Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Antimicrobial agents active against anaerobic bacteria
Infections caused by anaerobic bacteria are common and may be serious and life-threatening. Anaerobes are predominant components of the bacterial flora of the normal human skin and mucous membranes and are a common cause of endogenous bacterial infections. Because of their fastidious nature, they are difficult to isolate and are often overlooked. Their isolation requires appropriate methods of collection, transportation, and cultivation. Treatment of anaerobic bacterial infections is complicated by the relatively slow growth of these organisms, frequent polymicrobial nature, and growing resistance to antimicrobials.
Antimicrobial resistance among anaerobes has increased in the past three decades, and their susceptibility has become less predictable. The most commonly isolated antibiotic-resistant anaerobes are those that belong to the Bacteroides fragilis group. This increase makes the choice of appropriate empiric therapy more difficult. Resistance patterns have been monitored through national and local surveys, but susceptibility testing of anaerobic bacteria at individual hospitals is rarely done. , This chapter describes the antimicrobials effective against anaerobic bacteria and the resistance of these organisms against them.
Antimicrobial agents effective against anaerobic bacteria
Table 109.1 illustrates the antimicrobials effective against anaerobic bacteria and their efficacy against both aerobic and anaerobic bacteria. Table 109.2 illustrates the resistance of bacteria from the B. fragilis group and other anaerobes to antimicrobials.
TABLE 109.1
Antimicrobial Agents Effective Against Mixed Infections
| ANAEROBIC BACTERIA | AEROBIC BACTERIA | |||
|---|---|---|---|---|
| Antimicrobial Agent | Beta-Lactamase–Producing AGNB | Other Anaerobes | Gram-Positive Cocci | Enterobacteriaceae |
| Penicillin a | 0 | + + + | + | 0 |
| Chloramphenicol a | + + + | + + + | + | + |
| Cephalothin | 0 | + | + + | ± |
| Cefoxitin | + + | + + + | + + | + + |
| Carbapenems | + + + | + + + | + + + | + + + |
| Clindamycin a | ++ | + + + | + + + | 0 |
| Ticarcillin | + | + + + | + | + + |
| Amoxicillin + clavulanate a | + + + | + + + | + + | + + |
| Piperacillin + tazobactam | + + + | + + + | + + | + + |
| Metronidazole a | + + + | + + + | 0 | 0 |
| Moxifloxacin | ++ | ++ | ++ | +++ |
| Tigecycline | ++ | +++ | +++ | ++ |
AGNB , Anaerobic gram-negative bacilli.
Degrees of activity: 0 to + + +.
TABLE 109.2
Percent Resistance of Bacteroides fragilis Group and Other Anaerobes to Antimicrobial Agents (Includes Intermediate-Resistant Strains)
Adapted from Mazuski JE, Solomkin JS. Intra-abdominal infections. Surg Clin North Am . 2009;89(2):421-ix.
| Amp-Sulb | Amx-Clav | Pip-Tazo | Fox | Erta | Imi | Mero | Dori | Clinda | Moxi | Tige | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Suscept. breakpoint | <8/4 | <4/2 | <32/4 | <16 | <4 | <4 | <4 | <4 | <2 | <2 | <4 |
| Resistant | >32/16 | >16/8 | >128/4 | >64 | >16 | >16 | >16 | >16 | >8 | >8 | >16 |
| Organism | |||||||||||
| Bacteroides fragilis | 2.8–11 | 4–37 | 0–5 | 4–25 | 1.4–10 | 0.3–7 | 1.2–22 | 1.3–12 | 10–42 | 10–41 | 2–11 |
| B. thetaiotaomicron | 4.9–15 | 12–37 | 0–12 | 6.8–68 | 1.3–3 | 0–7 | 0–3 | 0–3 | 39.8–60 | 13–75 | 0–5.8 |
| Parabacteroides distasonis | 15–20.6 | 21 | 0–14 | 11–60 | 0–6 | 0–1 | 0–1 | 0 | 14.3–64 | 12.5–52 | 0–3.2 |
| B. ovatus | 2–8 | 18 | 0 | 18–59 | 2–2.2 | 0 | 0 | 0 | 36–45.5 | 8–87 | 2–5.2 |
| B. vulgatus | 3–25 | 14 | 1.1–7 | 11–20 | 0–2 | 0–7 | 0 | 0 | 40–54 | 21–74 | 0–5 |
| B. fragilis group | 10–20 | 0–8 | 17–33 | <1–1 | 32–52 | 14–57 | 2–13 | ||||
| Prevotella spp. | 0 | 0–19 | 0–1 | 0–3 | 0 | 0–6 | 13–33 | 11–42 | 0 | ||
