Tutorial Article Antimicrobial Therapy for Bacterial Meningitis E

316 EQUINE VETERINARY EDUCATION / AE / July 2007

Tutorial Article Antimicrobial therapy for bacterial meningitis E. MITCHELL, M. O. FURR AND H. C. MCKENZIE Marion duPont Scott Equine Medical Center, Virginia-Maryland Regional College of Veterinary Medicine, Duck Pond Drive, Blacksburg, Virginia 24061, USA. Keywords: horse; bacterial meningitis; antibiotics

Introduction in a well-controlled internal environment that is separate from that of the internal environment of the rest of the body as a Bacterial meningitis is an uncommon condition in mature whole. The integrity of this barrier is due to the presence of horses (Newton 1988). It is more prevalent in neonates, where tight junctions between the cerebral endothelial cells forming it is reported to occur in 8–10% of septicaemic foals (Moore the BBB and between the blood and choroid plexus epithelial 1995), where reported survival rates are poor (Newton 1988; cells (blood-cerebrospinal fluid barrier) (Saunders et al. 1999). Santschi and Foreman 1989; Moore 1995). Survival rate for The presence of endothelial cell tight junctions and basement adult horses was reported as 60% in a case series of 5 horses membrane also restricts entry of certain therapeutic agents with bacterial meningitis (Mitchell et al. 2006). There are no into the CSF and CNS. The presence of the BBB, combined published comprehensive case series of bacterial meningitis in with the lack of a traditional lymphatic system, are important foals. Early diagnosis is essential to provide accurate prognosis factors in mediating the immune response within the CNS. As and to institute proper treatment (Santschi and Foreman such, the CNS is often classified as an ‘immune privileged’ site 1989). The primary goal of treatment is rapid sterilisation of (Wekerle et al.1986). the cerebrospinal fluid (CSF) using appropriate antimicrobial In health, the key factors that determine penetration of a therapy based on bacterial culture and sensitivity testing of the molecule into the CNS and CSF in adults are lipid solubility and CSF (Moore 1995). However, due to the specialist nature of molecular size (Saunders et al. 1999). Highly lipid soluble the central nervous system (CNS) and presence of the blood molecules are considered to dissolve in the lipid structure of cell brain barrier (BBB), CNS concentrations of antimicrobial membranes and can thus transverse cell membranes. For agents may be substantially below those obtained in serum, molecules of low lipid solubility there is a clear relationship and below the minimal inhibitory concentration or minimal between molecular size and penetration into the brain and CSF. bactericidal concentration for the bacterial isolates involved in In healthy human subjects, molecules with size greater than the disease process. 5000 Daltons are unable to penetrate from blood to CSF This paper reviews the nature of poor antimicrobial (Saunders et al. 1999). In addition, a high degree of plasma penetration into the CNS and discusses the antimicrobial drugs protein binding of therapeutic agents limits their permeability that may be appropriate to use in treatment of bacterial to the CNS, since plasma proteins (principally albumin) are too meningitis in horses. large to cross the BBB. Meningitis is defined as inflammation of the This situation is altered in acute CNS inflammation, 3 membranes, or meninges, surrounding the brain and spinal where penetration of molecules of larger molecular weight cord. These consist of the dura mater, the arachnoid and pia mater (Fig 1). Inflammation of the meninges due to bacterial infection is termed bacterial meningitis. The space between the arachnoid and pia mater is filled with CSF. This protects the Bone brain and spinal cord against impact from the surrounding Periosteum Dura mater Epidural space bony wall, provides nutrition to the brain and spinal cord and Subdural space permits variations in blood volume within the cranial cavity. Arachnoid Sub arachnoid The existence of a barrier between the brain or CSF and the { Pia mater Spinal cord space peripheral circulation was first recognised by Ehrlich in 1885 (Saunders et al. 1999), and allows the adult brain to function Pia arachnoid

