Propionibacterium acnes, an emerging pathogen: From acne to implant-infections

Propionibacterium acnes is a colonizer of the lipid-rich sebaceous glands of the skin. The pathogenicity of P. acnes has long been restricted to skin conditions. Its isolation from other anatomical sites or deep microbiological samples has often been considered as contamination. It is involved in the inflammation process of acne is well known, but until recently, it was neglected in other clinical presentations. P. acnes  has been considered to be of low virulence, but the new genomic, transcriptomic, and phylogenetic studies have allowed better understanding of this potential pathogen's importance in causing many chronic and recurrent infections, including orthopedic ( osteo-articular and spine )  and cardiac prosthetic, and breast or eye implant-infections, and neurosurgical infections of external ventricular shunts.

Hip Joint implant

These infections, are facilitated by the ability of P. acnes to produce a biofilm, requiring using anti-biofilm active antibiotics such as rifampicin. However, in the last 10 years, the rate of antibiotic-resistant bacteria has increased, especially for macrolides and tetracyclines. The antimicrobial susceptibility of P. acnes is not routinely performed in microbiology laboratories because of its susceptibility to a wide range of antibiotics.

Some antibiotics should be tested to adapt treatment because of the prevalence of antibiotic resistance in P. acnes: tetracycline, erythromycin, clindamycin, and cotrimoxazole. Furthermore, other antibiotics should be tested for severe infections, to optimize treatment and obtain a synergistic effect against P. acnes: penicillin, cephalosporins, vancomycin, quinolones, rifampicin, and the “new” antibiotics such as linezolid, daptomycin, and tigecycline, to which P. acnes is usually susceptible. Aminoglycosides and metronidazole are not active against P. acnes.

The treatment of severe infections caused by P. acnes includes a combination of antibiotics, administrated intravenously initially, and usually associated with optimal surgery (e.g., removal of the device and/or debridement of the surgical site). Penicillin G and ceftriaxone are still considered as first-line antibiotics for severe infections. Clindamycin, tetracycline, and levofloxacin are alternatives in those allergic to beta-lactams. Rifampicin and daptomycin are also active antimicrobial agents, effective also against P. acnes biofilm. Removal of the device associated with the infection is usually sufficient to reduce the inoculum causing chronic infection.

Gram stain of Propionibacterium acnes

Periodontal pathogens ( Porphyromonas gingivalis and Fusobacterium nucleatum) may promoting oral cancer ( Kaposi's sarcoma)

Kaposi's sarcoma  (KS) is a tumor caused by human herpesvirus 8 (HHV8, also known as Kaposi's sarcoma-associated herpesvirus, KSHV).  About 20% of HIV patients develop Kaposi's sarcoma (KS) lesions in the oral cavity while other patients never develop oral KS. It is not known if the oral micro environment plays a role in oral KS tumor development.

Xiaolan and colleagues from Case Western Reserve University, Cleveland, Ohio demonstrated that a group of metabolic by-products (short chain fatty acids), from bacteria that cause periodontal disease (Porphyromonas gingivalis and Fusobacterium nucleatum) promote lytic replication of KSHV. These new findings provide mechanistic support that periodontal pathogens create a unique micro environment in the oral cavity that contributes to KSHV replication and development of oral KS. However, more research is needed to find out if patients with KS suffer more often from periodontal disease and exhibit higher levels short chain fatty acids produced by the periodontal pathogens.

oral cavity Kaposi's sarcoma

Fecal transplants for the treatment of recurrent Clostridium difficile infection

Recurrent Clostridium difficile infection is difficult to treat, and failure rates for antibiotic therapy are high. Fecal microbiota transplantation has been shown to be a superior therapeutic modality for the treatment of recurrent C. difficile infection (RCDI) and disease is fecal transplantation. A recent review of 317 patients from 27 case-report series concluded that fecal transplantation was highly effective and resulted in disease resolution in 92% of patients involved in the study.

Van Nood and colleagues provided the first controlled study of treating RCDI with fecal transplantation. In an open-label, non-blinded manner, 43 adult patients were randomly assigned to oral vancomycin, oral vancomycin plus bowel lavage or vancomycin plus bowel lavage followed by fecal transplantation by nasoduodenal tube. Of the patients in the randomized group to receive fecal transplantation from a donor, clinical disease resolved in 81% (13/16) after the first infusion. An additional infusion from a different donor resulted in resolution in two additional patients. Of the control groups, clinical resolution occurred in 31% (4/13) of patients who received vancomycin alone, and in 23% (3/13) of those who received vancomycin plus bowel lavage.

