Infections caused by anaerobic bacteria are common, and may be serious and life-threatening. Anaerobes predominant in the bacterial flora of normal human skin and mucous membranes, and are a common cause of bacterial infections of endogenous origin. Infections due to anaerobes can evolve all body systems and sites. The predominate ones include: abdominal, pelvic, respiratory, and skin and soft tissues infections. Because of their fastidious nature, they are difficult to isolate and are often overlooked. Failure to direct therapy against these organisms often leads to clinical failures. Their isolation requires appropriate methods of collection, transportation and cultivation of specimens. Treatment of anaerobic bacterial infection is complicated by the slow growth of these organisms, which makes diagnosis in the laboratory only possible after several days, by their often polymicrobial nature and by the growing resistance of anaerobic bacteria to antimicrobial agents.

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Treatment and Prevention of Anaerobic Infections

The recovery from an anaerobic infection depends on prompt and proper management. The principles of managing anaerobic infections include neutralizing bacterial toxins, preventing bacterial proliferation by changing the environment and hampering bacterial spread into healthy tissues.
Toxin neutralization by specific antitoxins may be employed, especially in infections caused by Clostridium spp. (tetanus and botulism). Controlling the environment is achieved by debriding of necrotic tissue, draining the pus, improving circulation, alleviating the obstruction and increasing the tissue oxygenation. The primary role of antimicrobials is in limiting the local and systemic spread of the organism.


Hyperbaric oxygen (HBO)

There is controversy regarding whether HBO should be used in infection of spore-forming Gram-positive anaerobic rods. Several uncontrolled reports demonstrated efficacy in individual cases.1 However, the efficacy of HBO is unproved in well-controlled studies. Using HBO in conjunction with other therapies is not contraindicated, except when it delays other essential procedures. Topical application of oxygen-releasing compounds may be useful.


Hyperbaric oxygen chamber 


Surgical therapy

In many cases surgical therapy is the most important and sometimes the only form of treatment required, whereas in others it is an adjunct to a pharmacologic approach. It includes draining abscesses, debriding necrotic tissues, decompressing closed space infections and relieving obstructions. Without drainage the infection may persist and serious complications can develop.


Antimicrobial therapy

Appropriate management of mixed aerobic and anaerobic infections requires the administration of antimicrobials effective against both components. (Table 3) A number of factors should be considered when choosing appropriate antimicrobial agents. They should have efficacy against all target organisms, induce little or no resistance, achieve sufficient levels in the infected site, and have minimal toxicity and maximum stability.



Antimicrobials often fail to cure the infection. Among the reasons for this are the development of bacterial resistance, achievement of insufficient tissue levels, incompatible drug interaction and the development of an abscess. The abscess environment is detrimental to many antibiotics. The abscess capsule interferes with the penetration of drugs, and the low pH and the presence of binding proteins or inactivating enzymes (i.e. beta-lactamase) may impair their activity. The low pH and the anaerobic environment within the abscess are especially unfavorable for the aminoglycosides and quinolones. However, an acidic pH, high osmolarity and an anaerobic environment can also develop in the absence of an abscess.

When choosing antimicrobials for the therapy of mixed infections, their aerobic and anaerobic antibacterial spectrum (Table 1) and their availability in oral or parenteral form should be considered. Some antimicrobials have a limited range of activity. For example, metronidazole is active only against anaerobes and therefore cannot be administered as a single agent for the therapy of mixed infections. Others (i.e. carbapenems) have wide spectra of activity against aerobes and anaerobes.
The selection of antimicrobials is simplified when reliable culture results are available. However, this may be difficult to achieve in anaerobic infections because of problems in obtaining appropriate specimens. Many patients are treated empirically on the basis of suspected, rather than established, pathogens. Fortunately, the types of organisms involved in many anaerobic infections and their antimicrobial susceptibility patterns tend to be predictable. However, the pattern of resistance to antimicrobials may vary in a particular hospital and resistance to antimicrobial agents may emerge while a patient is receiving therapy.

The susceptibility of the B. fragilis group to the frequently used antimicrobial drugs has been studied systemically over the past 2 decades.2 These surveys have failed to reveal strains resistant to chloramphenicol or metronidazole and minimal resistance (<1%) to carbapenems or the combinations of a penicillin and beta-lactamase inhibitors, but resistance to other agents varies. The rate differs among various medical centers and generally increases with extensive use of some antimicrobial agents (penicillins, cephalosporins and clindamycin).