Fig 1: Diagrammatic transverse section through the spinal cord *Author to whom correspondence should be addressed. and its meninges. EQUINE VETERINARY EDUCATION / AE / July 2007 317

and lower lipid solubility can occur. During CNS inflammation process. Too few reports exist in the literature to make both microglial cells and brain endothelial cells can express generalisations about bacterial isolates causing meningitis major histocompatability complex (MHC) class II and thus where no previous focus of infection could be established. activate T lymphocytes. These activated T cells, microglial and Escherichia coli and Klebsiella species are the organisms most endothelial cells release cytokines which increase permeability frequently isolated from foals with bacterial meningitis of the BBB (Duchini et al. 1996). Cytokines increase (Jamison 1988). Other case reports include Salmonella agona permeability of the BBB by causing reorganisation of the actin- (Stuart et al. 1973), and Listeria monocytogenes in a foal with cytoskeleton (Duchini et al. 1996). They also contribute to the severe combined immunodeficiency (Clark et al. 1978). inflammatory response by stimulating the expression of Given the wide range of isolates and emerging adhesion molecules on endothelial cells (Tang et al. 1996). antimicrobial resistance, broad spectrum antimicrobial These adhesion molecules bind with their leucocyte ligand and therapy is necessary while culture of CSF is pending. In some promote leucocyte entry into the CNS, and release of reactive cases positive blood culture may provide an indication of oxygen species and further inflammatory mediators occurs. bacterial type, but in the clinical situation, these results are This leads to further swelling of endothelial cells and tight not likely to be available sooner than CSF culture results. junction disruption. Release of matrix metalloproteinases (MMPs) from endothelium, T cells and microglia degrades Should bactericidal or bacteriostatic collagen type IV, laminin and fibronectin matrix components antimicrobial therapy be used? of the basement membrane and causes further tight junction disruption (Webb and Muir 2000). The loss of BBB integrity The minimal inhibitory concentration (MIC) is the lowest drug allows leucocyte migration and passive diffusion of concentration that inhibits bacterial growth (Dowling 2004). macromolecules including pharmacological agents into the The minimum bactericidal concentration (MBC) is the lowest CNS (Nau 1998). Antimicrobial penetration is therefore drug concentration that kills 99.9% of the bacteria (Dowling substantially enhanced by CNS inflammation. 2004). If the ratio of MBC:MIC is small (<4–6), the agent is In patients with meningitis, the severity of CNS inflammation considered to be bactericidal and it is possible to obtain drug appears highly variable, and therefore it is not possible to concentrations that will kill 99.9% of the bacteria (Dowling accurately predict penetration of antimicrobial agents in 2004). If the ratio of MBC to MIC is large it may not be conditions of meningeal inflammation. It is therefore desirable to possible to safely administer dosages of the drug to kill use an antibiotic that readily crosses the normal blood brain 99.9% of the bacteria and the agent is considered barrier, so that known effective concentrations can be achieved bacteriostatic. Bacteria unable to divide and multiply in this within the CNS, and subsequently maintained to eliminate any situation are then cleared by the body’s immune response. residual microorganisms when the acute inflammatory phase of The lack of traditional lymphatic system in the CNS, the the condition has subsided (Sisodia 1980). In addition, many presence of the BBB, and the lack of traditional antigen- bacteria now have such highly complex resistance patterns that presenting cells has lead researchers to question the ability of mere penetration of the CNS is not enough, and antimicrobial the CNS to mount an effective immune response to the therapy may fail despite the presence of therapeutic presence of foreign antigen within the CNS (Brass 1994). antimicrobial concentrations within the CNS. In vitro A low concentration of macrophages and T lymphocytes are antimicrobial sensitivity testing of all bacterial isolates is therefore present in the CNS under normal conditions (Lassmann 1997; critical in aiding selection of appropriate therapy. Furr et al. 2001). T lymphocytes in their activated state (Hickley et al. 1991) (i.e. after peripheral antigen exposure) can enter Bacterial isolates from cases of bacterial the CNS by crossing the BBB. Antigen recognition by T meningitis lymphocytes requires the presentation of small peptides of the antigenic protein by antigen presenting cells (APCs) in the A literature review of equine bacterial meningitis finds that a context of MHC antigens. Both microglial cells and number of organisms have been recovered from the CSF of adult horses. These include Staphylococcus aureus (Mitchell et al. 2006), Sphingobacterium multivorum (Pellegrini-Masini Tightly apposed et al. 2005), Streptococcus suis (Devriese et al. 1990), Klebsiella endothelial cells sp. (Timoney et al. 1983), Actinomyces sp. (Rumbaugh 1977), Streptococcus zooepidemicus (Santschi and Foreman 1989), Tight junctions Streptococcus equi (Ford and Lokai 1980) and Listeria sp. Brain microvessel (Emerson and Jarvis 1968; Clark et al. 1978). In 3 of these cases, foci of infection were present outside the CNS, with Basement membrane presumed haematogenous spread. It seems logical therefore, Astrocyte podocytes that in these cases organisms present within the CNS were the Astrocytes same as those from other body sites. In cases of bacterial meningitis secondary to trauma, environmental and skin contaminants would be likely to be involved in the pathological Fig 2: The blood brain barrier. 318 EQUINE VETERINARY EDUCATION / AE / July 2007