Fecal transplantation appears to be a promising therapy for RCDI, but important unkowns exist. These include the most effective dose, method of preparation, route of administration, and the safety of using donor samples. With the publication of one controlled trial, more data are needed to address these concerns. 

Multidrug-Resistant Bacteroides fragilis isolated in the US

B. fragilis strains, especially in the US, are virtually always susceptible to metronidazole, carbapenems, and beta-lactam antibiotics. Although isolated cases of resistance to single agents have been reported, multidrug-resistant (MDR) B. fragilis strains are exceptionally rare. In May 2013, an MDR B. fragilis strain was isolated from the bloodstream and intra-abdominal abscesses of a patient who had recently received health care in India. The organism was resistant to metronidazole, imipenem, piperacillin/tazobactam, clindamycin, tcefotetan, ampicillin/sulbactam, and moxifloxacin. It was susceptible to minocycline, linezolid, and tigecycline. He was successfully treated with linezolid and ertapenem. This is only the second published case of MDR B. fragilis in the US.

Although B. fragilis has long been considered reliably susceptible to a number of broad-spectrum anti-anaerobic drugs, this case and others like it 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. They also underscore the need for improved antibiotic stewardship. 

American Surgical Society and American Society of Infectious Diseases guidelines for the treatment of abdominal infection.

In 2010 the American Surgical Society and American Society of Infectious Diseases have updated their guidelines for the treatment of abdominal infection.

The recommendations suggest the following:

For mild-to-moderate community-acquired infections in adults, the agents recommended for empiric regimens are: ticarcillin- clavulanate, cefoxitin, ertapenem, moxifloxacin, or tigecycline as single-agent therapy or combinations of metronidazole with cefazolin, cefuroxime, ceftriaxone, cefotaxime, levofloxacin, or ciprofloxacin. Agents no longer recommended are: cefotetan and clindamycin ( Bacteroides fragilis group resistance) and ampicillin-sulbactam (E. coli resistance) and aminoglycosides (toxicity).

 For high risk community-acquired infections in adults, the agents recommended for empiric regimens are: meropenem, imipenem-cilastatin, doripenem, piperacillin-tazobactam, ciprofloxacin or levofloxacin in combination with metronidazole, or ceftazidime or cefepime in combination with metronidazole. Quinolones should not be used unless hospital surveys indicate >90% susceptibility of E. coli to quinolones.

Aztreonam plus metronidazole is an alternative, but addition of an agent effective against gram-positive cocci is recommended. The routine use of an aminoglycoside or another second agent effective against gram-negative facultative and aerobic bacilli is not recommended in the absence of evidence that the infection is caused by resistant organisms that require such therapy.

Empiric use of agents effective against enterococci is recommended and agents effective against methicillin-resistant S. aureus (MRSA) or yeast is not recommended in the absence of evidence of infection due to such organisms.

Empiric antibiotic therapy for health care-associated intra-abdominal infection should be driven by local microbiologic results. Empiric coverage of likely pathogens may require multidrug regimens that include agents with expanded spectra of activity against gram-negative aerobic and facultative bacilli. These include meropenem, imipenem-cilastatin, doripenem, piperacillin-tazobactam, or ceftazidime or cefepime in combination with metronidazole. Aminoglycosides or colistin may be required.

Antimicrobial regimens for children include an aminoglycoside-based regimen, a carbapenem (imipenem, meropenem, or ertapenem), a beta-lactam/beta-lactamase-inhibitor combination (piperacillin-tazobactam or ticarcillin-clavulanate), or an advanced-generation cephalosporin (cefotaxime, ceftriaxone, ceftazidime, or cefepime) with metronidazole.

Infectious Diseases Society of America guideline for the diagnosis and treatment of diabetic foot infections.

Foot infections are a frequent and serious problem in individuals with diabetes. The Infectious Diseases Society of America recently published clinical practice guideline for the diagnosis and treatment of diabetic foot infections.  Diabetic foot infections (DFIs) usually starts as a wound, most often a neuropathic ulceration. While all wounds are colonized with microorganisms, the presence of infection is defined by ≥2 classic findings of inflammation or purulence.
Infections are then classified into:

·       Mild (superficial and limited in size and depth).