| Fusobacterium spp. | 0–11 | 0 | 0 | 0 | 4 | 8 | 0 | 8–31 | 10–25 | 0 | |
| Clostridium spp. | 0 | 0–5 | 0 | 16–35 | 0–4 | 15 | 0–5 | 0 | 16–25 | 7–53 | 14 |
| Anaerobic gram-positive cocci | 0 | 0–6 | 0–3 | 0–2 | 0 | 0 | 0 | 0 | 5–27 | 3–36 | 0 |
Amx-Clav, Amoxicillin/clavulanate; Amp-Sulb, ampicillin/sulbactam; Clinda, clindamycin; Dori, doripenem; Erta, ertapenem; Fox, cefoxitin; Imi, imipenem; Mero, meropenem; Moxi, moxifloxacin; Pip-Tazo, piperacillin/tazobactam; Tige, tigecycline.
Metronidazole is not included because >99% of gram-negative strains are susceptible.
Beta-lactam antibiotics
Penicillin G is the classical drug of choice when the infecting strains are susceptible. Most Clostridium strains (except some C. ramosum, C. clostridioforme, and C. innocuum ) and Peptostreptococcus spp. remain susceptible to penicillin. Most B. fragilis groups are resistant to penicillin. Other strains that may show resistance are growing numbers of anaerobic gram-negative bacilli (AGNB), such as pigmented Prevotella and Porphyromonas spp., Prevotella oralis, P. bivia, B. disiens , strains of Clostridia, Fusobacterium spp. ( F. varium and F. mortiferum ), and microaerophilic streptococci. Some of these strains show minimum inhibitory concentration (MIC) of 8–32 units/mL of penicillin G. In these instances, administration of very high dosages of penicillin G (for non–beta-lactamase producers) may eradicate the infection.
Ampicillin, amoxicillin, and penicillin are generally equal in activity to penicillin G, but the semisynthetic penicillins are less active. Methicillin, nafcillin, and the isoxazolyl penicillins ( oxacillin, cloxacillin, and dicloxacillin ) are ineffective against the B. fragilis group, have unpredictable activity, and are frequently inferior to penicillin G against anaerobes.
Penicillin and ampicillin/amoxicillin are of limited utility because of the production of beta-lactamases by many oral and most intraabdominal anaerobes. Clavulanate, sulbactam, and tazobactam irreversibly inhibit beta-lactamase enzymes produced by beta-lactamase–producing Fusobacterium spp. and AGNB. When used in combination with a beta-lactam antibiotic (e.g., ampicillin-sulbactam, amoxicillin-clavulanate, and piperacillin-tazobactam ), they are effective in treating anaerobic infections caused by beta-lactamase–producing bacteria (BLPB).
Beta-lactam/beta-lactamase inhibitor combinations (BL-BLICs) are appropriate choices for mixed aerobic-anaerobic infections. They have maintained good activity against most anaerobes. Whereas 89% of B. fragilis are susceptible to ampicillin-sulbactam, 98% are susceptible to piperacillin-tazobactam compared with 86% and 92%, respectively, for B. thetaiotaomicron isolates. Recently, the Infectious Diseases Society of America (IDSA) removed ampicillin-sulbactam from the recommended list of drugs for intraabdominal infections because of increased Escherichia coli resistance. Amoxicillin-clavulanate remains the agent of choice for human and animal bite wound infections, especially when anaerobes may be involved. Piperacillin-tazobactam is also a frequently and appropriately prescribed agent for serious intraabdominal infections. It has also maintained good activity against most anaerobes.
The semisynthetic penicillins, the carboxy-penicillins ( carbenicillin and ticarcillin ) and ureidopenicillins ( piperacillin, azlocillin, and mezlocillin ), generally are administered in large quantities to achieve high serum concentration. These drugs are effective against Enterobacteriaceae and have good activity against most anaerobes at these concentrations. However, up to 30% of the bacteria in the B. fragilis group is resistant.
