PROCEEDINGS
AN UPDATE ON MIXED AEROBIC AND ANAEROBIC INFECTIONS*
John G. Bartlett, MD
ABSTRACT
In many respects, anaerobic microbiology has
fallen out of the spotlight of infectious diseases, in
part due to the extraordinarily successful effort to
recognize and treat these infections. Today, anaer-
obic cultures of clinical specimens are rarely per-
formed and the treatment is fairly standardized.
This article reviews the microbiology and patho-
genesis of anaerobes, the concept of synergy in
mixed infections, and specific anaerobic infections
such as lung infections, intra-abdominal sepsis, and
female genital tract infections, and a historical
overview of the study of anaerobic infection. The
more recent developments include some disturbing
trends in in vitro sensitivity test results and a contin-
uing controversy about the role of the microbiology
lab in these infections.
(Advanced Studies in Medicine 2002;2(4):104-109)
*This article is based on a presentation given by
Dr Bartlett at a satellite symposium at the 39th Annual
Meeting of the Infectious Diseases Society of America.
Correspondence to: John G. Bartlett, MD, Chief,
Infectious Diseases Division, Johns Hopkins Medical School,
1830 East Monument Street, Suite 439, Baltimore, MD
21287-0003; Tel: 410-955-7634; Fax: 410-955-7889;
E-mail: jb@jhmi.edu.
104
naerobes were discovered by Louis
A Pasteur in 1862 when he grew
Clostridium butyricum. Veillon and
Zuber in 1893 wrote the first report of
a clinical isolate of an anaerobe,
Bacteroides fragilis. Its name was based on the difficul-
ty of growing it in a laboratory compared with
C butyricum. In fact, B fragilis is quite easy for a labo-
ratory to grow. The Veillon and Zuber publication is
considered a first recognition of anaerobes.1
A variety of clinical studies from 1909 to about 1938
are now considered classical studies of anaerobes.
Schottmueller, in 1910, observed that puerperal sepsis
could be caused by Group A streptococci, but the anaer-
obes were far more important.2 David Smith conducted
his famous studies at Duke University (1927-1930) on
lung abscesses showing that the bacterium in the gingi-
val crevice matched those at autopsy and postulated aspi-
ration as the mechanism. Altemeier wrote his famous
papers in 1938 on intra-abdominal sepsis finding recov-
ered anaerobes in 99 of 100 people with appendicitis. In
one of his papers, he named the essential diagnostic sign
of anaerobic infection, putrid discharge.3
The period from 1939 to 1964 was a time of gross
neglect in research on anaerobes. Medical schools teach-
ings on anaerobes focused on discussions of tetanus, bot-
ulism, and gangrene. That was the total menu of
anaerobic bacteria and anaerobic infections. The period
from 1965 to 1980 is therefore a Renaissance Period in
anaerobic microbiology. What changed? Three major
advances occurred: 1) the Virginia Polytechnic Institute
established a formal taxonomy, to help remove the con-
fusion that existed until then; 2) the GasPak jar became
an easy way for clinical laboratories to handle oxygen-
Vol. 2, No. 4 March 2002
 PROCEEDINGS