·       Moderate (deeper or more extensive).

·       Severe (accompanied by systemic signs or metabolic perturbations).

This classification system, along with a vascular assessment, helps determine which patients should be hospitalized, which may require special imaging procedures or surgical interventions, and which will require amputation.
Most DFIs are polymicrobial infections caused by aerobic gram-positive cocci (GPC), and especially staphylococci, the most common causative organisms. Aerobic gram-negative bacilli are frequently copathogens in infections that are chronic or follow antibiotic treatment, and obligate anaerobes may be copathogens in ischemic or necrotic wounds.
The Guidelines stat that wounds without evidence of soft tissue or bone infection do not require antibiotic therapy. For infected wounds, they suggest obtaining a post-debridement specimen (preferably of tissue) for aerobic and anaerobic culture. Empiric antibiotic therapy can be narrowly targeted at GPC in many acutely infected patients, but those at risk for infection with antibiotic-resistant organisms or with chronic, previously treated, or severe infections usually require broader spectrum regimens.
According to the Guidelines imaging is helpful in most DFIs; plain radiographs may be sufficient, but magnetic resonance imaging is far more sensitive and specific. Osteomyelitis occurs in many diabetic patients with a foot wound and can be difficult to diagnose (optimally defined by bone culture and histology) and treat (often requiring surgical debridement or resection, and/or prolonged antibiotic therapy).
It is recommended that in most DFIs some surgical intervention, ranging from minor (debridement) to major (resection, amputation) is performed. Wounds must also be properly dressed and off-loaded of pressure, and patients need regular follow-up. An ischemic foot may require revascularization, and some nonresponding patients may benefit from selected adjunctive measures. Employing multidisciplinary foot teams improves outcomes. The guidelines encouraged clinicians and healthcare organizations to monitor, and thereby improve, the outcomes and processes in caring for DFIs.

Diabetic foot ulcer

Clostridial Spores for Cancer Therapy

Solid tumor accounts for 90% of all cancers. The current treatment approach for most solid tumors is surgery; however it is limited to early stage tumors. Other treatment options such as chemotherapy and radiotherapy are non-selective, thus causing damage to both healthy and cancerous tissue.

Recent research has shifted towards understanding the tumor microenvironment and it's differences from that of healthy cells/tissues in the body and then to exploit these differences for treatment of the tumor. One such approach is utilizing anaerobic bacteria. Several strains of bacteria have been shown to selectively colonize in solid tumors, making them valuable tools for selective tumor targeting and destruction.

Clostridium-based cancer therapy is a promising approach for the treatment of solid tumours. Bacterial-based cancer therapy using Clostridium spp. offers a selective advantage in overcoming the obstacles of hypoxia and necrosis. Clostridium spp., being strictly anaerobic will only colonize in areas devoid of oxygen, and when systematically injected, spores germinate and multiply in the hypoxic/necrotic areas of solid tumors. Clostridium, although anaerobic, possesses the ability to sporulate, allowing them to remain dormant in environments where oxygen is present. However, when growth conditions are suitable (i.e., in the hypoxic/necrotic milieu of solid tumors), the Clostridium spores germinate and begin to colonize these areas. This aspect of Clostridium growth is being exploited for use in a number of various novel cancer treatment strategies currently being developed which utilize Clostridium as a vector to deliver therapeutics directly to the solid tumor site. Clostridial vectors can be safely administered as spores, and their efficacy in delivering and secreting therapeutic proteins has been demonstrated in a number of preclinical trials.

Clostridium spp. with spore formation.

Necrotizing fasciitis-a newly recognized complication of laryngectomy

Necrotizing fasciitis (NF) was recently recognized as a new post surgical complication of laryngectomy. NF is an unusual, life threatening, rapidly advancing serious infection characterized by widespread fascial and subcutaneous tissue necrosis and gangrene of the skin. It most commonly affects the extremities, abdominal wall and perineum, whereas cervical NF is rare. NF of the head and neck is often caused by both aerobic and anaerobic microorganisms found in the upper aerodigestive tract. Usually, cervical NF originates from odontogenic, tonsillar and pharyngeal infection, and it is very rarely a complication of surgical procedure. Without immediate surgical treatment, cervical NF leads to mediastinitis and fatal sepsis. There was only one case of cervical NF after total laryngectomy described in the literature. Hadzibegovic and colleagues recently reported two additional cases of cervical NF after total laryngectomy, selective neck dissection and primary vocal prosthesis insertion. In both cases, the infection spread to thoracic region and in one of the patients NF was associated with Lemierre's syndrome ( thrombosis of the internal jugular vein). In both patients, vocal prosthesis was inserted during the infection and did not influence the healing process.

