Bacillus anthracis (Anthrax)

Authors: Arthur M. Friedlander, M.D., Henry Heine, Ph.D.

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Microbiology

Bacillus anthracis is an aerobic, non-motile, sporulating, large non-hemolytic Gram-positive rod that grows well on blood agar. Individual colonies are gray-white, rough, and sticky when teased with a bacteriologic loop. On bicarbonate agar in the presence of 5-20% CO2 the colonies are mucoid and the organism has a prominent capsule. Susceptibility to a gamma bacteriophage and PCR for the presence of toxin and capsule genes confirms the identity of the organism. All virulent strains are pathogenic for mice.

Epidemiology

B. anthracis spores may persist in a dormant state in the soil for long periods of time, probably at least decades. Infection of mammals results in massive amplification of the vegetative bacillus and subsequent seeding of the soil with spore formation after death of the animal. Anthrax is largely a disease of herbivores, and humans become accidentally infected through contact with infected animals or their contaminated products (11). Naturally occurring human anthrax in the United States is now a rare disease, with fewer than one cutaneous case per year reported to the CDC over the last 20 years, although it continues to be a significant disease in less developed countries. Until the recent bioterrorist-related outbreak, inhalational anthrax has been a disease mainly of historic interest, but epidemics of gastrointestinal anthrax continue to be sporadically reported from developing countries.

Clinical Manifestations

The clinical manifestations of human anthrax are quite striking. Cutaneous anthrax, the most common form of naturally occurring disease, begins as a small, painless, pruritic papule that within 2 days enlarges, develops vesicles, and ulcerates to form an eschar. Cultures of the vesicular fluid are usually positive. Prompt antibiotic treatment, while not stopping the progression of the local infection to eschar formation, is associated with low mortality rates (<1 %).

Inhalational anthrax follows inhalation of infectious doses of anthrax spores. During the first several days, symptoms are non-specific with myalgia, fatigue that may be profound, fever and chills, sweats, minimal non-productive cough, nausea or vomiting and some chest discomfort. Symptoms of an upper respiratory infection are characteristically absent. Patients then develop the rapid onset of severe dyspnea, cyanosis, increased chest pain, and eventually shock. Chest x-rays show a widened mediastinum secondary to hemorrhagic necrotic mediastinal lymphadenitis and mediastinitis. About half of all patients develop secondary anthrax meningitis, and virtually all cases are fatal if untreated. Oropharyngeal and gastrointestinal anthrax follow ingestion of grossly contaminated and undercooked meat. Pharyngeal ulcers, lymphadenitis, and brawny edema of the neck result from local oropharyngeal multiplication of anthrax bacilli. Gastrointestinal anthrax is associated with ulcers in the terminal ileum, cecum, or stomach with mesenteric lymphadenitis, ascites, diarrhea, and septicemia. Mortality rates from oropharyngeal and particularly gastrointestinal anthrax are high (approximately 40%).

Laboratory Diagnosis

The organism grows readily on routine microbiological media. Definitive diagnosis is established by isolation of the organism from tissues. A non-motile, spore-forming, large, non-hemolytic Gram-positive rod that produces a capsule in the presence of 5-20% CO2 should be presumptively considered B. anthracis. Confirmation is established by sensitivity to gamma bacteriophage, identification of cell wall antigen and capsule by immunofluorescence, and PCR for toxin and capsule genes. Immunohistological stains of tissue for cell wall polysaccharide and capsule are available. PCR on bodily fluids obtained after institution of antibiotics may be of particular value as cultures may be negative. Serologic diagnosis is possible with use of a sensitive and specific ELISA test but is only of value retrospectively.