sensitive forms (few research laboratories could work

with anaerobes before this); and 3) clinical studies were
spearheaded by Sid Fiengold who devoted his lifes work
to anaerobic bacteria and put them on the map. For Table 1. Clinically Important Anaerobes Seen
this, he is often referred to as the Father of the with Greatest Frequency
Renaissance. As a result, clindamycin became the drug of
choice for anaerobic infections in the United States and
metronidazole was used in the United Kingdom.
Table 1 shows an example of the current nomen- Gram-negative Bacteria
clature, which has undergone some major changes. For Bacteroides fragilis group
example, Prevotella sp are now the former B melanino- B fragilis
genicus, which is a group of black pigmented strains. B thetaiotamicron
B distasonis
A now-famous paper from John Washington II B ovatus
showed the results of his experience with culturing gram- B vulgatus
negative rods in blood. As shown in Table 2, Escherichia Pigmented Prevotella (formerly B melaninogenicus)
P intermedia
coli was the most common, as it was in most other stud- P melaninogenics
ies from that period; more than half of the cases were due P corporis
to E coli. Bacteroides bacteremia was second to E coli.4 P denticola
P loescheii
Since 1980, Bacteroides bacteremia is rarely seen, testify- P nigrescens
ing to the success of the campaign in the 1970s to raise Prevotella (other)
awareness about anaerobes. B fragilis is recovered so P bivia (formerly B bivius)
infrequently in blood cultures in the year 2001 that P disiens (formerly B disiens)
P oralis (formerly B oralis)
many laboratories are considering discontinuation of the
Porphyromonas asaccharolyticus (formerly B asaccharolyticus)
anaerobic blood culture bottle as a method of cost reduc- Fusobacterium
tion for the laboratory. In fact, the clinical laboratory at F nucleatum
Johns Hopkins has an anaerobic chamber plus all of the F necrophorum
F varium
appropriate equipment for transporting specimens, but
Bilophila
still seem to infrequently detect anaerobes. B wadsworthia
With that in mind, James Dick, PhD, Associate
Professor in the Department of Pathology who also
heads the microbiology lab at Johns Hopkins, was
asked to record positive blood cultures for E coli and
Bacteroides for a period of 1 year. The results were sur-
prising: 22 positive blood cultures for Bacteroides spp
Table 2. Gram-negative Bacteremia: Mayo Clinic
from 13 patients, and 192 positive cultures for E coli
(July 1968 to December 1970)
from 196 patients.
The period of gross neglect in the 1940s through
the early 1960s was followed by a period of great
emphasis. Many laboratories were doing extensive Bacterium No. of Isolates
studies of anaerobic bacteria and the annual meetings
of the Infectious Diseases Society of America and the E coli 533
Interscience Conference on Antimicrobial Agents and Bacteroides 332
Chemotherapy (ICAAC) were heavily focused on Klebsiella 245
anaerobesthe bacteria, infections, culturing, clinical P aeruginosa 213
features, etc. By contrast, there was not a single session Enterobacter 90
at the 40th or 41st ICAAC on anaerobic bacteria or Proteus sp 88
anaerobic infection. S marcenscens 54
One of the main reasons behind the current shift in Data from: Washington JA 2nd. Comparison of two commercially available
emphasis is the existing awareness of anaerobes and media for detection of bacteremia. Appl Microbiol. 1971;22:604-607.

Advanced Studies in Medicine 105

 PROCEEDINGS

our success in identifying and treating them. Most

infectious disease specialists know that clindamycin
should be used to treat a lung abscess, because it is Table 3. Costs of Blood Cultures:
most commonly an anaerobic lung infection and that Johns Hopkins Hospital (October 15, 2000 to
is the standard treatment. Culturing is not necessary. October 15, 2001)
Because anaerobic bacteriology is not cost effective,
there is a movement to eliminate anaerobic culturing
in laboratories.
Table 3 outlines how much it costs to identify an Bacteroides sp E coli
anaerobe and conduct sensitivity tests, based on data
Identification $12 $5-7
gathered at Johns Hopkins laboratories. Included are
the labor, reagents, and overhead. Clearly the costs are Susceptibility tests $20
not enormous, but this is to be part of an overall dimin- Data from personal communication, J. Dick, PhD. October 18, 2001.
ishing emphasis on microbiology, which had, until very
recently, become an epidemic in American medicine.