macrophages located in the Vichow-Robin space between 2004). Adverse effects of gastrointestinal bleeding were CNS microvessels and brain tissue, can act as APCs. Both the equally divided between the treatment and placebo groups expression of MHC and the expression of adhesion molecules (van de Beek et al. 2004). These studies did not address the required for lymphocyte migration are low in health but up- minimum duration of steroid therapy or the maximum length regulated in disease states (Lassmann 1997). The initial of time after parenteral antibiotic therapy for antigen recognition triggers a cascade of secondary events, commencement. Starting steroid medication before or with including cytokine release, (in particular interleukin 1[IL-1] and the first dose of parenteral antibiotics is more effective than tumour necrosis factor alpha [TNF alpha]), and production of starting after the first dose of antibiotics (McIntyre et al. complement components, lipolytic enzymes and oxygen 1997). In human medicine, 4 days of dexamethasone radicals. In addition to bacterial destruction, these compounds therapy has been used for most clinical trials (van de Beek et are toxic to neuronal tissue, which would be detrimental to al. 2004). The conclusion of 3 meta-analyses stated that survival of the individual. Much research has proved the adjunctive administration of dexamethasone and carefully controlled down regulation of this inflammatory antimicrobial therapy was beneficial in routine management response in the CNS, presumably to minimise tissue self of suspected bacterial meningitis in industrialised countries destruction. Incubation of activated T lymphocytes with CSF (McIntyre 2005). The use of steroid medication results in 83 ± 8% inhibition of the pro-inflammatory cytokine (betamethasone) was reported in one case of bacterial interferon gamma (INF-γ) in humans and similar results were meningitis in an adult horse, 24 h after initiation of obtained in rabbits (Taylor and Streilein 1996). This antimicrobial therapy (Timoney et al. 1983). This horse did immunosuppressive effect of CSF is believed to be mediated not survive. There is no published comprehensive data by transforming growth factor beta (TGF-β) (Taylor and assessing use of steroid medication in equids suffering from Streilein 1996). These studies suggest a higher level of bacterial meningitis. inhibitory control of CNS inflammation, preventing overheated local immune responses that could be deleterious to brain Antibiotic classes for use in cases of bacterial function. As a result there is concern that the CNS may not be meningitis able to effectively respond to bacterial infection. Whether the host response is adequate to clear infection It should be noted that most of the pharmacokinetic data for in cases of bacterial meningitis, allowing the use of these pharmacological agents in the treatment of bacterial bacteriostatic drugs, or whether bactericidal drugs are meningitis comes from studies performed in humans and necessary in treatment of bacterial meningitis is debated in laboratory animals. While limited in nature, specific equine the literature (Brass 1994). Reports within the human literature is noted when available. This data is summarised in literature and individual case reports of horses show Table 1. successful outcomes with the use of bacteriostatic drugs (Newton 1988; Duke et al. 2003), suggesting that these can Beta lactam antibiotics be affective therapeutic agents in some CNS infections. Beta lactam antibiotics act on enzymes called penicillin- Use of anti-inflammatory therapy in cases of binding proteins near the bacterial cell wall, interfering with bacterial meningitis the peptidoglycan synthesis and causing cell lysis in hypo-osmotic environments. They are therefore bacteriocidal Concurrent administration of dexamethasone along with in nature. Spectrum of activity varies between individual appropriate antimicrobial therapy has been repeatedly drugs within this group. Resistance occurs due to failure of associated with a reduction in mortality in human patients drug to penetrate through the outer layer of with bacterial meningitis (de Gans and van de Beek 2002; lipopolysaccharide present in Gram-negative bacteria, van de Beek et al. 2004; Weisfelt et al. 2006). Five trials preventing diffusion into the cell wall and from bacterial involving 623 patients showed a significant reduction in production of β-lactamase enzymes. These enzymes mortality (relative risk 0.6, P = 0.002) and a reduction in hydrolyse the cyclic amide bond of the β-lactam ring and neurological sequelae (0.6, P = 0.05) (van de Beek et al. inactivate the antibiotic.