Pathogenesis

B. anthracis is an invasive bacterium that grows to high concentrations in the blood and tissues. It produces three well-established virulence factors: an antiphagocytic capsule, and the lethal and edema toxins. The toxins interfere with neutrophil and macrophage function and likely contribute to the edema observed in tissues. The lethal toxin is lytic for macrophages and may release proinflammatory cytokines and other mediators that contribute to the sepsis syndrome, toxemia, and shock. In inhalational anthrax, mediastinitis is associated with lymphatic and vascular obstruction, pleural effusions and pulmonary hemorrhage and edema, all of which contribute to death. Pathologically, vasculitis involving large and small vessels is prominent (16).

SUSCEPTIBILITY IN VITRO AND IN VIVO

There have only been a few studies of antimicrobial susceptibility testing in B. anthracis. The methods of testing have varied and until the most recent studies, there has not been any attempt to standardize the testing nor are there guidelines for interpretation of results. The National Committee for Clinical Laboratory Standards (NCCLS) is only now attempting to address standards and interpretive criteria for B. anthracis. Until those criteria are available, staphylococci antibiotic breakpoints are being used as a guide. Lightfoot et al. (22) evaluated nine antimicrobial agents with 33 epidemiologically distinct isolates by the agar dilution method. The criteria for setting susceptibility breakpoints was not specified, but 90% of the strains were determined to be sensitive to penicillin, amoxicillin, gentamicin, streptomycin, erythromycin, tetracycline, chloramphenicol and ciprofloxacin (Table 1). Most of the strains tested were resistant to cefuroxime. Doganay et al (10) also used the agar dilution method for testing thirty antibiotics with 22 B. anthracis strains. They identified additional beta-lactams, aminoglycosides, clindamycin, vancomycin, ofloxacin and co-trimoxazole as antibiotics having activity (Table 1). A second study also showed susceptibility to azithromycin, clarithromycin, erythromycin and roxithromycin (35). In another study using a disk diffusion assay, 44 isolates were tested and susceptibilities determined by comparing inhibition zones to a Staphylococcus aureus type strain with generally similar results (28). All 44 isolates in this study were reported as resistant to sulfamethoxazole and trimethoprim. Co-trimoxazole was not tested. It should be noted that in all of these studies penicillin resistance and beta-lactamase activity was observed for only one isolate tested (22).

The two most recent studies have come from the Centers for Disease Control (CDC) and the United States Army Medical Research Institute for Infectious Diseases (USAMRIID) (26,17,18). These studies utilized the broth microdilution assay system and have attempted to follow NCCLS (27) standards. Both studies were in general agreement of susceptibilities with the exception of penicillin and chloramphenicol (Table 1). The CDC study looked at 9 antibiotics with 62 isolates. Included in those 62 isolates were 12 clinical isolates from the recent bio-terrorism release in the United States (7). Using Staphylococcal breakpoints they established that greater than 90% of the strains tested were sensitive to chloramphenicol, ciprofloxacin, clindamycin, penicillin, rifampin, tetracycline and vancomycin. The majority of the strains were of intermediate activity for erythromycin and ceftriaxone. It was noted that 3 of the 12 clinical isolates did show some measurable beta-lactamase activity, even though the actual MIC determinations showed susceptibility to penicillin (26). The USAMRIID studies looked at 20 B. anthracis strains and 39 antibiotics including many recently approved by the FDA and others in phase 3 trials (17,18). Data from this study indicates susceptibilities to additional fluoroquinolones, sparfloxacin and levofloxacin. In addition, three new classes of antibiotics show in vitro activity: the streptogramins, quinupristin/dalfopristin; the oxazolidinones, linezolid; and the carbapenems, imipenem, meropenem (Table 1). Several antibiotics that are currently in clinical trials also have in vitro activity. These are oritavancin, tigecycline and daptomycin.