ANAEROBIC MICROBIOLOGY

Anaerobic infections are endogenous; there is only

one anaerobic infection that can be transmitted from
patient to patientClostridium difficile. Most anaero-
bic infections are polymicrobial, and they often pro-
duce gas in the soft tissue and a putrid discharge, at
least in the late stages.
Mucosal surfaces such as saliva, teeth, the stomach,
ileum, and vagina usually share a 1:1 ratio of anaero-
bic to aerobic bacteria, although the vagina may have
as high as 5 times more anaerobes than aerobes. The
gingival crevice and colon have a 1000:1 ratio of
anaerobic to aerobic bacteria. So, dental infections and
colonic perforation are associated with very high rates
Table 4. Anaerobic Bacterial Infections
of anaerobic infection. Table 4 distinguishes the fre-
quent and rare anaerobic infections. Most anaerobic
infections are endogenous, meaning they originate
from the hosts flora. An exception is urinary tract Frequent Rare
infections (UTIs). UTIs are endogenous but rarely
involve anaerobes. UTIs originate from the urethral Head and neck Brain abscess Meningitis
flora, which is teeming with anaerobes, but these Dental infections Pharyngitis
organisms cannot replicate in the pO2 of urine. The Space infections
(Chronic sinusitis) Acute sinusitis
same applies to spontaneous bacterial peritonitis. Chronic otitis Acute otitis
Chest Aspiration pneumonia Bronchitis
PATHOGENESIS Lung abscess
Empyema
Anaerobes are the primary cause of abscess for- Abdomen Peritonitis Cholecystitis
mation at most anatomic sites (Table 5).5-11 The pre- Phlegmon/abscess SBP
sumed biologic explanation is the capsular GU tract Female genital tract UTIs
polysaccharide which has been studied with B frag- STDs
ilis and appears to be abscessogenic in animals. That GU = genitourinary; UTIs = urinary tract infections; STDs = sexually trans-
is, intraperitoneal abscesses can be produced in ani- mitted diseases; SBP = spontaneous bacterial peritonitis.

106 Vol. 2, No. 4 March 2002

 PROCEEDINGS

mals with the injection of capsular material from the

B fragilis.12 Further, Tzianobos et al showed in 1993 that
the charge of the B fragilis polysaccharide capsule (ie,
Table 5. Anaerobes in Abscesses
the positively charged amino groups and negatively
charged carboxyl or phosphate groups) is critical for this
biological result; chemical modification has shown that
the oppositely charged groups are an important motif Site Frequent Source (Ref. No.)
for abscess formation. In their 1994 study, the
Salmonella capsule, which normally contains only one Brain 16/18 (89%) Heineman and Braude
19638
carboxyl group, was chemically modified to possess
Dental 29/31 (94%) Roser et al 19777
charges which then gave this organism the property of
producing abscesses.13,14 Lung 53/39 (93%) Bartlett et al 19746
Most anaerobic bacteria do not have biologically Intra-abdominal 67/72 (94%) Onderdonk et al 19745
active endotoxin; the most notable exception is Tubo-ovarian 32/37 (86%) Golde et al 197711
Fusobacterium necrophorum, which is associated with Cutaneous 81/135 (60%) Meislin et al 19779
Lemierres disease and septic shock. B fragilis does not Prostatic 16/18 (94%) Bartlett et al 198110
cause septic shock. One common pathogenic mechanism Data from references 5-11.
of anaerobes focuses on synergy, because they are usually
polymicrobial infections. Synergy is the correlated action
of 2 or more organismssomething that cannot be
achieved by a single organism. Meleney conducted the
sentinel study of anaerobic synergy. He demonstrated
that when a mouse is coinfected with S aureus and an
anaerobic streptococcus, the characteristic lesion forms.
But inoculating with only one or the other organism
alone does not produce Meleneys gangrene.15
Does synergy have anything to do with this? A
study was conducted in the late 1970s using a Wistar
rat model of intra-abdominal sepsis that, following
intraperitoneal challenge with the mixed flora of stool,
showed that there is an early active peritonitis stage Figure 1. Stages of Peritoneal Infection
and a late abscess stage (Figure 1). For peritonitis and
bacteremia, E coli was critical and for abscess forma-
tion B fragilis was critical. There was no synergy. E coli
seemed to be totally responsible for the early stage asso-
ciated with bacteremia and B fragilis was responsible for
the late stage with abscess formation.16 This was sup-
ported by studies of antibiotic probes using gentamicin,
showing that gentamicin was active against E coli and
clindamycin was active against anaerobes but not active
against E coli. Gentamicin reduced mortality but had no
effect on abscesses. Clindamycin had no effect on mor-
tality but prevented abscesses (Figure 2).17

ANAEROBIC INFECTIONS

LUNG INFECTIONS
The bacteriology of anaerobic pulmonary infec-
tions has been studied in more than 300 cases pub- Data from reference 16.

