Present Status of Therapy for Anaerobic Infections

89 Present Status of Therapy for Anaerobic Infections Sydney M. Finegold and Hannah M. Wexler From the Medical and Research Services, Veterans Affairs Medical Center West Los Angeles, and the Department of Medicine, UCLA School of Medicine, Los Angeles, California Therapeutic approaches to anaerobic infections are changing. Debridement, drainage, and other surgical approaches remain extremely important. Resistance to antimicrobial agents currently used for treatment of anaerobic infections is increasing. However, promising new agents are being introduced. We review the current status of therapy for anaerobic infections and discuss the potential role of these new agents. We stress an empirical approach to therapy that is based on the usual infecting flora in various types of infections. Treatment of anaerobic infections may be difficult. Failure to provide coverage for anaerobes in mixed infections may lead to a poor response or to no response. Many antibacterial agents including aminoglycosides, trimethoprim-sulfamethoxazole, most quinolones, and monobactams have poor activity against many or most anaerobes. Antimicrobial resistance is increasing among anaerobes. All of these factors account for the difficulty in managing anaerobic infections. At the same time, there are some promising new agents that have recently become available. Classification of The most important anaerobes clinically are the genera of gram-negative rods. Bacteroides, especially the B. Jragilis group (made up of 10 species, one of which is the species B. Jragilis), is particularly important. The other principal gram-negative genera are Prevotella, Fusobacterium, Porphyromonas, Bilophila, and Sutterella. Among the gram-positive anaerobes, there are cocci (primarily Peptostreptococcus) and spore-forming (Clostridium) and non-spore-forming bacilli (especially Actinomyces and Propionibacterium). Table I lists the anaerobes most commonly encountered. Therapeutic Considerations The two key approaches to treatment of anaerobic infections are surgery (or nonsurgical drainage) and antimicrobial therapy. Debridement and drainage typically are essential. Failure to carry out necessary surgical therapy promptly and thoroughly may lead to failure of response to appropriate antimicrobial This article has been modified from a chapter in [9]. Reprints or correspondence: Dr. Sydney M. Finegold, Infectious Disease Section (Ill-F), Veterans Affairs Medical Center West Los Angeles, 11301 Wilshire Boulevard, Los Angeles, California 90073. Clinical Infectious Diseases 1996;23 (Suppl1):S9-14 1996 by The University of Chicago. All rights reserved. 1058-4838/96/2306-0003$02.00 agents. Some abscesses are amenable to percutaneous drainage under ultrasonographic or CT guidance. Hyperbaric oxygen (HBO) therapy may be of value only in selected circumstances, such as cases of gas gangrene; in the case of an infected extremity, demarcation of the infection may indicate at what level amputation should be done. However, there has never been clear-cut clinical evidence that HBO therapy is significantly beneficial; thus one should certainly never delay needed surgical therapy to administer HBO. Initial antimicrobial therapy for anaerobic infections is necessarily empirical: it may take several days or longer to obtain definitive information on the infecting flora because such floras are usually complex. Rational empirical therapy is based on the following factors: the clinician's assessment of the nature of the infectious process, his/her knowledge of the usual flora in such infections (tables 2-6), and patterns of resistance to antimicrobial drugs in the hospital where he/she practices. The clinician must also take into account how the usual flora may have been modified by pathophysiology or disease or by prior antimicrobial prophylaxis or therapy. Careful analysis of a gram stain of the specimen may also suggest the need to modify the empirical approach. In certain situations, the pharmacological properties of drugs and their bactericidal activity are important considerations. For example, one must use a drug that crosses the blood-brain barrier well for treatment of CNS infections; accordingly, clindamycin would not be suitable. Bactericidal activity is an important consideration in the treatment of CNS infections, endocarditis, and infections in patients with impaired defenses. Most of the drugs that are active against anaerobes have good bactericidal activity; chloramphenicol is the principal exception. Other factors may need to be taken into consideration under certain circumstances. Stevens et al. [6] have shown that clindamycin and metronidazole may suppress the production of toxins by clostridia and that clindamycin may have important inmlunomodulatory effects. Good clinicians maintain close contact with the microbiology laboratory, particularly in the case of a very sick pa-