Recent reports of multiple drug resistant B. fragilis 7,8  underscores the need for improved antibiotic stewardship. Although B. fragilis has long been considered reliably susceptible to a number of broad-spectrum anti-anaerobic drugs (3), these cases suggest clinicians should no longer rely on cumulative susceptibility data from surveys alone to direct treatment and should consider requesting susceptibility testing when treating serious infections caused by B. fraglis.

Aside from susceptibility patterns, other factors influencing the choice of antimicrobial therapy include the pharmacologic characteristics of the various drugs, their toxicity, their effect on the normal flora and bactericidal activity. Although identification of the infecting organisms and their antimicrobial susceptibility may be needed for selection of optimal therapy, the clinical setting and Gram-stain preparation of the specimen may indicate the types of anaerobes present in the infection as well as the nature of the infectious process.


Antimicrobial agents (Tables 3-5)

Some classes of agents have poor activity against anaerobic bacteria. These include the aminoglycosides, the monobactams and the older quinolones. Antimicrobials suitable for use in anaerobic infections are discussed in more detail below.



Penicillins
Penicillin G is still the drug of choice against most non-beta lactamase producing bacteria (BLPB). These include anaerobic streptococci, Clostridium spp., nonsporolating anaerobic bacilli, and non-beta-lactamase-producing Gram-negative anaerobic rods.3 However, in addition to the B. fragilis group, which is known to resist the drug, many other anaerobic Gram-negative rods are showing increased resistance. These include Fusobacterium spp., pigmented Prevotella and Porphyromonas spp. (prevalent in orofacial infections), Prevotella bivia and Prevotella disiens (common in obstetric and gynecologic infections), and Bilophila wadsworthia and Bacteroides splanchinus. Resistance to penicillin of some Clostridium spp. (C. ramosum, C. clostridioforme and C. butyricum ) through production of beta-lactamase was also noted.

The increase in the number of penicillin-resistant bacterial strains has important implications for antimicrobial therapy. Many penicillin-resistant bacteria can produce enzymes that degrade penicillins or cephalosporins by releasing the enzyme in the area of the infection. Therefore, these organisms may protect not only themselves but also penicillin-sensitive pathogens. Penicillin therapy directed against a susceptible pathogen might therefore be rendered ineffective by the presence of BLPB.4
The utilization of combinations of beta-lactamase inhibitors (e.g. clavulanic acid, sulbactam, tazobactam) plus a beta-lactam antibiotic (ampicillin, amoxicillin, ticarcillin, or piperacillin) can overcome this phenomenon. However, if other mechanisms of resistance emerge, blockage of the enzyme beta-lactamase will not prevent resistance. Other mechanisms of resistance include alteration in the porin canal and changes in the penicillin-binding protein.

The semisynthetic penicillins, carbenicillin, ticarcillin, piperacillin and mezlocillin are generally administered in large quantities to achieve high serum concentrations. These drugs have good activity against Enterobacteriaceae and most anaerobes in these concentrations. However, they are not absolutely resistant to beta-lactamase produced by Gram-negative anaerobic bacilli.

Cephalosporins
The efficacy of cephalosporins varies against Bacteroides spp.3 The activity of the first-generation cephalosporins against anaerobes is similar to that of penicillin G, although on a weight basis they are less active. Most strains of the B. fragilis group and many Prevotella and Porphyromonas spp. are resistant by virtue of cephalosporinase production. The second generation cephalosporin cefoxitin is relatively resistant to this enzyme and is the most effective cephalosporin against the B. fragilis group and is often used for the therapy and prophylaxis of mixed infections However, 5–15% of B. fragilis group may be resistant, reflecting hospital use pattern. Cefoxitin is relatively inactive against most species of Clostridium (including C. difficile); C. perfringens is an exception. The second-generation cephalosporins, cefotetan and cefmetazole, have a longer half-life than cefoxitin, are as effective as cefoxitin against B. fragilis, but have poor efficacy against other members of the B. fragilis group (i.e. B. thetaiotaomicron). Third-generation cephalosporins have inferior activity against Bacteroides spp.