TABLE 1: Summary of penetration of antimicrobial agents into the CNS

Good CNS penetration Fair-Good CNS penetration (normal meninges) (penetration may be affected by meningeal inflammation) Poor CNS penetration

Chloramphenicol Penicillin Aminoglycosides Ampicillin Macrolides Rifampin Amoxicillin Tetracyclines Metronidazole Potentiated sulphonamides Fluoroquinolones 3rd and 4th generation cephalosporins EQUINE VETERINARY EDUCATION / AE / July 2007 319

Penicillin G (benzyl penicillin) this time and all usage is extralabel. Ceftriaxone has been investigated in the horse, and a dose of 50 mg/kg bwt i.v. Benzyl penicillin has activity against some Gram-positive resulted in a CSF concentration of 0.6 mg ± 0.14 µg/ml at 3 h species and anaerobic bacteria. Activity against Gram- after dosage, and 0.4 mg/ml ± 0.31 µg/ml at 8 h after dosage negative bacteria is poor due to inadequate penetration (Ringger et al. 1996). This concentration exceeds the MIC for through the lipopolysaccharide outer layer. Sodium and many equine pathogens, making ceftriaxone a potential potassium salts of penicillin are available for i.v. choice for treatment of bacterial meningitis in foals and small administration. A recommended and commonly used dosage ponies. However, its cost may prohibit use in mature equines. in the horse is 20,000 iu i.v. every 6 h (Papich 2001), although Cefotaxime has been used successfully in foals with meningitis use is extralabel. CSF concentrations only reach approximately at a dose of 40 mg/kg bwt q. 6 h (Morris et al. 1987). 10% of plasma concentration unless the meninges are inflamed (Barling and Selkon 1978). This poor penetration is Imipenem due to a high degree of ionisation at physiological pH and subsequent poor lipid solubility (Barling and Selkon 1978). In Imipenem is a carbapenem antibiotic and is highly resistant to meningial inflammation therapeutic concentrations may or most β-lactamases. It has the broadest spectrum of all may not be achieved depending on the minimal inhibitory antibiotics. Penetration in to the CSF is excellent, and levels are concentration for the bacterial isolate (Thea and Barza 1989). commonly above MIC for common meningial isolated in In children recovering from bacterial meningitis, obtainable human patients (Asensi et al. 1996). Recommended dosage in CSF concentrations of penicillin reduced approximately 3-fold equine patients is 5–10 mg/kg bwt i.m. q. 12 h or as CNS inflammation decreased (Heiber and Nelson 1977). 10–20 mg/kg bwt i.v. q. 6 h (Wilkins 2003). This use is Successful treatment of bacterial meningitis due to coagulase- extralabel. negative Staphylococci and Sphingobacterium multivorum infection in adult horses has been reported with potassium Chloramphenicol penicillin at a dose of 22,000–38,000 iu/kg bwt i.v. q. 6 h (Pellegrini-Masini et al. 2005). Chloramphenicol acts by binding to the 50S ribosomal subunit, and inhibiting bacterial protein synthesis. It is therefore Aminopenicillins (amoxicillin and ampicillin) bacteriostatic. Chloramphenicol has a favorable spectrum of activity for equine pathogens including Haemophillus, These