CT scan of the neck demonstrates gas in the soft tissue of the left side of the neck associated with necrotizing fasciitis.

Individuals with oral cancer are colonized with greater number of bacteria and yeast

Changes in the microbial flora on the oral mucosa after cancerous alteration may lead to both local and systemic infections. Researchers from India assessed the microbial flora associated with the surfaces of oral squamous cell carcinoma and compared the oral microbial contents with healthy mucosa. They also assessed the microbial flora from the saliva culture in subjects with oral squamous cell carcinoma and healthy controls.

The study included 30 subjects with oral squamous cell carcinoma and 30 healthy matched controls. The investigators found that oral squamous cell carcinoma sites harbor significantly more bacteria and yeasts compared to the control group. The microbial flora predominantly isolated from the carcinoma site were Streptococcus, Staphylococcus, Moraxella, Klebsiella, Citrobacter, Proteus, and Pseudomonas spp., Enterococcus feacalis, and Candida albicans. The median number of colony forming units (CFU)/mL at carcinoma sites (3.85 x 105 CFU/mL) was significantly higher than that of the healthy mucosa (0.571 x 105 CFU/mL) Similarly, in saliva of carcinoma subjects, the median number of CFU/mL (2.408 x 105 CFU/mL) was significantly higher than that of saliva in control subjects (0.78 x 105 CFU/mL)  

The study clearly indicates that the subjects with oral squamous cell carcinoma harbor significantly more microbial flora. The study's implications are that emphasis has to be made to prevent changes in the microbial flora of the oral cavity. This can be achieved by reducing sugar intake, using probiotics when indicated, avoiding unnecessary use of antibiotics, and maintaining good dental and oral hygiene. 

Microscopic view of oral bacteria and yeast 

Antibiotics treatment can be as effective as surgery for appendicitis

A meta-analysis published in the British Medical Journal of four randomised controlled trials including 900 adult patients ( > 18 years ) compared antibiotic treatment and appendicectomy for uncomplicated acute appendicitis showed that antibiotics can be used safely as primary treatment in patients presenting with acute uncomplicated appendicitis. Antibiotic treatment was not associated with an increased perforation rate compared with surgery, nor were any significant differences seen in the length of stay or treatment efficacy between antibiotics and appendicectomy. Antibiotic treatment was associated with a 63% success rate and a reduced risk of complications. About 20% of patients who were treated with antibiotics had appendicectomy for recurrence of symptoms, and of these only about one in five had complicated appendicitis. 

The authors concluded that an early trial of antibiotics may merit consideration as the initial treatment option for uncomplicated appendicitis. They suggested that the possibility that perforated and non-perforated appendicitis could have different patterns and pathological processes needs further evaluation. Future studies may show if uncomplicated acute appendicitis should be treated in a similar fashion as other conditions such as acute colonic diverticulitis in which antibiotic treatment plays an important role.

Effects of exposure to smoking on the aerobic and anaerobic microbial flora of children and their parents

Several studies investigated the effects of exposure to direct and indirect smoking on the oro-pharyngeal colonization with potential pathogenic bacteria and aerobic and anaerobic organisms that can interfere with their growth. The potential pathogens included Streptococcus pneumoniae, Hamophillus influenzae, Staphylococcus aureus , and Streptococcus pyogenes. Bacteria with interference capability of potential respiratory pathogens include alpha- hemolytic streptococci, non-hemolytic streptococci, and Prevotella and Peptostreptococcus spp.

The flora of smokers contained less aerobic and anaerobic organisms with interfering capability and more potential pathogens as compared with non-smokers. The high number of pathogens and the low number of interfering organisms found in the nasopharynx of smokers revert to normal levels after complete cessation of smoking.