SIO Finegold and Wexler em 1996;23 (Suppl 1) Table 1. most commonly encountered in infections. Bacteroides fragilis group (especially B. fragilis) Pigmented and nonpigmented Prevotella species Fusobacterium nucleatum Peptostreptococcus Clostridium perfringens, Clastridium ramosum NOTE. These five groups together account for about two-thirds of anaerobes recovered from clinically significant infections involving anaerobes. Table 2. Usual flora recovered from patients with anaerobic pleuropulmonary infections. Peptostreptococcus (P. micros, P. anaerobius, and P. magnus) Pigmented Prevotella (P. denticola, P. melaninogenica, P. intermedia, P. nigrescens, and P. loescheii) Nonpigmented Prevotella (P. oris, P. buccae, and P. oralis) Fusobacterium nucleatum (subspecies nucleatum and polymorphum) Bacteroides fragilis group Non-spore-forming, gram-positive rods (Actinomyces, Eubacterium, and Lactobacillus) Viridans streptococci NOTE. In hospital-acquired infections (e.g., aspiration pneumonia), various nosocomial pathogens such as Staphylococcus aureus, Enterobacteriaceae, and Pseudomonas may be involved in addition to the elements of the indigenous flora listed above. Data are from [1]. tient. Such contact should begin before the specimen is submitted and be maintained until the full culture results are available. The microbiologist may decide to use special selective media or other media in setting up a culture because of information Table 3. Usual flora recovered from patients with intra-abdominal infections. Predominant anaerobes Bacteroides fragilis Bacteroides thetaiotaomicron Bilophila wadsworthia Peptostreptococcus (especially P. micros) Clostridium Predominant aerobes and facultatives Escherichia coli Streptococci (viridans group and group D) Pseudomonas aeruginosa Predominant organisms isolated from patients with biliary tract infections Uncomplicated E. coli, Klebsiella, Enterococcus, and Clostridium perfringens Complicated (prior surgery or malignancy) Bacteroides fragilis group may also be involved NOTE. In hospital-acquired infections, nosocomial pathogens such as Staphylococcus aureus and various Enterobacteriaceae may also be involved. Data are from [2]. Table 4. Usual flora recovered from patients with female genital tract infections. Peptostreptococcus Bacteroides fragilis group Prevotella (especially P. bivia, P. disiens, and pigmented Prevotella) Clostridium (especially C. perfringens) Actinomyces, Eubacterium (in intrauterine contraceptive deviceassociated infections) Nonanaerobes Streptococcus (groups A and B and others) Escherichia coli Klebsiella Gonococcus (in sexually active females) Chlamydia trachomatis (in sexually active females) Mycoplasma hominis (in postpartum patients) NOTE. Data are from [3]. provided by the clinician, and the culture might be examined more frequently than would be done for routine cultures (this can be done with use of a device that permits examination of the culture without exposing it to oxygen during the crucial early period of incubation). Preliminary culture results may suggest a need for modification of the initial empirical antimicrobial regimen. Table 7 summarizes the activity of various antimicrobials against the major anaerobes encountered clinically, as determined by the Wadsworth Anaerobic Bacteriology Laboratory (Veterans Affairs Medical Center West Los Angeles, Los Angeles) with use of the Wadsworth agar dilution method. Antimicrobials not listed in the table are not approved by the U.S. Food and Drug Administration or are generally not recommended for treatment of anaerobic infections. In most cases, clinical data are available and support the use of these agents as therapy for infection with anaerobes. Susceptibility patterns Table 5. Usual flora recovered from diabetic foot ulcers. Peptostreptococcus (especially P. magnus, P. prevotii, P. anaerobius, and P. asaccharolyticus) Bacteroides fragilis group (especially B. fragilis and B. thetaiotaomicron) Other Bacteroides Pigmented Prevotella Nonanaerobes Enterococcus Staphylococcus aureus Streptococci (especially group B) Proteus mirabilis Escherichia coli Other Enterobacteriaceae Pseudomonas aeruginosa NOTE. Data are from [4].