compounds have better penetration through the outer Staphylococci, Salmonella, Pasteurella, E. coli and Chlamydiae layer of Gram-negative bacteria increasing their Gram- and rickettsiae (Sisodia 1980). In man chloramphenicol negative spectrum of activity. The recommended dose of achieves almost 60% of serum concentrations within the CNS ampicillin sodium is 10–20 mg/kg bwt i.v. q. 8 h (Papich 2001), when administered orally (Friedman 1979). Chloramphenicol is although use is extralabel. Penetration into the CNS is poor not administered i.v. to equids due to its very short half life unless the meninges are inflamed, in which case therapeutic (Brown et al. 1984), which makes frequent dosing necessary. concentrations are often obtained (Thea and Barza 1989). Dose recommendations in horses vary, but are reported as 25–50 mg/kg bwt per os q. 6 h (Knight 1975; Robinson 1992). Cephalosporins Three cases of bacterial meningitis in adult horses were successfully treated with chloramphenicol at 50 mg/kg bwt per Four generations of cephalosporin antibiotics exist. In general os q. 6 h for 28 days (Mitchell et al. 2006). Use in equids is all generations have good spectrum of activity against Gram- extralabel. Adverse effects of chloramphenicol administration positive organisms and subsequent generations have include reversible dose-related bone marrow suppression and increasing Gram-negative coverage due to increased irreversible and dose-independent bone marrow aplasia. Only resistance to Gram-negative beta-lactamases. First generation the former syndrome has been reported in domestic animals cephalosporins (cefalotin, cefalozin) do not cross the BBB (Sisodia 1980). (Dowling 2004). Second generation cephalosporins and some third generation cephalosporins (ceftiofur) also tend to Potentiated sulphonamides penetrate into the CNS poorly. In the case of ceftiofur (licensed for equine use in respiratory infections due to Streptococcus Sulphonamides compete with para-amino benzoic acid (PABA) zooepidemicus at 2–4 mg/kg bwt i.m. q. 24 h) this is related for the binding site on the bacterial enzyme dihydropteroate to a high degree of plasma protein binding. After a dosage synthetase (DPS), therefore blocking bacterial nucleic acid of 2 mg/kg bwt ceftiofur sodium i.m. to adult horses, synthesis. They are bacteriostatic. Diaminopyrimidines detectable concentrations of ceftiofur were not present in CSF (trimethoprim [TMP]) inhibits the conversion of dihydrofolic 50 h after administration (Cervantes et al. 1993). In general, acid to tetrahydrofolic acid by inhibiting dihydrofolate the third (ceftazidime, ceftizoxime, ceftriaxone, cefoperazone, reductase (DHFR). This is a subsequent step in the production cefotaxime) and fourth generation cephalosporins (cefepime) pathway for folic acid. The 2 drugs are used in combination penetrate the CSF well. Correct dosages and dose intervals for due to their synergistic effects, which are considered many of these drugs have not been established in the horse at bacterocidal. Potentiated sulphonamides are usually active 320 EQUINE VETERINARY EDUCATION / AE / July 2007