A notable discrepancy between the USAMRIID and CDC studies is the penicillin data that is likely explained by differences in the inoculum preparation used in the two testing methods. The USAMRIID study adjusted log-phase broth cultures while the CDC study resuspended colonies from 18-hour plates. Both methodologies are accepted NCCLS methods for inoculum preparation (27). Induction of beta-lactamase has been observed both in vitro (22,25,26) and as the result of suboptimal treatment in a nonhuman primate model (14). Older studies have previously shown that B. anthracis has the ability to increase expression of a "penicillinase" as a function of inoculum size (2) and this may well explain the differences between the results of the two studies. In the CDC study observation of beta-lactamase production was variable, while the USAMRIID study consistently observed activity. There was overlap in the strains tested in these two studies and it may be that in addition to inoculum size, growth phase and other factors effect beta-lactamase induction. This will hopefully be resolved as NCCLS establishes definitive methods for B. anthracissusceptibility testing. It should be emphasized that the previous data of Lightfoot et al. (22) and Doganay et al. (10) showed all 55 strains except one to be highly susceptible to penicillin. Nevertheless, the possibility of an inducible beta-lactamase activity should be taken into consideration under clinical conditions where high numbers of organisms are to be expected.

Combination Drugs

There are no published studies that have evaluated in vitro susceptibility of B. anthracis to antibiotic combinations. Limited animal data suggest that streptomycin and presumably other aminoglycosides may enhance the effectiveness of penicillin (23). In addition, there are no published data on possible antagonism between combinations of antibiotics.

ANTIMICROBIAL THERAPY

Cutaneous Anthrax

Penicillin remains the drug of choice for the treatment of cutaneous anthrax. Organisms are rapidly cleared from skin lesions; 25 patients with cutaneous anthrax and positive initial cultures of vesicular fluid were given 2 million units of penicillin G intravenously and the fluid was cultured hourly (31); 5 h after the initiation of therapy, all cultures were negative.T he duration of therapy with penicillin is not well established, and in the absence of controlled observations, therapy with penicillin for 7 to 10 days is recommended.P arenteral therapy should be used for cases with systemic symptoms while in mild cases, oral drugs can be used.

Very rarely naturally occurring strains resistant to penicillin have been reported. (5,9,33). As noted above induction of penicillin resistance due to a beta-lactamase can occur in vitro (2,17,22,26) and has been reported in one case of an inadequately treated non-human primate (14). It has never been reported in any human case of anthrax treated with penicillin. The inducible penicillinase may be clinically significant when a large number of organisms are present as would be expected in a patient with established systemic infection such as in inhalational anthrax.

Tetracyclines, chloramphenicol, and erythromycin have also been highly effective in treating cutaneous anthrax and are alternative drugs for penicillin-sensitive patients (15).

Single-dose oral therapy with doxycycline has also been evaluated clinically (32). Thirty-three patients with cutaneous anthrax were treated with a single oral dose of doxycycline and observed in a hospital setting for 3 days. There was dramatic clinical improvement, and all patients were bacteriologically negative by the fourth day. The authors propose that cutaneous anthrax in adults can be safely treated with a single 500-mg oral dose of doxycycline, while children and adolescents could be treated with single doses of 100 to 300 mg orally. Nevertheless, conservative practice suggests that treatment should be given for a minimum of 7 to 10 days.

Case fatality rates as high as 20% have been reported for untreated cutaneous anthrax, but with appropriate antibiotic treatment, fatalities are now very unusual. However, cutaneous lesions, even if promptly treated with antibiotics, continue to progress through the eschar phase.