A high recovery rate of potential pathogens and low number of interfering organisms were observed in otitis media prone (OMP) children. This was not related to their parents smoking habits. The flora of smoking parents contains more potential pathogens that are similar to the one recovered from their OMP children, and less interfering organisms as compared to non-smoking parents.

Parents that smoked were more often colonized by potential pathogens than parents that did not smoke. The flora of healthy children of smoking parents contained high number of potential pathogens similar to the one found in their parents and OMP children. Concordance with pathogens in the parent was high among the OMP children of smoking parents but this was not observed in OMP children of non-smoking parents. A higher recovery rate of potential pathogenic organisms was observed in OMP children of both smoking and non-smoking parents, as compared to healthy children whose parents were non-smoking. Since smoking parents harbor more potential pathogens and less interfering organisms they may serve as a source of pathogens that can colonize and/or infect their children.

These studies illustrate the adverse effects of direct and indirect exposure to smoking on colonization with potential bacterial pathogens

Vagina flora and its influence on women's health and disease

Explorations of the vaginal flora started over 150 years ago. Using light microscopy and bacterial cultures, the concept of normal versus abnormal flora in women began to emerge. The latter became known by the term "bacterial vaginosis" . Bacterial vaginosis flora is dominated by Gardnerella vaginalis and includes a number of anaerobic organisms. In contrast, normal flora is dominated by various Lactobacilli. Bacterial vaginosis flora is associated with vaginal discharge, poor pregnancy outcomes, pelvic inflammatory disease, postoperative wound infections and endometritis after elective abortions. In addition, bacterial vaginosis flora predisposes women to infection by human immunodeficiency virus (HIV) and sexually transmitted diseases.  

The small and short Gram-negative rodes are clustered onto the squamous epithelium forming        “clue cells”, typical of Garderella vaginalis infection

The application of molecular techniques over the past decade has significantly advanced the understanding of the vaginal flora. It is much more complex than previously recognized and is composed of many previously unknown organisms in addition to those already identified by culture. Analyses using high-throughput sequencing techniques have lead to the discovery of unique microbial communities not previously recognized within the older, established vaginal flora categories. These new findings will inform the design of future clinical investigations of the role of the vaginal flora in health and disease.

                                                       Lactobacillus species 

The possible role of anaerobes in inflammatory bowel disease ( ulcerative colitis and Crohn's disease)

The distal ileum and colon harbors very high concentrations of bacteria. These may include potential pathogens that could initiate inflammatory bowel disease (IBD). Increased underlying genetic predisposition due to genetic mucosal or immune defect may enhance IBD in some individuals. As study by sutton et al provided support for this hypothesis in finding of an immune response directed against a particular bacterial DNA segment (I2) in affected mucosa from 54 % of patients with Crohn's disease compared to 4 to 10 % of normal individuals. However, no specific organism has been shown to have a consistent relationship to IBD.

Because of the high number of anaerobic bacteria within the intestinal flora, any disturbance of the intestinal epithelium could generate an inflammatory response. This can be due to the effects of microbial products that effect  the underlying epithelium, or from defects in the epithelium which permits bacterial and food antigens to stimulate the mucosal immune system. Studies in genetically engineered mice support the importance of an intact epithelium as an altered gut epithelium lead to the development of spontaneous colitis. Genetic studies have described susceptibility loci that regulate innate responses to the microbial flora and provide support for the role of microbes in the pathogenesis of IBD.

 The ability of the microbial flora to induce disease has been demonstrated in murine models of IBD. A genetically engineered mice that was deficient in cytokines IL-2 and IL-10 or rats containing the HLA-B27 transgene develop inflammatory bowel disease in the presence of a normal microflora but not in germ-free conditions. Mow et al found that immunoreactivity to microbial antigens correlates with complications of small bowel Crohn's disease in humans.

A Link Between Fusobacterium species and Colon Cancer

The possibility that are associated of Fusobacterium species with colonic cancer was suggested in two studies published in Genome Research. The organism was detected in colon cancer cells by both Meyerson et al from the Dana Farber Cancer Institute and Holt et al from the British Columbia Cancer Agency Genome Sciences Center. The two research groups used genetic probes to identify the bacteria found in the tumor tissues.  

Fusobacterium species are mostly found in the mouth and are linked to periodontal disease and oral infections. It is rarely found among the usual gastrointestinal bacteria, but it appears to the only type of bacteria inside colonic cancer cells.  