em 1996; 23 (Supp! 1) Therapy for Anaerobic Infections Sll Predominant flora recovered from skin and soft-tissue ab Table 6. scesses. In intravenous drug abusers Fusobacterium nucleatum Peptostreptococcus micros Actinomyces odontolyticus Pigmented Prevotella N onanaerobes Staphylococcus aureus Streptococcus (" S. milleri group," viridans group, and group A) In nonintravenous drug abusers Peptostreptococcus (P. magnus, P. micros, and P. asaccharolyticus) Pigmented Prevotella Actinomyces species F. nucleatum Nonanaerobes S. aureus Streptococcus ("s. milleri group," viridans group, and group A) NOTE. Data are from [5]. vary in different geographic locations and even in different hospitals in the same city, which is primarily related to patterns of antibiotic use. Thus, periodic susceptibility testing should be carried out to establish patterns of resistance in local hospitals [8]. Susceptibility testing of individual isolates recovered from patients also may be indicated. Such testing would be of special importance in cases in which an antibiotic plays a pivotal role in the outcome, an empirical decision is difficult because of lack of precedent, or the susceptibility pattern of the organism is not well known or displays considerable variability (e.g., that of the B. fragilis group, certain other anaerobic gram-negative bacilli, and clostridia other than Clostridium perfringens). In terms of infections per se, susceptibility testing is indicated for serious infections (e.g., brain abscess, bacteremia, or endocarditis), infections requiring prolonged therapy (e.g., osteomyelitis or an infection associated with a prosthesis), and infections that fail to respond to empirical therapy or that relapse after an initial response to such therapy. Four drugs or groups of drugs are active against the majority of anaerobic bacteria of clinical significance; these are nitroimidazoles such as metronidazole, carbapenems such as imipenem, chloramphenicol, and combinations of,b-lactam drugs with a,b-iactamase inhibitor. Non-sporeforming, anaerobic, gram-positive bacilli (e.g., Actinomyces, Eubacterium, and Propionibacterium) are commonly resistant to metronidazole, as are a number of strains of Sutterella. There have been disturbing reports of resistance to all of the above agents in small numbers of strains of the B. fragilis group. Three other drugs or groups of drugs have good activity against anaerobes but are less active than the four groups mentioned above; these agents are cefoxitin, clindamycin, and broad-spectrum penicillins such as ticarcillin or piperacillin. Of B. fragilis group strains, 15%-25% are resistant to these compounds in many hospitals in the United States and elsewhere. and clindamycin have relatively weak activity against clostridia other than C. perfringens (20%-35% of such strains are resistant to these drugs), and some anaerobic cocci are resistant to clindamycin. Penicillin G is not reliable for treating serious infections involving any of the anaerobic gram-negative bacilli because the incidence of,b-iactamase production among these organisms is high. Some of the newer cephalosporins such as ceftizoxime and cefotetan have sufficient antianaerobic activity to be useful in treating certain anaerobic infections, and these drugs have been found to be comparable to cefoxitin and clindamycin plus gentamicin in double-blind comparative studies of therapy for some anaerobic infections. The three types of infections for which these newer cephalosporins clearly have been shown to be effective are appendicitis (with only localized complications), female genital tract infections such as pelvic inflammatory disease and endometritis, and infected foot ulcers or similar soft-tissue infections (with or without underlying bone infection). Some of these agents are less expensive. Use of such agents also serves to save the more potent drugs for serious infections. However, it is important not to treat patients who are quite ill with these drugs unless and until careful studies establish that to do so would be reasonable. Most anaerobic infections are mixed, involving aerobic or facultative bacteria in addition to anaerobes; antimicrobial therapy must cover the key pathogens of all types. Some of the drugs discussed above have significant activity against certain nonanaerobes, but it is ordinarily necessary to add another agent to cover all of the flora. In general, for treatment of serious anaerobic infections, antimicrobials should be given parenterally in the maximum approved dosages based on the weight and renal and hepatic function of the patient. This dosage recommendation is based on the fact that penetration of drugs into abscesses, necrotic tissue, or poorly perfused tissue (all common situations in serious anaerobic infections) is less than optimal. To minimize the risk of relapse, duration of therapy is also an important consideration for patients with anaerobic infections; for example, lung abscesses usually require therapy for several weeks, empyema requires therapy for 2-3 months, and actinomycosis requires therapy for 6-12 months or longer. Duration of therapy must be individualized, taking into account the site, type, extent, and severity of the infection; the nature of the infecting organisms; whether the host is immunocompromised or in poor condition because of associated or underlying illness; and the speed of response to treatment.