Carbapenems (imipenem, meropenem, doripenem, ertapenem)
Carbapenems have excellent activity against a broad spectrum of aerobic bacteria and anaerobic bacteria, including beta-lactamase-producing Bacteroides spp., Enterobacteriaceae and Pseudomonas spp. Resistance of B. fragilis group is very rare (<1%). Ertapenem  has similar efficacy , but is not active against  Pseudomonas spp. and Acinetobacter spp. 5

Chloramphenicol
Chloramphenicol has excellent in-vitro activity against most anaerobic bacteria, resistance is rare and it penetrates well into the cerebro-spinal fluid (CSF). It is also effective against many Enterobacteriaceae and aerobic Gram-positive cocci. The toxicity of chloramphenicol, the rare but fatal aplastic anemia and the dose-dependent leukopenia limit its use.

Clindamycin and lincomycin
Clindamycin and lincomycin are effective against anaerobes and have good activity against aerobic Gram-positive cocci.3 Clindamycin has the broader coverage against anaerobes, including beta-lactamase-producing Bacteroides spp. Resistance of the B fragilis group in some centers in the United States recently reached about 40%. Up to 10% resistance was noted for Prevotella spp., Fusobacterium spp., Porphyromonas spp., and Peptostreptococcus spp., with higher rates for some Clostridium spp.  Because of the increasing worldwide and geographical variation in clindamycin resistance it is no longer recommended as empiric therapy for abdominal infections. A recent study found resistance to clindamycin in up to 10% of Prevotella, Porphyromonas, Fusobscterium, and Peptodtreptococcus spp. Among the other resistant anaerobes are various species of clostridia especially C. difficile. Approximately 20% of Clostridium ramosum are resistant to clindamycin, as are a smaller number of C. perfringens.


 Antibiotic associated colitis caused by C. difficile was first described after clindamycin therapy. However, colitis has been associated with many other antimicrobial agents, including penicillins and cephalosporins.

Metronidazole
Metronidazole has excellent activity limited to anaerobes. Microaerophilic streptococci, Propionibacterium acnes and Actinomyces spp. are often resistant. It penetrates well into the CSF Concern was raised about the carcinogenic and mutagenic effects of this drug; however, these effects were shown only in one species of mice and were never substantiated in other animals or humans.1

Macrolides (erythromycin, azithromycin, clarithromycin)
The macrolides have moderate to good in vitro activity against anaerobic bacteria other than B. fragilis group strains and fusobacteria . Macrolides are active against pigmented Prevotella and Porphyromonas spp. and microaerophilic streptococci, Gram-positive non-sporeforming anaerobic bacilli, and certain clostridia. They are less effective against Fusobacterium andPeptostreptococcus spp. They show relatively good activity against C. perfringens and poor or inconsistent activity against AGNB. Emergence of erythromycin-resistant organisms during therapy has been documented.

Glycopeptides (vancomycin, teicoplanin)
The glycopeptides are effective against all Gram-positive anaerobes (including C. difficile), but are inactive against Gram-negative bacilli.

Tetracyclines (Tetracycline, doxycycline, minocycline)
Resistance to tetracycline has increased. The newer tetracycline analogs (doxycycline and minocycline) are more active than tetracycline. Because of significant resistance to these drugs, they can be used if the organisms are susceptible or in less severe infections in which a therapeutic trial is feasible.

Quinolones
Quinolones with low activity against anaerobes include ciprofloxacin, ofloxacin, levofloxacin, fleroxacin, pefloxacin, enoxacin and lomefloxacin. Compounds with intermediate antianaerobic activity include sparfloxacin and grepafloxacin. Trovafloxacin, gatifloxacin and moxifloxacin yield low MICs against most groups of anaerobes. Quinolones with the greatest in vitro activity against anaerobes include clinafloxacin and sitafloxacin.6  Moxifloxacin was approved by the FDA for the treatment of complicated skin and skin-structure infections and complicated intra-abdominal infections. However, up to 40% of Bacteroides are resistant to moxifloxacin.
The use of the quoinolones is restricted in growing children and pregnancy because of their possible adverse effects on the cartilage.