Many anaerobes possess cephalosporinases, and therefore cephalosporins have limited utility. The activity of cephalosporins against the beta-lactamase–producing AGNB varies. The antimicrobial spectrum of the first-generation cephalosporins against anaerobes is similar to penicillin G, although on a weight basis, they are less active. Most strains of the B. fragilis group and many Prevotella, Porphyromonas, and Fusobacterium spp. are resistant to these agents. Cephalosporinases have little or no hydrolytic activity against the second-generation cefoxitin (a cephamycin), which is the most effective cephalosporin against the B. fragilis group. However, susceptibility may vary by geographic location and is generally directly related to its clinical use. Cefoxitin is relatively inactive against most species of Clostridium, including C. difficile, with the exception of C. perfringens .
Cefoxitin is often used for surgical prophylaxis at most body sites that involve mucous membranes. With the exception of moxalactam, the third-generation cephalosporins are not as active against B. fragilis .
Currently, approximately 85% of B. fragilis isolates are susceptible to cefoxitin, but the other B. fragilis group species are more resistant. Cefotetan is less effective than cefoxitin against B. fragilis and other members of the B. fragilis group. Recently, the IDSA removed cefotetan from the recommended list of drugs against intraabdominal infections because of poor B. fragilis group activity and resultant clinical failures.
The carbapenems (imipenem, meropenem, doripenem, and ertapenem) have excellent activity against anaerobes. Imipenem, a thienamycin, is a beta-lactam antibiotic that is effective against a wide variety of aerobic and anaerobic gram-positive and gram-negative organisms, including B. fragilis . , It is also effective against most Enterobacteriaceae, with about 5%–15% of Pseudomonas spp. resistance. To overcome the problem of renal metabolism of imipenem, it is combined at a 1:1 ratio with an inhibitor of the renal dipeptidase, cilastatin. This agent is an effective single agent for the treatment of mixed aerobic-anaerobic infections. Recarbrio (imipenem, cilastatin, and the beta-lactamase inhibitor relebactam) has been approved by the Food and Drug Administration (FDA) for the treatment of complicated intraabdominal infections. Relebactam is active against both class A and class C beta-lactamases and restores imipenem susceptibility to many imipenem-resistant isolates of AmpC-producing Pseudomonas aeruginosa and Enterobacteriaceae expressing Klebsiella pneumoniae carbapenemases (KPC) or combinations of impermeability and extended-spectrum beta-lactamases (ESBLs)/AmpCs.
Meropenem antibacterial activity is similar to imipenem. However, it is less active against staphylococci and enterococci and provides better coverage of aerobic and facultative gram-negative bacteria. Meropenem has been effective in abdominal infections, meningitis in children and adults, community-acquired and nosocomial pneumonia, and neutropenic fever.
Ertapenem, a newer 1-beta-methyl carbapenem, is stable to dehydropeptidase and has a broad antibacterial spectrum for aerobic and anaerobic bacteria, including C. perfringens, Fusobacterium spp., Peptostreptococcus spp., and AGNB. Compared with other available carbapenems, ertapenem has a long half-life of 4.5 hours and is given as a single daily dose. It is not active against P. aeruginosa, Enterococcus spp., and Acinetobacter spp.
Doripenem, a synthetic 1-beta-methyl carbapenem, possesses a similar antimicrobial spectrum to meropenem and imipenem. It has significant in vitro activity against aerobic and anaerobic bacteria, including the B. fragilis group. In vitro, resistant P. aeruginosa mutants appear to be harder to select with doripenem than with other carbapenems.
Carbapenems are generally employed in more serious anaerobic infections such as intraabdominal and skin and soft tissue infections. Recent reports have noted the development of some carbapenem resistance among anaerobes, ranging from 1.1% to 2.5% in a multicenter US survey but higher in a small number of isolates from Taiwan.