[fj tv Table 7. Susceptibility of anaerobes to antimicrobial agents. Percent sllsceptible* Bacteroides Fagilis Other B. }Yagilis group! Bacteroides gracilis Other Bacteroides Prevotella POlphyromonas Sutterella wadsworthensis >95 85-95 70-84 )0-69 <50 Ampicillin + + tazobactam Cefoperazone + Cefotetan Cefoperazone Ceftazidime Penicillin at Ciprofioxacin Ampicillin + Cefoperazone + + tazobactam c1avulanate Cefoperazone Cefolelan Penicillin a Ceftazidime + tazobactam Meropenem Ciprofioxacin Fleroxocin Ampicillin + Cefoperazone Cefoperazone + Cefolelan Ceftazidime Penicillin G Ciprofioxacin Ciprofloxacin Clinaftoxacin Ciproftoxacin c1avulanate clavulanatc + tazobactarn.." S (JQ '" 0 0: '" 0. " '" x 1:f n 5 'D "-D p' tv '" (/3

n Table 7. (Continued) 8 -\0 \0 Fusobacterium. Percent Fusobacterium mortiferuml Other Bilophila Clostridium Clostridium Clostridium Other N V.l susceptible nucleatum varium Fusobacterium wadsworthia Peptostreptococcus difficilei ramosum perfringeus Clostridium NSF-GPRiI til >95 Ampicillin + Ampicillin + Ampicillin + Ampicillin Ampicillin + Ampicillin + '-'- Ampicillin + Penicillin G Ampicillin + + Penicillin G tazobactam Amoxicillin + Carbenicillin Penicillin G + Ticarcillin c1avulanate tazobactam Penicillin G tazobactam Cefoperazone Ampicillin Cefoperazone + Ticarcillin Ticarcillin Cefotetan Ampicillin Clinafioxacin Cefotetan lmipenem Ciprofioxacin Ceftazidime Ticarcillin Clinafioxacin Cefttiaxone Cefotetan hnipenem Ciprofioxacin lmipenem Ciprofloxacin 85-95 Ampicillin + Cefoperazone +.,... '" Cefoperazone Ampicillin Cefotetan Cefoperazone + S' (t> ("). Cefotetan '" Cefttiaxone 70-84 Ciprofioxacin Ceftazidime Cefoperazone 50-69 Ciprofloxacin Cefoperazone Ciprofioxacin Cefttiaxone <50 Amoxicillin Ciprofioxacin Ceftazidime Ampicillin Ciprofioxacin Penicillin G Ciprofloxacin.a (j>... NOTE. Data from Wadsworth Anaerobic Bacteriology Laboratory. Drugs not listed have not been tested. The order of listing of drugs within percent susceptible categories is not significant. According to the NCCLS-approved breakpoints (Mll-A3), using the intermediate category as susceptible. t NCCLS-approved breakpoint is 4 j.<glml. However, the breakpoint should probably be lowered to I j.<glml, which will considerably lower the values for percent snsceptible. For example, at I j.<glml, no strains of the B. fragilis group were susceptible.! Excluding B. fragilis. i Breakpoint is used ouly as a reference point. C. difficile is primarily of interest in relation to antimicrobial-induced pseudomembranous colitis. These data mnst be interpreted in the context of level of drug achieved in the colon and effect of agent on indigenous colonic flora. II Non-spore-forming gram-positive rod. en -V.l