Inhalational Anthrax

The life-threatening nature of inhalational anthrax requires intravenous therapy with two or more antibiotics at the very first consideration of this disease. This is all the more important because of the possibility of an antibiotic resistant organism being used in a biological attack. Resistance to multiple antibiotics (34) including the fluoroquinolones has been described (8,30). Thus, initial therapy should include a fluoroquinolone or doxycycline and one or more drugs to which the organism is usually sensitive as indicated above (clindamycin, rifampin, penicillin, ampicillin,vancomycin, aminoglycosides, i mipenem, chloramphenicol, clarithromycin, erythromycin, linezolid). The CDC (7) and the Johns Hopkins Working Group on Civilian Biodefense (20) have given similar recommendations. Because of the possibility of an inducible beta-lactamase, a penicillin should not be given by itself. The rationale for these recommendations is based primarily on in vitrosensitivities, as well as the limited data from treatment of experimental inhalational anthrax in animal models (13), the experience treating cutaneous anthrax in humans and the small number of recent human cases of inhalational anthrax. Definitive recommendations based on extensive human experience and controlled studies can not be made at this time. As soon as antibiotic sensitivities are determined, patients should be treated with the most sensitive, least toxic, available antibiotics. Special consideration should be given to patients who may have meningitis by using antibiotics (e.g. penicillin, chloramphenicol, rifampin, vancomycin) that are likely to achieve therapeutic concentrations in the cerebrospinal fluid. The use of corticosteroids in adult meningitis remains controversial and there are no controlled studies supporting their use in anthrax.

The optimal duration of therapy in inhalational anthrax is unknown. The particular issue of persistence of ungerminated spores that dictates the prolonged use of antibiotics in the setting of prophylaxis after exposure but before the onset of clinical illness (see below) may not apply in the treatment of established disease. It is anticipated that sufficient antigenic mass would be present in a patient presenting with inhalational anthrax and bacteremia such that a robust immune response would occur. This has indeed been observed in the survivors of the recent outbreak of inhalational anthrax. Thus, the duration of treatment should be based upon clinical judgment but a minimum of 14 days is recommended.

Prior to the recent outbreak of inhalational anthrax, mortality was thought to approach 100%. However, this was based upon cases that were most often untreated or seen when moribund. Nine survivors out of approximately 75 cases were reported during the epidemic of inhalational anthrax in Sverdlovsk in 1979 (24). However, no definitive diagnosis was established for any of the nine purported survivors so it is impossible to interpret this data. The recent survival of 6 of the 11 recent cases of inhalational anthrax shows that with aggressive antibiotic and supportive modern therapy, survival can be anticipated particularly when patients present early in their course. In fact, of the patients that died, one had meningitis and several were moribund or in severe respiratory distress when treatment was begun (1,21). This experience in humans is supported by experiments showing non-human primates can survive even when treatment is begun after the onset of mediastinitis (14).

Gastrointestinal Anthrax

Gastrointestinal and oropharyngeal anthrax are also associated with high rates of mortality and antibiotic recommendations are similar to those for inhalational anthrax.

VACCINES

Prevention of anthrax in animals has largely depended on the use of vaccines, since widespread decontamination of contaminated soil is impractical. The Sterne vaccine is composed of spores of a live, toxinogenic, unencapsulated attenuated B. anthracis strain and is used throughout the world as a veterinary vaccine. The main limitation to its use in humans is safety. A similar live spore vaccine has been used for humans in countries of the Former Soviet Union and is considered highly effective against cutaneous anthrax. A sterile protein-based anthrax vaccine was licensed for human use in the U.S. in 1970 and is currently produced by Bioport (Lansing, Michigan) (3). A less potent precursor of this vaccine has been field-tested and was found to be highly effective in preventing anthrax in woolen mill workers (4). The current vaccine is an aluminum hydroxide-adsorbed cell-free culture filtrate of a strain of B. anthracis containing the protective antigen component of the anthrax toxins.

Indications

Anthrax vaccine is recommended for persons whose occupations require frequent contact with imported animal products likely to be contaminated with B. anthracis spores and for laboratory workers who perform studies using B. anthracis. Beginning in 1998, members of the armed forces have been vaccinated to protect against the use of B. anthracis as a biowarfare weapon (12).

Doses and Schedules

The current FDA-approved dose schedule for anthrax vaccine consists of 0.5 mL administered subcutaneously at 0, 2, and 4 weeks and 6, 12 and 18 months, followed by yearly boosters.

Adverse Effects

Mild local reactions occur in approximately 30% of individuals with moderate and severe local reactions occurring in 4% and <1% respectively and 1% reporting systemic symptoms (12,29) Reactions are self-limited and resolve without therapy.