Advanced Studies in Medicine 107

 PROCEEDINGS

lished in 2 studies.18,19 Of the 865 total anaerobes, the

3 major isolates were pigmented Prevotella (n = 139),
Bacteroides spp (n = 117), and peptostreptococci (n = Figure 2.Antibiotic Probes of Peritoneal Infection
165). Others included other spp of Prevotella (n = 40),
Fusobacteria (n = 90), and Clostridia (n = 30).

INTRA-ABDOMINAL SEPSIS Abscess

The major anaerobic pathogens are B fragilis, pep- Mortality
formation
tostreptococci, and Clostridia. In one study, 808
patients with polymicrobial infection of the peritoneal Control 37% 100%
cavity or nonvisceral soft tissues were candidates for
treatment with 1 of 2 antibiotic regimens. Of the iso- Gentamicin 4% 98%
lated anaerobic organisms, E coli and Bacteroides sp
were the most common.20 Clindamycin 35% 5%

FEMALE GENITAL TRACT INFECTIONS Gentamicin & 9% 6%

In pelvic inflammatory disease, the major isolates Clindamycin
are Prevotella bivia, Prevotella disiens, Bacteroides spp,
and peptostreptococcus.21 Data from reference 17.

TREATMENT OF ANAEROBIC INFECTIONS

Table 6 lists the classes of antibiotics and their

activity against anaerobes. Of note, 4 antibiotics are
always active against anaerobic bacteria: metronida-
zole, imipenem, and a -lactam/-lactamase inhibitor.
There are only about 6 recorded isolates resistant to
metronidazole, but they are clearly very rare. The
macrolides/ketolides are active against most anaerobes Table 6. Antibiotics vs Anaerobes
but not fusobacteria. Tetracycline is quite variable, and
vancomycin and linezolid are active against gram-pos-
itive anaerobes.
With regard to resistance, Snydman et al measured
Always Active
the activity of clinical isolates of B fragilis from 1990 Metronidazole
to 1996 for 4000 strains obtained from 8 different Imipenem
centers. The results showed an increase in resistance to -lactam/-lactamase inhibitors
cefotoxitin, clindamycin, and piperacillin.22,23 A more Usually Active
recent survey by Aldridge et al shows that 100% of 3 Cefotoxitin/cefotetan
most common pathogens (B fragilis, Prevotella, and Clindamycin
peptostreptococcus) were uniformly sensitive to Piperacillin
piperacillin/tazobactam, imipenem, and metronida- Variable Activity
Macrolides/ketolides
zole. Also, 100% of Prevotella and peptostreptococci
Gatifloxacin/moxifloxacin
but only 93% of B fragilis were sensitive to cefotoxitin. Tetracycline
Lower susceptibility rates were noted for penicillin G, Vancomycin/linezolid
ciprofloxacin, and clindamycin. The results highlight Cephalosporins
the variability in resistance patterns among anaerobes, Never Active
which may be both regional and temporal. The results Aminoglycosides
seem to be sufficiently predictable so that most labora- Trimethoprim-sulfamethoxazole
Aztreonam
tories do not perform these tests.24

108 Vol. 2, No. 4 March 2002

 PROCEEDINGS
CONCLUSION
Anaerobic bacterial microbiology went through a
substantial evolution of change so that diagnosis and
treatment are now standardized to recognize these
microbes and treat them without assistance from the
laboratory.
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109