against Streptococci, Staphylococci and some Gram-negative reported to decrease the seizure threshold when administered organisms. The widespread bacterial resistance to to human patients (Schmuck et al. 1998). No reports exist sulphonamides is due to production of altered forms of DPS. of seizure activity in equids after fluoroguinolone Resistance to diaminopyrimidines results from production of administration, but in patients prone to seizure activity due to diaminopyrimidine resistant DHFR. The degree of plasma CNS inflammation, and with CSF concentrations likely to reach protein binding and volume of distribution varies between greater than 25%, due to increased permeability of the BBB, individual drugs in this class, but trimethoprim this is a potential concern. sulphamethoxazole (TMP/SMZ) is reported to reach therapeutic concentrations in the CSF of young calves (Shoaf Rifampin et al. 1989). At a dose of 2.5 mg/kg bwt TMP and 12.5 mg/kg bwt SMZ, concentrations in the CSF of one horse were Rifampin suppresses RNA synthesis by selectively inhibiting 0.15 µg/ml TMP and 4.8 µg/ml SMZ (28% and 43% of the bacterial DNA-dependent RNA polymerase. The drug is corresponding serum concentrations, respectively; Brown therefore bacteriostatic. Rifampin is effective against et al. 1988). These concentrations were not adequate to be Staphylococcus aureus, Haemophilus spp. and Rhodococcus effective against a number of the equine pathogens reported equi. Rifampin but must be administered with other antibiotics by the authors. Meningeal inflammation does not appear to due to the rapid development of resistance caused by enhance the CSF concentration of TMP/SMZ (Levitz and chromosomal mutation (Farr and Mandell 1982). The drug is Quintaliani 1984), hence the use of this drug in CNS infections highly lipophilic and achieves high CSF concentrations. The may not be optimal. The recommended dosage in equids is a concentration obtained in CSF approaches 25% of serum combination of sulphadiazine and trimethoprim with a ratio concentrations in man with meningeal tuberculosis (D’Oliveira of one part diaminopyrimidine to 5 parts sulphonamide 1972). Based on bacterial sensitivity data for human and administered at 30 mg/kg bwt per os q. 12 h (Papich 2001). canine isolates, the daily oral administration of 10 mg/kg bwt A number of labelled equine preparations premixed at this 1:5 rifampin in the feed represents a reasonable dose for ratio are available. A case of suspected bacterial meningitis in susceptible Gram-positive bacterial pathogens (Burrows et al. an adult horse was successfully treated with trimethoprim- 1985). Microsomal enzyme induction may shorten the half life sulphamethoxazole (30 mg/kg per os q. 12 h in combination of rifampin and decrease concentrations of concurrently with rifampin and potassium penicillin (Pellegrini-Masini et al. administered drugs (Dowling 2004). Its administration also 2005). Sulphonamide administration decreases vitamin K leads to red discolouration of sweat, urine, faeces and tears. production by enteric bacteria in the gastrointestinal tract and Use in equids is extralabel. sulphonamides should not be concurrently administered with warfarin. Folate deficiency has been associated with Metronidazole long-term diaminopyrimidine administration in human patients (Lambie and Johnson 1985), and in a horse treated Metronidazole is taken up by anaerobic bacteria and for equine protazoal myelencephalitis with sulphadiazine and converted to cytotoxic free radicals that damage bacterial pyrimethamine (Piercy et al. 2002). DNA. It is not effective against aerobic bacteria as they lack the reductive pathway to produce the free radicals. Metronidazole Fluoroquinolones is lipophilic and distributes well into the CSF (Redondo et al. 1993). In adult horses CSF concentration reaches 31% of Fluoroquinolones act by inhibiting DNA gyrase in the bacterial serum concentration after i.v. administration (Specht et al. nucleus and are therefore bactericidal. The fluoroquinolones 1992). Recommended dosage in equids is 15–25 mg/kg bwt have a broad spectrum of activity including most aerobic per os q. 6 h (Sweeney et al. 1986). No licence for equine use Gram-negative bacteria, some Gram-positive bacteria, exists, so its use is extralabel. No reported cases of bacterial Mycoplasma, Chlamydia and Rickettsia. Fluoroquinolones are meningitis in adult horses due to anaerobic pathogens could extremely lipid soluble and distribute well to all tissues be found in the literature, so this drug is rarely indicated for including CSF (Cottagnoud and Tauber 2003). After a 5 mg/kg this disease process. bwt per os or i.v. dose, MIC for most Gram-negative pathogens was exceeded (0.5 µg/ml) in the CSF (Giguere et al. Macrolides 1996). CSF concentration was approximately 15 and 25% of corresponding serum concentration at 74 and 48 h following Macrolide antibiotics bind to the 50S ribosomal subunit and treatment (Giguere et al. 1996). Use of fluroquinolones in inhibit bacterial protein synthesis. They are therefore equids is extralabel (Enrofloxacin is licensed for i.v. and oral use bacteriostatic. The spectrum of activity is broad for Gram- in small animals and subcutaneous use in cattle). The positive pathogens including Staphylococci, Streptococci, recommended dosage in equids is 5 mg/kg bwt i.v. q. 24 h or Rhodococcus equi, Mycoplasma and Chlamydia. The 7.5 mg/kg bwt per os q. 24 h (Giguere et al. 1996). penetration of erythromycin into the CNS is reported to be Fluroquinolones have been shown to have chondrotoxic poor (Griffith and Black 1970) with concentration obtained in effects on articular chondrocytes from juvenile dogs and uninflammed brain tissue reaching 4% of serum levels horses (Egerbacher et al. 2001). Fluoroquinolones are also (Wellman et al. 1954). EQUINE VETERINARY EDUCATION / AE / July 2007 321