S14 Finegold and Wexler cm 1996;23 (Suppl 1) References 1. Civen R, Jousimies-Somer H, Marina M, Borenstein L, Shah H, Finegold SM. A retrospective review of cases of anaerobic empyema and update of bacteriology. Clin Infect Dis 1995;20 (suppi2):s224-9. 2. Bennion RS, Thompson JE, Baron EJ, Finegold SM. Gangrenous and perforated appendicitis with peritonitis-treatroent and bacteriology. Clin Ther 1990; 12(suppl C):13-24. 3. Duerden BI. in genitourinary infections. In: Duerden BI, Drasar BS, eds. in human disease. New York: Wiley-Liss, 1991. 4. Sapico FL, Canawati HN, Witte JL, et al. Quantitative aerobic and anaerobic bacteriology of infected diabetic feet. J Clin Microbiol1980; 12:413-20. 5. Summanen PH, Talan DA, Strong C, et al. Bacteriology of skin and softtissue infections: comparison of infections in intravenous drug users and individuals with no history of intravenous drug use. Clin Infect Dis 1995; 20(suppl 2):S279-82. 6. Stevens DL, Maier KA, Laine BM, Mitten JE. Comparison of clindamycin, rifampin, tetracycline, metronidazole, and penicillin for efficacy in prevention of experimental gas gangrene due to Clostridium perfringens. J Infect Dis 1987; 155:220-8. 7. Wexler HM, Reeves D, Summanen PH, et al. Sutterella wadsworthensis gen. nov., sp. nov., bile-resistant microaerophilic Campylobacter gracilis-like clinical isolates. Int J Syst BacterioI1996;46:252-8. 8. National Committee for Clinical Laboratory Standards. Methods for antimicrobial susceptibility testing of anaerobic bacteria: approved standard; 3rd ed. NCCLS document Mll-A3. Villanova, Pennsylvania: National Committee for Clinical Laboratory Standards, 1993. 9. Finegold SM, Wexler HM. Anaerobic infections. In: Schlossberg D, ed. Current therapy of infectious disease. st. Louis: Mosby, 1996:369-75. Suggested Reading Borriello SP, ed. Clinical and molecular aspects of anaerobes. Petersfield, United Kingdom: Wrightson Biomedical Publications, 1990. Brook I. Pediatric anaerobic infection. Diagnosis and management. 2nd ed. St. Louis: Mosby, 1989. Duerden BI, Drasar BS, eds. in human disease. New York: Wiley Liss, 1991. Finegold SM. Anaerobic bacteria in human disease. New York: Academic Press, 1977. Finegold SM. Anaerobic infections in humans: an overview. Anaerobe 1995; 1:3-9. Finegold SM, George WL eds. Anaerobic infections in humans. San Diego: Academic Press, 1989. Summanen P. Microbiology terminology update: clinically significant anaerobic gram-positive and gram-negative bacteria (excluding spirochetes). Clin Infect Dis 1995;21:273-6. Summanen P, Baron EJ, Citron DM, Strong CA, Wexler HM, Finegold SM: Wadsworth anaerobic bacteriology manual. 5th ed. Belmont, California: Star Publishing Co., 1993. Willis AT. Clostridia of wound infection. London: Butterworths, 1969.