, Montgomerie JZ. Pyogenic vertebral osteomyelitis: report of nine cases and review of the literature. Rev Infect Dis 1979;1:754-76 28. Allen HE Bacterial endophthalmitis after cataract extraction. In: Bellows JG, ed. Cataract and anomalies of the lens. New York: Grune and Stratton, 1975:421