Other agents 
Bacitracin is active against pigmented Prevotella and Porphyromonas sp. but is inactive against B. fragilis and Fusobacterium nucleatum.1 Quinupristin/dalfopristin is active against Clostridium perfringens, Lactobacillus spp and Peptostreptococcus. Linezolid is active against Fusobacterium, Porphyromonas, Prevotella, and Peptostreptococci spp. Little clinical experience has been, however, gained in the treatment of anaerobic bacteria using these agents.





The available parenteral antimicrobials in most infections (Tables 3-5) are clindamycin, metronidazole, chloramphenicol, cefoxitin, a penicillin (i.e. ticarcillin, ampicillin, piperacillin) and a beta-lactamase inhibitor (i.e. clavulanic acid, sulbactam, tazobactam), and a carbapenem (i.e. imipenem, meropenem, ertapenem). An agent effective against Gram-negative enteric bacilli (i.e. aminoglycoside) or an antipseudomonal cephalosporin (i.e. cefepime ) are generally added to clindamycin, metronidazole and, occasionally, cefoxitin when treating intra-abdominal infections to provide coverage for these bacteria. (Table 5) Penicillin can be added to metronidazole in the therapy of intracranial, pulmonary and dental infections to cover for microaerophilic streptococci, and Actinomyces. A macrolide (i.e. erythromycin) is added to metronidazole in upper respiratory infections to treat S. aureus and aerobic streptococci. Penicillin is added to clindamycin to supplement its coverage against Peptostreptococcus spp. and other Gram-positive anaerobic organisms.

Doxycycline is added to most regimens in the treatment of pelvic infections for chlamydia and mycoplasma. Penicillin is still the drug of choice for bacteremia caused by non-BLPB. However, other agents should be used for the therapy of bacteremia caused by BLPB.
Because the duration of therapy for anaerobic infections, which are often chronic, is generally longer than for infections caused by aerobic and facultative anaerobes, oral therapy is often substituted for parenteral therapy. The agents available for oral therapy are limited and include clindamycin, amoxicillin plus clavulanic acid, chloramphenicol and metronidazole.

Clinical judgment, personal experience, safety and patient compliance should direct the physician in the choice of the appropriate antimicrobial agents. The length of therapy generally ranges between 2 and 4 weeks, but should be individualized depending on the response. In some cases, such as lung abscesses, treatment may be required for as long as 6–8 weeks, but can often be shortened with proper surgical drainage.

PREVENTION
Proper therapy of acute infections can prevent the occurrence of chronic infections where anaerobes predominate. In settings where anaerobic infections are expected to occur, such as intra-abdominal and wound infections after surgery, proper antimicrobial prophylaxis reduces the chance of such infections.

Prevention and early therapy of conditions that may lead to anaerobic infection can reduce their rate. Preventing oral flora aspiration by improving the neurologic status of the patient, repeated suctioning of oral secretion, improving oral hygiene and maintaining lower stomach pH can reduce the risk of aspiration pneumonia and its complications. Skin and soft-tissue infections can be prevented by irrigation and debridement of wounds and necrotic tissue, drainage of pus and improvement of blood supply.







Prophylactic therapy before surgery is generally administered when the operative field is expected to be contaminated by the normal flora of the mucous membrane at the operated site. Cefazolin is effective in surgical prophylaxis in sites distant from the oral or rectal areas, when anaerobic cover is not required. Cefoxitin or cefotetan are used in procedures that involve the oral, rectal or vulvovaginal surfaces because their spectrum includes the anaerobic flora likely to be encountered.



REFERENCES
1.   Finegold SM. Anaerobic bacteria in human disease. Orlando, FL: Academic Press Inc; 1977.
2.  Snydman DR, Jacobus NV, McDermott LA, et al. Lessons learned from the anaerobe survey: historical perspective and review of the most recent data (2005-2007). Clin Infect Dis. 2010 ;50 Suppl 1:S26-33.
3.   Hecht DW. Anaerobes: antibiotic resistance, clinical significance, and the role of susceptibility testing. Anaerobe.12:115-21, 2006.76.
4.   Brook I. The role of beta-lactamase-producing bacteria in the persistence of streptococcal tonsillar infection. Rev Infect Dis;6:601–7, 1984.
5.     Hoellman DB, Kelly LM, Credito K, Anthony L, Ednie LM, Jacobs MR, Appelbaum PC. In vitro antianaerobic activity of ertapenem (MK-0826) compared to seven other compounds. Antimicrob Agents Chemother.;46:220-4, 2002.
6.   Stein, GE, Goldstein, EJ.: Fluroquinolones and anaerobes. Clin Infect Dis 42: 1598-607, 2006.
7.  Sherwood JE, Fraser S, Citron DM, et al. Multidrug resistant Bacteroides fragilis recovered from blood and severe leg wounds caused by an improvised explosive device (IED) in Afghanistan. Anaerobe 2011;17:152–5; 
8. Centers for Disease Control and Prevention (CDC ).Multidrug-resistant Bacteroides fragilis--Seattle, Washington, 2013. MMWR Morb Mortal Wkly Rep. 2013 Aug 30;62(34):694-6 . 