PREVENTION

General

B. anthracis spores are highly resistant to physical and chemical agents and they may persist in an inanimate environment. Parformaldehyde vapor and liquid disinfectants such as 5% hypochlorite or 5% phenol may be used for decontamination. Until recent times, prevention of anthrax ultimately depended on control of disease in animals. Effective vaccines for animals are available.

Postexposure Prophylaxis Of Inhalational Anthrax

The recent bioterrorist-related outbreak of 11 cases of inhalational anthrax in the U.S. has refocused interest on the question of postexposure prophylaxis that was most recently addressed after the threat of anthrax during the 1990 Gulf War (11). This issue represents an unusual therapeutic situation that was appreciated in early animal trials of treatment, because inhaled spores may remain dormant and fail to germinate for prolonged periods of time (11). Earlier studies in experimental animals had shown that treatment with penicillin beginning 1 day after aerosol exposure to anthrax spores was protective during the 5 to 10 days of drug therapy, but animals died when the antibiotic was discontinued (19). In more recent studies, monkeys were challenged with aerosolized anthrax spores and beginning 1 day after exposure, groups of animals were given penicillin, ciprofloxacin or doxycycline for 30 days. A fourth group was immunized with anthrax vaccine after exposure and treated with doxycycline. All antibiotic regimens completely protected animals while they were on therapy and provided better long-term protection than the shorter 5- and 10-day treatment protocols. All animals that were immunized and treated with doxycycline survived. When these groups of monkeys were rechallenged with airborne anthrax spores, all succumbed except those who had been immunized (13). These data offer convincing proof that postexposure prophylaxis is effective, although if given early after exposure it will prevent an immune response. Based upon these studies, recommendations have been made to provide prophylactic oral antibiotics with a fluoroquinolone or doxycycline for a 60-day period (6,20). As for treatment of established disease, once sensitivities of isolated organisms are obtained, the most sensitive, least toxic, available antibiotic should be used. Optimal prophylaxis would include vaccination in addition to antibiotics. The addition of vaccination to a postexposure prophylactic antibiotic regimen may allow for reduction of the course of antibiotics to 30 to 45 days, although only limited animal data exist to support this recommendation.

REFERENCES

1. Barakat LA, Quentzel HL, Jernigan JA, Kirschke DL, Griffith K, Spear SM, Kelley K, Barden D, Mayo D, Stephens DS, Popovic T, Marston C, Zaki SR, Guarner J, Shieh W-J, Carver HW II, Meyer RF, Swerdlow DL, Mast EE, Hadler JL. 2002. Fatal inhalational anthrax in a 94-year-old Connecticut Woman. JAMA 2002;287:863-868. [PubMed]

2. Barnes JM. Penicillin and B. anthracis. J. Pathol Bacteriol 1947;59:113-125.

3. Brachman P, Friedlander AM. Anthrax. In Vaccines 1999;629 (Plotkin SA, Orenstein WA., eds.) WB Saunders, Philadelphia.

4. Brachman PS, Gold H, Plotkin SA, Fekety FR, Werrin M, Ingraham NR. Field evaluation of a human anthrax vaccine. Am J Public Health 1962;52:632-645.

5. Bradaric N, Punda-Polic V. Cutaneous anthrax due to penicillin-resistant Bacillus anthracis transmitted by an insect bite. Lancet 1992;340:306-307. [PubMed]

6. CDC. Update: Investigation of anthrax associated with intentional exposure and interim public health guidelines. MMWR 2001;50:889-897. [PubMed]

7. CDC. Investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy. MMWR 2001;50:909-919. [PubMed]

8. Choe C, Bouhaouala S, Brook I, Elliot TB, Knudson GB. In vitro development of resistance to ofloxacin and doxycycline in Bacillus anthracis Sterne. Antimicrob Agents Chemother 2000;44:1766 [PubMed]

9. