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Sunday, October 21, 2007

Treatment of Acute and Chronical Bacterial Prostatitis Caused by Staphylococcus Epidermidis

27th August 2005
Author: Dan Pop

Staphylococcus epidermidis is normally resident in the skin flora, the gut and upper respiratory tract. It is a true opportunistic pathogen, normally requiring a major breach in the host's defence to establish infection.Previously considered solely as the laboratory contaminants and normal flora of skin in man, coagulase negative Staphylococci are now a major cause of nosocomial and opportunistic infections.

Adherence to a foreign surface is facilitated by the production of a viscous extracellular slime (proteoglycans). Staph. epidermidis is coagulase - negative (1).

Phagocytosis is the major host - defence mechanism for combatting staphylococcal infection. Antibodies are produced which neutralize toxins and promote opsonization. However, the bacterial capsule and protein A may interfere with phagocytosis. Biofilm formation and growth is also impervious to phagocytosis.

Infections acquired outside hospitals can usually be treated with penicillinase-resistant ߭lactams. Hospital acquired infection is often caused by antibiotic resistant strains and can only be treated with vancomycin.

Treatment of prostatitis is challenging in general, because many antimicrobial agents do not effectively diffuse into prostatic tissue. The relapsing nature of bacterial prostatitis is in part due to the ductal anatomy of the peripheral zone of the prostate. The anatomy of the ductal system prevents dependent drainage of secretions. Ductal fibrosis and prostatic calculi, if present, further inhibit the drainage of secretions.

E coli accounts for 80% of cases of chronic bacterial prostatitis. The other members of the Enterobacteriaceae family, Klebsiella species, Pseudomonas aeruginosa, and Proteus species also are known pathogens.

Chlamydia trachomatis has also been implicated as a cause of chronic bacterial prostatitis. However, we consider that this organism is unlikely to play a major role in the etiology of chronic bacterial prostatitis, being a pathogen confined to the urethra.

The role of the gram-positive organisms Staphylococcus epidermitis and Staphylococcus saprophyticus is still controversial and a matter of dispute. According to some authors these organisms typically may colonize the anterior urethra.

The mainstay for treatment of chronic bacterial prostatitis is the use of oral antimicrobial agents. So far, the most effective medications for the treatment of chronic prostatitis were the fluoroquinolones and TMP-SMZ (trimethoprim-sulfomethoxazol). However these drugs are not effective against Staphylococcus Epidermidis. All other oral agents are unlikely to eradicate the pathogenic bacteria successfully within the prostate, because of suboptimal tissue penetration. Longer courses of antibiotic use are associated with better treatment outcomes. Relapse is not uncommon.

In an excellent article of Jukka Hyvarinen et al. (2), 570 Staphylococcus spp. isolates were tested for susceptibility to oxacillin and 19 other antimicrobial agents. Of the 238 Staphylococcus Epidermidis isolates, 58 % were identified as methicillin - resistant in vitro . Of the 332 Staphylococcus aureus isolates only 1 (0,3%) was phenotypically resistant to methicillin.The percentage (%) of Staphylococcus Epidermidis isolates resistant to the 20 tested antibiotics was : Oxacillin (58%) , Penicillin (82 %), Amoxicillin/ClavulanicAcid (34 %), Cephalothin (4 %),Cefuroxime (31%), Cefotaxime (20%), Imipenem (46%) , Gentamicin (46 %) , Tobramycin (57%) , Netilmicin (16 %), Ciprofloxacin(23 %), Ofloxacin (21%), Erythromycin (36%), Fusidic Acid ( 27% ) , Clindamycin (34 %), Cloramphenicol (19 %), Rifampin (4 %), Vancomycin ( 0 % ) , Co-trimoxazole(62%), Trimethoprim (53%) ; From this data we conclude that only vancomycin and to some extent rifampin and cephalothin are suitable for the treatment of bacterial prostatitis caused by Staphyloccocus epidermidis. However, rifampin cannot be used as monotherapy since microbial resistance to it seems to develop rapidly.

Vancomycin is recognized as one of the most potent antistaphylococcal drugs available. It is the drug-of-choice in the treatment of serious methicillin-resistant Staph. aureus infections. Vancomycin interferes with peptidoglycan biosynthesis in multiplying organisms and is bactericidal. It is also the preferred therapy for Clostridium difficile (antibiotic-associated) colitis. Vancomycin interferes with peptidoglycan biosynthesis in multiplying organisms and is bactericidal.

Vancomycin is supplied as the hydrochloride salt and isavailable in 500-mg ampuls. Vancomycin is usually administered intravenously or orally. I.V. vancomycin should be administered slowly (over 30--60 min) and in an adequate volume (100--250 ml) of 5% dextrose injection. Usual adult dose is 500 mg every six hours or 1 g every 12 hours. Vancomycin is almost completely eliminated through the kidneys. Mean vancomycin concentrations in the presence of inflamed meninges, pleural fluid, pericardial fluid, ascitic fluid, synovial fluid, and bile are approximately 15% of the serum concentrations, and this value may be probably recorded also in the prostate.
The various treatments of bacterial prostatitis caused by Staphylococcus epidermidis , which we consider a true pathogen , when found in the prostate or in the seminal fluid , are presented below:

Methicillin-sensitive Staphylococcus Epidermidis strains should be treated with (3) :

1. oxacillin/nafcillin 1.5-3 gm IV 6h,
2. cefazolin 1-2 gm IV q 8h,
3. clindamicin 600 mg IV q 8h,

Methicillin resistance is equivalent to resistance to oxacillin and nafcillin, which are commonly used and extremely effective anti-staph drugs, in fact they are the drugs of choice.

Methicillin-resistant Staphylococcus Epidermidis (MRSE) strains (3) should be treated with vancomycin with or without rifampin.

The Standard treatment for Staphylococcus Epidermidis deep infection is (3) :

Vancomycin IV q 12 h +/- Rifampin 3- bid IV/PO +/- Gentamicin 3-5 mg/kg/d IV

Vancomycin + Methicillin-resistant (VRSE / MRSE) strains of Staphylococcus Epidermidis should be treated with (3) :

1. Linezolid (Zyvox) 600 mg IV/PO bid + Rifampin +/or Gentamicin
or with
2. Daptomycin IV 4 mg/kg/d + Rifampin +/or Gentamicin.
3. Quinupristin / Dalfopristin (Synercid)

The existence of mixed species biofilms of Candida albicans and Staphylococcus epidermidis have also been reported (4). Biofilms are notoriously difficult to eliminate and are a source of recalcitrant infections. The novel lipid formulation of amphotericin and the echinocandins (caspofungin, micafungin) have demonstrated unique antifungal activity against Candida biofilms (5).

In a Japanese laboratory and clinical study on 11 patients (6) , Sulbactam/cefoperazone (SBT/CPZ) exhibited 8 fold or more potent antimicrobial activity than cefoperazone against beta-lactamase producing E. coli and coagulase-negative staphylococci (Staphylococcus Epidermidis).

Staphylococcus saprophyticus has also been shown to be an important pathogen in prostatic infections (7). Thirty-five isolates from 27 patients with staphylococci in the prostatic fluid of men with bacterial prostatitis were evaluated for the presence of S. saprophyticus. Three patients (11 per cent) with this organism were identified by novobiocin resistance (disk diffusion test), absence of hemolysis, and coagulase. These patients tended to be younger, more symptomatic, and more responsive to appropriate antibiotic therapy than those with staphylococcus epidermidis.

So far a vaccine against Staphylococcus Aureus has been developed by Nabi Biopharmaceuticals (8) for patients who are at high risk of S. aureus infections and who are able to respond to a vaccine by producing their own antibodies. StaphVAX? (Staphylococcus aureus Polysaccharide Conjugate Vaccine) is an investigational polysaccharide conjugate vaccine that presents a novel approach to the prevention of S. aureus infections. StaphVAX is intended to stimulate a patient's immune system to produce antibodies to S. aureus that provide active, long-term protection from the bacteria. StaphVAX targets S. aureus types 5 and 8, which are responsible for approximately 85 percent of S. aureus infections.

Altastaph? [Staphylococcus aureus Immune Globulin Intravenous (Human)] is an investigational human antibody-based product containing high levels of antibodies to capsular polysaccharides (protective outer sugar coatings on S. aureus bacteria) from S. aureus types 5 and 8, which together account for approximately 85 percent of all S. aureus infections. These antibodies are the same antibodies that are developed in patients who are vaccinated with StaphVAX?), Nabi Biopharmaceuticals' investigational vaccine to prevent S. aureus infections, and, indeed, Altastaph is produced by vaccinating healthy volunteers with StaphVAX, and then harvest the anti-staphylococcus antibodies.

Nabi Biopharmaceuticals is focused on developing a broad portfolio of vaccines and antibody-based therapies that target Gram-positive bacteria, most notably S. aureus, Staphylococcus epidermidis and Enterococcus. These bacteria are the leading causes of serious hospital-acquired infections.

EpiVAX? (Staphylococcus epidermidis Conjugate Vaccine) is an investigational vaccine in preclinical development for the prevention of S. epidermidis infections (8). EnteroVAX? (Enterococcus faecalis Conjugate Vaccine) is an investigational vaccine also in preclinical development for the prevention of enterococcal infections (8) . Both EpiVAX and EnteroVAX have been shown to induce antibodies that are protective in animal models and facilitate elimination of bacteria by the same type of immune system response as StaphVAX (8).

EpiVAX? (Staphylococcus epidermidis Conjugate Vaccine) will probably be used both as a vaccine in order to prevent S. epidermidis infections, and as a potential therapeutic vaccine to be administrated before onset of antibiotherapy.

The objective of a recent article of John (9) was to determine the in vitro susceptibilities of a large series of speciated coagulase-negative staphylococci (CNS) against three new antibiotics, linezolid, quinupristin/dalfopristin and telithromycin. Resistance to linezolid was not observed in any isolates, although MIC90 values varied between species. Fifteen of 658 (2.3%) isolates were resistant to quinupristin/dalfopristin, but < 1% of the clinically most important isolates of Staphylococcus epidermidis, Staphylococcus haemolyticus and Staphylococcus hominis demonstrated resistance to this agent. Telithromycin was the least active of the new agents tested, showing activity similar to that of clindamycin. Susceptibility and resistance to clindamycin were predictive of susceptibility and resistance to telithromycin. Resistance to clindamycin did not predict quinupristin/dalfopristin resistance.

Quinupristin/dalfopristin and linezolid show good activity against both mecA-positive and -negative CNS.

Quinupristin-dalfopristin(10) also appeared to be an efficient and safe antimicrobial drug for the rescue treatment of staphylococcal infections in critically ill patients. It may be considered as a treatment option in cases of vancomycin treatment failure. Patients received, intravenously, quinupristin-dalfopristin (Q-D) 7.5 mg/kg body weight 3 times daily. The duration of Q-D therapy averaged 11.8 days (range: 1-26 days)(10).

Conclusions : Prostatitis caused by Staphylococcus Epidermidis and/or by other coagulase - negative staphylococci should not be neglected or left untreated, since some potential treatments for this infection of the prostate exist and are available. Newly introduced or experimental drugs, such as streptogramins (quinupristin-dalfopristin), oxazolidinones (linezolid), carbapenems (LY 333328 i.e. Oritavancin )(11), everninomicins (SCH 27899) (12) , and glycylcyclines ( tigecycline i.e. GAR-936 )(11), could be useful for therapy of infections caused by multiresistant staphylococci in general and for the treatment of Staphylococcus Epidermidis caused prostatitis in particular.

References :

1. Staphylococcus Summary :

2. Jukka Hyvarinen et al. , Multiresistance in Staphylococcus spp. blood isolates in Finland with special reference to the distribution of the mecA gene among the Staphylococcus Epidermidis isolates , APMIS , 103 : 885-891, 1995;

3. Antibiotic Guide , Johns Hopkins Point of Care, , ;

4. Adam B, Baillie GS, Douglas LJ, Mixed species biofilms of Candida albicans and

Staphylococcus epidermidis , J. Med. Microbiol. , 2002 , 51: 344-9;

5. Mary Ann Jabra-Rizk , Fungal Biofilms and Drug Resistance, Emerging Infectious Diseases, Vol.10,No. 1, January 2004 ;

6. Suzuki K, Horiba M., Laboratory and clinical study of sulbactam/cefoperazone (SBT/CPZ) on bacterial prostatitis, Hinyokika Kiyo. 1991 Oct;37(10):1333-43.

7. Carson CC, McGraw VD, Zwadyk P , Bacterial prostatitis caused by Staphylococcus saprophyticus. Urology. 1982 Jun;19(6):576-8.

8. , Nabi Biopharmaceuticals web-site, EpiVAX? (Staphylococcus epidermidis Conjugate Vaccine)

9. John MA, Pletch C, Hussain Z., In vitro activity of quinupristin/dalfopristin, linezolid, telithromycin and comparator antimicrobial agents against 13 species of coagulase-negative staphylococci. J Antimicrob Chemother. 2002 Dec;50(6):933-8.

10. Sander A, Beiderlinden M, Schmid EN, Peters J. Clinical experience with quinupristin-dalfopristin as rescue treatment of critically ill patients infected with methicillin-resistant staphylococci.Intensive Care Med. 2002 Aug;28(8):1157-60. Epub 2002 Jun 20. (

11. Guay DR. Oritavancin and tigecycline: investigational antimicrobials for multidrug-resistant bacteria. Pharmacotherapy. 2004 Jan;24(1):58-68. (

12. Nakashio S, Iwasawa H, Dun FY, Kanemitsu K, Shimada J. Everninomicin, a new oligosaccharide antibiotic: its antimicrobial activity, post-antibiotic effect and synergistic bactericidal activity. Drugs Exp Clin Res. 1995;21(1):7-16.

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