Table 1:  Susceptibility of anaerobic bacteria to antimicrobial agents






Bacteria



Penicillin
A penicillin and a beta-lactamase inhibitor
Ureido- and carobxy- penicillin



Cefoxitin



Chloramphenicol



Clindamycin



Macrolides



Metronidazole



Carbapenem
Peptostreptococcus sp.
4
4
3
3
3
3
2-3
2
3
Fusobacterium sp.
3-4
3-4
3
3
3
2-3
1
3
3
B. fragilis group
1
4
2-3
3
3
3
1-2
4
4
Prevotella and Porphyromonas sp.
1-3
4
2-3
3
3
3
2-3
4
4
Clostridium perfringens
4
4
3
3
3
3
3
3
3
Clostridium sp.
3
3
3
2-3
3
2
2
3
3
Actinomyces sp.
4
4
3
3
3
3
3
1
3
Degrees of activity:        1 = minimal
                                    2 = moderate
                                    3 = good
                                    4 = excellent











Table 2:  Antimicrobial drugs of choice for anaerobic bacteria




First
Alternate
Peptostreptococcus sp.
Penicillin
Clindamycin, chloramphenicol, cephalosporins
Clostridium sp.
Penicillin
Metronidazole, chloramphenicol, cefoxitin, clindamycin
C. difficile
Vancomycin
Metronidazole, bacitracin
Gram-negative rods* (BL-)
Penicillin
Metronidazole, clindamycin, chloramphenicol
Gram-negative rods* (BL+)
Metronidazole, a carbapenem, a penicillin and beta-lactamase inhibitor, clindamycin
Cefoxitin, chloramphenicol, piperacillin
BL = beta lactamase
  • = B. fragilis group; Prevotella spp. Porphyromonas spp., Fusobacterium spp.







Table 3: Antimicrobial recommended for the therapy of site-specific anaerobic infections

Surgical




prophylaxis
Parenteral
Oral

Intracranial
1. Penicillin
1. Metronidazole4
1. Metronidazole4


2. Vancomycin
2. Chloramphenicol
2. Chloramphenicol

Dental
1. Penicillin
1. Clindamycin
1. Clindamycin, amoxicillin + CA


2. Erythromycin
2. Metronidazole4, chloramphenicol
2. Metronidazole4, chloramphenicol

Upper respiratory tract
1. Cefoxitin
1. Clindamycin
1. Clindamycin, amoxicillin + CA


2. Clindamycin
2. Chloramphenicol, metronidazole4
2. Chloramphenicol, metronidazole5

Pulmonary
NA
1. Clindamycin5
1. Clindamycin8



2. Chloramphenicol, ticarcillin + CA, ampicillin + SU6, a carbapenem 
2. Chloramphenicol, metronidazole5, amoxicillin + CA

Abdominal
1. Cefoxitin
1. Clindamycin3, cefoxitin3, metronidazole3
1. Clindamycin8, metronidazole8


2. Clindamycin3
2. A carbapenem, ticarcillin + CA
2. Chloramphenicol, amoxacillin + CA

Pelvic
1. Cefoxitin
1. Cefoxitin6, clindamycin3
1. Clindamycin6


2. Doxycycline
2. Ticarcillin + CA6, ampicillin + SU6, metronidazole6
2. Amoxicillin + CA6, metronidazole6

Skin
1. Cefazolin7
1. Clindamycin, cefoxitin
1. Clindamycin, amoxicillin + CA


2. Vancomycin
2. Metronidazole4 + vancomycin
2. Metronidazole5

Bone and joint
1. Cefazolin7
1. Clindamycin, A carbapenem
1. Clindamycin


2. Vancomycin
2. Chloramphenicol, metronidazole4, ticarcillin + CA
2. Chloramphenicol, metronidazole4

Bacteremia with BLPB
NA
1. A carbapenem, metronidazole
1. Clindamycin, metronidazole