Gram staining of Fusobacterium nucleatum 

Meyerson et al looked for bacterial DNA, comparing tumor tissue and healthy colon samples from nine patients with colonic cancer. They found Fusobacteria DNA mostly in the cancer tissue. In further studies these investigators found Fusobacterium species in 95 other colon cancer patients.  

Holt et al. focused on RNA instead of DNA. These investigators studied colon cancer biopsies and normal tissues of 11 patients and found that Fusobacteria were more likely to be in cancer tissue than in normal cells. In some specimens, the number of Fusobacteria was hundreds of time higher in cancer cells than in normal tissues.   The investigators also found that other types of bacteria that commonly reside in the gut are depleted in colon cancer tissues. Whether the Fusobacteria are crowding out these more common bugs, or whether they tend to die off in the presence of malignant cells isn't known.  

Currently it is unclear whether or how Fusobacteria might be contributing to the development of cancer. These organisms may promote inflammation, which can contribute to malignant transformation in normal cells. Alternatively, the tumor environment may be more hospitable to Fusobacterial growth, and the high number of this bacterium would be a consequence, not the cause, of the cancer.

Colonic cancer

A link between colonization of the gastrointerstinal tract with Desulfovibrio species and autism

Autism is a complex disorder with no specific diagnostic test so the disease is defined by its characteristics including cognitive defects, social, communication and behavioral problems, repetitive behaviors, unusual sensitivity to stimuli such as noise, restricted interests, and self stimulation. The incidence of this disease has increased remarkably in recent years and was 110/10,000 children (∼1%) in multiple areas of the US in 2007. The financial burden on families and communities is enormous. In terms of predisposing factors, heredity plays a role in some subjects, but it is clear that environmental factors are also important.

Environmental toxins can affect the immune system adversely. Intestinal bacteria are recognized by a few investigators as potentially important and we have proposed that certain antimicrobial drugs may be a key factor in modifying the intestinal bacterial flora adversely, selecting out potentially harmful bacteria that are normally suppressed by an intact normal intestinal flora.

Finegold  et al hypothesis that clostridia in the gut might be involved in autism because they are virulent organisms and spore-formers; spores would resist antibacterial agents so that when antibiotics were discontinued the spores would germinate and by toxin production or another mechanism lead to autism. A recent study by Finegold et al. employing the powerful pyrosequencing technique on stools of subjects with regressive autism showed that Desulfovibrio was more common in autistic subjects than in controls. The investigators  subsequently confirmed this with pilot cultural and real-time PCR studies and found siblings of autistic children had counts of Desulfovibrio that were intermediate, suggesting possible spread of the organism in the family environment.

Desulfovibrio is an anaerobic bacillus that does not produce spores but is nevertheless resistant to aerobic and other adverse conditions by other mechanisms and is commonly resistant to certain antimicrobial agents (such as cephalosporins) often used to treat ear and other infections that are relatively common in childhood. This bacterium also produces important virulence factors and its physiology and metabolism position it uniquely to account for much of the pathophysiology seen in autism. If these results on Desulfovibrio are confirmed and extended in other studies, including treatment trials with appropriate agents and careful clinical and laboratory studies, this could lead to more reliable classification of autism, a diagnostic test and therapy for regressive autism, development of a vaccine for prevention and treatment of regressive autism, tailored probiotics/prebiotics, and important epidemiologic information.

Propionibacterium species as pathogens

Propionibacterium species are part of the normal bacterial flora that colonize the skin, conjunctiva, oropharynx, and gastrointestinal tract. These non-spore-forming, anaerobic, gram-positive bacilli are frequent contaminants of specimens of blood and other sterile body fluids and have been generally considered to play little or no pathogenic role in humans.

Propionibacterium acnes and other Propionibacterium species have, however, been recovered with or without other aerobic or anaerobic organisms as etiologic agents of multiple infection sites. These include conjunctivitis, intracranial abscesses, mycotic aneurysm, peritonitis, and dental, parotid, pulmonary, and other serious infections. They have often been recovered as a sole isolate in specimens obtained from patients with infections associated with a foreign body (such as joint infection, an artificial valve), endocarditis, and central nervous system shunt and post surgical intracranial infections.  Some P. acnes strains possess synergistic capabilities with facultative and aerobic bacteria. The possible role of P. acnes in the pathogenesis of acne vulgaris was suggested. The data that support this are based on the recovery of this organism in large numbers from sebaceous follicles, especially in patients with acne, on its ability to elaborate enzymes such as lipase, protease, and hyaluronidase, and on its ability to activate the complement system and enhance chemotactic activity of neutrophils.