Tetracyclines and chloramphenicol (Mitchell et al. 2006). Three cases of suspected bacterial meningitis and variable immunodeficiency Oxytetracycline and doxycycline both inhibit bacterial protein were reported to recover after treatment with potassium synthesis by binding to the 30S ribosomal subunit and are penicillin and enrofloxacin, potassium penicillin and rifampin, therefore bacteriostatic. They have a broad spectrum of and potassium penicillin, rifampin and trimethoprim- activity including Gram-positive and negative pathogens, sulphamethoxazole respectively. Two of the cases had Mycoplasma, Rickettsia, Chlamydia and Ehrlicia. However, complications related to immunodeficiency after 5 months plasmid mediated resistance, either as a result of decreased and 2 years (Pellegrini-Masini et al. 2005). Too few reported drug uptake into the bacterial cell or increased efflux, is cases exist in the equine literature to make evidence-based widespread. Oxytetracycline does not reach therapeutic recommendations. concentrations in CSF in healthy patients due to a high degree of plasma protein binding and moderate lipid solubility (Thea Summary and Barza 1989). Administration of doxycycline at 10 mg/kg bwt did not result in measurable concentrations of the drug Reasonable choices of antimicrobial therapy for treatment of within the CSF of healthy horses (Bryant et al. 2000). bacterial meningitis in adult horses include ampicillin and chloramphenicol. Potentiated sulphonamides may be Aminoglycosides appropriate depending on the MIC of the organism involved. Choice of therapeutic agent may initially be based on CSF Aminoglycoside antibiotics also bind to the 30S ribosomal cytology and Gram stain, but culture and sensitivity data subunit, interrupting normal bacterial protein synthesis. This should be obtained. Use of enrofloxacin may be appropriate if leads to changes in membrane permeability and bacterial cell antimicrobial isolates show resistance to the aforementioned lysis. The aminoglycoside antibiotics are bacteriocidal. They drugs, but the possibility of induction of, or worsening of have a wide range of action against Gram-negative seizure activity should be considered. Rifampin may be pathogens, most Staphylococci spp. and some Streptococci beneficial when used in combination with other antimicrobial spp. However, they are large polar molecules and are highly agents. Use of many of these antimicrobials agents is ionised at physiological pH. This prevents them from reaching extralabel. Use of third and fourth generation cephalosporins therapeutic concentrations in the CNS (Dowling 2004). may be appropriate in foals and small ponies or in adult horses The use of macrolide antibiotics, tetracyclines or with no financial constraints to treatment. aminoglycoside antimicrobial drugs cannot be recommended for treatment of bacterial meningitis in horses due to poor References penetration into the CSF. Administration of antimicrobials is a recognised risk factor Asensi, V., Carton, J.A., Maradona, J.A., Asensi, J.M., Perez, F., in the development of Clostridium difficile diarrhoea in adult Redondo, P., Lopez, A. and Arribas, J.M. (1996) Imipenem therapy horses (Baverud 2004), and case reports of diarrhoea after of brain abscesses. Eur. J. Clin. Microbiol. Infect. Dis. 15, 653-657. administration of many antimicrobial classes exist in the Barling, R.W.A. and Selkon, J.B. (1978) The penetration of antibiotics equine literature. 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(1984) In a 12 year review of 103 cases of human bacterial Chloramphenicol sodium succinate in the horse: Serum, synovial, meningitis at a large emergency centre, 14% of patients with peritoneal and urine concentrations after single-dose intravenous bacterial meningitis received a third or fourth generation administration. Am. J. vet. Res. 45, 578-580. cephalosporin alone, 14% received ampicillin alone, 20% Bryant, J.E., Brown, M.P., Gronwall, R.R. and Merritt, K.A. received a third generation cephalosporin plus ampicillin or (2000) Study of intragastric administration of doxycycline: penicillin, and the majority (42%) received one or more third pharmacokinetics including body fluid, endometrial and minimal inhibitory concentrations. Equine vet. J. 32, 233-238. generation cephalosporin, penicillin, ampicillin and/or chloramphenicol. Ceftriaxone and cefotaxime are commonly Burrows, G.E., MacAlister, C.G., Beckstrom, J.T. and Nick, B.S. (1985) Rifampin in the horse: Comparrison of intravenous, intramuscular used at twice the standard dose rate to aid CNS penetration and oral administrations. Am. J. vet. Res. 46, 442-446. (Nau et al. 1998). Previous case reports in the equine Cervantes, C.C., Brown, M.P., Gronwall, R. and Merritt, K. (1993) literature reported the use of streptomycin (Timoney et al. Pharmacokinetics and concentrations of ceftiofur sodium in body 1983), i.v. or oral TMP/SMZ (Rumbaugh 1977), a combination fluids and endometrium after repeated intramuscular injections in of sodium benzyl penicillin and gentamicin (Newton 1988), mares. Am. J. vet. Res. 54, 573-575. 322 EQUINE VETERINARY EDUCATION / AE / July 2007