2. Cefoxitin, ticarcillin + CA
2. Chloramphenicol, amoxacillin + CA

Bacteremia with non- BLPB
NA
1. Penicillin
1. Penicillin



2. Clindamycin, metronidazole, cefoxitin
2. Metronidazole, chloramphenicol, clindamycin

1 = drug(s) of choice
7 = in location proximal to the rectal and oral areas use cefoxitin
2 = alternative drugs
8 = plus a quinolone (only in adults)
3 = plus aminoglycoside
NA = not applicable
4 = plus penicillin
CA = clavulanic acid
5 = plus a macrolide (erythromycin or spiramycin)
SU = sulbactam
6 = plus doxycycline
BLPB = Beta-lactamase-producing bacteria









Table 4: Antimicrobial agents effective for the therapy of anaerobic infections


Antimicrobials

Route of administration
Dose (interval) newborn mg/kg/d
Dose (interval) Children <40 kg mg/kg/d
Dose (interval)
adults and
children >40 kg
Penicillin G
IV, IM
50,000-100,000 units (q.8-12h.)
100,000-250,000 units (q.4h.)
10-20 million units/d
Piperacillin
IV, IM
N/A
200-300 (q.4-6h.)
3-4 g (q.4-6h.)
Ticarcillin
IV, IM
150-225 (q.8-12h.)
200-300 (q.4-6h.)
3-4 g (q.4-6h.)
Ticarcillin plus clavulanic acid
IV
150-225 (q.8-12h.)
200-300 (q.4-6h.)
3.1 g (q.4-8h.)-6.2 g (q. 6h.)
Amoxicillin plus clavulanic acid
Oral
N/A
20-40 (q.8h.)
250-500 mg (q.8h.)
Ampicillin plus sulbactam
IV
N/A
50-100 (q.6h)
1.5-3.0 g (q.6h.)
Cefoxitin
IV, IM
N/A
80-160 (q.4-6h.)
1-2 g (q.4-6h.)
Chloramphenicol
IV or Oral
25 mg once a day
50-75 (q.6h.)
1 g (q.6h.)
Clindamycin
IM, IV
10-15 (q.8-12h.)
25-40 (q.6-8h.)
600 mg (q.6h.), 900 mg (q.8h.)

Oral
10-15 (q.8-12h.)
10-30 (q.6h.)
150-450 mg (q.6h.)
Metronidazole
IV
15 (q.12h.)
30 (q.6h.)
500-1000 mg

Oral
15 (q.12h.)
15-35 (q.8h.)
500 mg (q.6h.)
Imipenem
IV
N/A
40-60 (q.6h.)
250-500 mg (q.4-6h.)
Meropenem
IV
N/A
60-120 (q.8h)
500-1000 mg (q.8h)
N/A = not available
g = gram
IV = intravenous
IM = intramuscular















Table 5         Antimicrobial agents effective against mixed infectiona

Anaerobic bacteria
Aerobic bacteria




Antimicrobial agent
Beta-lactamase-Producing Bacteroides


Other Anaerobes

Gram-positive cocci



Enterobacteriaceae

Penicillinb
0
+ + +
+
0

Chloramphenicolb
+ + +
+ + +
+
+

Cephalothin
0
+
+ +
+ / –

Cefoxitin
+ +
+ + +
+ +
+ +







Imipenem
+ + +
+ + +
+ + +
+ + +

Clindamycinb
+++
+ + +
+ + +
0

Ticarcillin
+
+ + +
+
+ +

Amoxicillin +





clavulanic acidb
+ + +
+ + +
+ +
+ +

Ticarcillin +





clavulanic acid
+ + +
+ + +
+ +
+ +

Metronidazoleb
+ + +
+ + +
0
0

Moxifloxacinb
++
++
++
+++

a = Degrees of activity: 0 to + + +
b = Available also in oral form