Resistance to beta-lactam antibiotics
Anaerobes manifest three major resistance mechanisms to beta-lactam antibiotics: inactivating enzymes, mainly beta-lactamases (BLAs), which include penicillinases and cephalosporinases; low-affinity penicillin binding proteins (PBPs); and decreased permeability through alterations in the porin channel. The production of BLAs is the most common mechanism of resistance to beta-lactam antibiotics in anaerobes, especially among the B. fragilis group and Prevotella spp. Typically, the cephalosporinases belong to the 2e class type and can be inhibited by three beta-lactamase inhibitors: clavulanic acid, sulbactam, and tazobactam. Each individual cephalosporin may have either a class or specific inhibitor enzyme that is able to inactivate it.
Carbapenemases are active against the carbapenems and all beta-lactam antibiotics. Carbapenem resistance occurs in <1% of US isolates, and up to 3% of Bacteroides strains harbor one of the genes that is expressed at a very low level.
With a few exceptions among some Clostridium spp., strains of Clostridium, Porphyromonas, and Fusobacterium have also been found to express resistance by one or more of the BLAs. BLA-producing Fusobacterium and Clostridium spp. express enzymes that are generally inhibited by clavulanic acid. Resistance to beta-lactam antibiotics through changes in the OMP/porin channels, decreased PBP affinity, and efflux pumps is less well studied. The bacteria in the B. fragilis group are generally resistant to penicillins (average 90%), piperacillin (25%), cefoxitin (25%), cefotetan (30%–85%), and third-generation cephalosporins. , The combinations of BL-BLICs inhibitors and carbapenems have maintained their excellent antibacterial activity. The combination of ampicillin-sulbactam, amoxicillin-clavulanate, ticarcillin-clavulanate, and piperacillin-tazobactam is generally very active against members of the B. fragilis group. However, species-to-species variation in susceptibility occurs. Resistance to co-amoxiclav (8%) was reported in Slovania. B[6]. fragilis group resistance rates for piperacillin-tazobactam is generally <1%. However, resistance of Parabacteroides distasonis to ampicillin-sulbactam has risen to 20% in 2002–2004 but continued to be low for the other B. fragilis group species.
The carbapenems (imipenem, meropenem, doripenem, and ertapenem) are very effective against all members of the B. fragilis group, and resistance is rare at <0.1%. , , Geometric mean MICs for imipenem and meropenem for P. distasonis, B. thetaiotaomicron, and B. ovatus have been reported to be onefold dilution lower than those for ertapenem in 2004. The non– B. fragilis group (including B. intestinalis, B. nordii, B. pyogenes, B. stercoris, B. salyersiae, and B. cellulosilyticus ) was found resistant to meropenem (14%) between 2014 and 2016 in Korea. Imipenem resistance was found in a quarter of metronidazole-resistant isolates.
Beta-lactams are generally effective against non– B. fragilis group species, and resistance to them is generally low, except that more than half of Prevotella spp. may also produce BLAs. A multicenter survey found penicillin resistance for Fusobacterium spp., Porphyromonas spp., and Peptostreptococcus spp. at 9%, 21%, and 6%, respectively. No resistance was found to cefoxitin, cefotetan, beta-lactam/BLA inhibitor combinations, and carbapenems in that survey, with the exception of Peptostreptococcus spp. and Porphyromonas spp. (4% and 5% resistance to ampicillin-sulbactam, respectively). BLAs were identified in several Prevotella and Porphyromonas spp. recovered from pediatric intraabdominal infections.
Chloramphenicol
Chloramphenicol, a bacteriostatic agent, is active against most anaerobic bacteria but is rarely used in the United States. , Resistance is rare. Although several failures to eradicate anaerobic infections with chloramphenicol have been reported, this agent has been used for over 65 years for treatment of anaerobic infections. In the past, it was the drug of choice for the treatment of serious anaerobic infections, including the central nervous system (CNS). However, the drug has potential significant toxicity. The risk of fatal aplastic anemia with chloramphenicol is estimated to be approximately 1 per 25,000–40,000 patients treated. This serious complication is unrelated to the reversible, dosage-dependent leukopenia. Other side effects include the production of the potentially fatal “gray baby syndrome” when given to neonates, hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, and optic neuritis in those who take the drug for a prolonged time.
Chloramphenicol has a unique property of lipid solubility to permit penetration across lipid barriers. Levels in the cerebrospinal fluid, with or without meningitis, usually are one-third to three-fourths the serum concentrations. Levels in brain tissue may be substantially higher than serum levels.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here