Anaerobic beta-lactamase-producing-bacteria in mixed infections

Aerobic and anaerobic beta-lactamase-producing bacteria (BLPB) can play an important role in polymicrobial infections. They can have a direct pathogenic impact in causing the infection as well as an indirect effect through their ability to produce the enzyme beta-lactamase. BLPB may not only survive penicillins therapy but can also, as was demonstrated in in vitro and in vivo studies, protect other penicillin-susceptible bacteria from penicillins by releasing the free enzyme into their environment ( see figure ). This phenomenon occurs in upper respiratory tract, skin, soft tissue, abdominal, surgical and other infections.

Many Gram negative anaerobic bacteria can produce the enzyme beta-lactamse (BL). Bacteroides fragilis group has been known as a BL producer. However recent studies illustrated that other anaerobes have also become BL producers. These include up to 50% of pigmented Prevotella and Porphyromonas and Fusobacterium spp. that predominate in respiratory and head and neck infections, and Prevotella bivia, and Prevotella disiens important in female pelvic infections).

The presence of free BL in clinical specimens was reported in abscesses and mixed infections. These include abdominal infections, empyema, cerebrospinal specimens, abscesses, ear aspirates of acute and chronic ear infections, and aspirates of acutely and chronically inflamed sinuses. Many of these infections had failed beta-lactam therapies and required surgical drainage to enhance cure.

The isolation of penicillin-susceptible bacteria mixed with BLPB in patients who have failed to respond to beta-actam therapy suggests the ability of BLPB to protect a susceptible organism from the activity of those drugs.

Aerobic and anaerobic BLPB may play a role in penicillin failure to eradicate Group A beta hemolytic streptococci tonsillitis (GABHS). BLPB were recovered in over 2/3 of tonsils removed from those who failed penicillin therapy.

The presence of BLPB in mixed infection warrants administration of drugs that will be effective in eradication of BLPB as well as the other pathogens. Antimicrobials active against aerobic and anaerobic BLPB as well as GABHS were more effective in the eradication of this infection and even prevented elective tonsillectomy compared to penicillin. These include lincomycin, clindamycin , and amoxicillin/clavulanate.

Other infections where this approach was superior to penicillins therapy were acute and chronic otitis media and sinusitis, aspiration and tracheostomy-associated pneumonia, and lung abscesses.

The management of polymicrobial infections is enhanced by directing antimicrobial therapy at the eradication of both aerobic and anaerobic BLPB. Although beta lactam antibiotics are still the mainstay in treatment of numerous infections, agents effective against BLPB should be considered in the treatment of those who failed these agents.

Bacterial Interference by anaerobes in ear, sinus, and tonsillar infections

Interactions between bacteria that include antagonism (interference) and synergism maintain balance between members of the normal endogenous flora and play a role in preventing colonization by potential pathogens.  Bacterial interference can assist in the recovery from infections, in promotion of health and prevention of upper respiratory tract infection. Bacteria capable of interfering with the growth of potential respiratory pathogens include alpha- hemolytic streptococci, non-hemolytic streptococci, and the anaerobic bacteria Prevotella and Peptostreptococcus spp.

Bacterial Interference in colonization by pathogens

Bacterial interference plays a role in the emergence of upper respiratory tract infections and their eradication. These infections include recurrent pharyngo-tonsillitis, otitis media , and sinusitis. The tonsils, and nasopharyngeal flora of patients with these infections harbor less interfering bacteria than those without that history. The presence of interfering bacteria may therefore play a role in preventing pharyngo-tonsillitis, otitis media, and sinusitis.

Treatment with antimicrobials and smoking can affect the balance between the interfering organisms and potential pathogens.  Antimicrobials that spare the normal flora, can assist in preserving the interfering flora.

Balance between interfering bacteria and pathogens

Introduction into the indigenous microflora of low virulence bacteria that are capable of interfering with colonization and infection with virulent organisms has been used as a means of preventing the failure of antimicrobials in the treatment of pharyngo-tonsillitis and otitis media.