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Culture from a freshly plucked bunch of affected hairs, carefully taken from the hair roots, can be used to confirm the bacterial species but this will not affect treatment regimes, and most horses will grow bacteria from normal hair plucks. Skin biopsy will confirm the diagnosis in difficult or atypical cases, and profuse bacterial growth from a sectioned punch biopsy.

Management

Cases related to sweat and abrasion with tack are best managed by daily cleansing of the affected skin immediately after exercise while the sweat is still present. Shampooing with an antiseptic shampoo, such as one containing chlorhexidine1 Fig 3: Sweat induced bacterial folliculitis in the saddle region. or povidone-iodine2 is usually satisfactory. These areas can often be matted with serum exudation, as in this horse, and are painful to palpate. For cases around the ergot and at the back of the fetlock joint close clipping of the hairs will often result in resolution. This can be combined with topical treatment with an antiseptic cream3 and protection of the affected area with barrier creams prior to exercise. For horses affected with folliculitis beneath the saddle the application of a towelling or cotton sheet, which is washed and changed daily, between the horse and the tack will reduce further contamination of affected skin during the treatment/ recovery period. Although this simple expedient is commonly used in racing stables as an effective way of limiting skin infections produced from reinfection from dirty tack it is seldom carried out by single horse riders. Where lesions occur on the shoulders and rug contact zones a clean natural fibre sheet, washed on a regular basis, will be required between the skin and the rug.

Manufacturers’ addresses Fig 4: Localised lesions of bacterial folliculitis can resemble ringworm. The differential diagnosis is usually that there are 1SSL International plc, Knutsford, Cheshire, UK. intact healthy growing hairs in the centre of the lesions of 2Animalcare Ltd, York, UK. alopecia as in this case. 3Seton Healthcare Group, Oldham, Lancashire, UK.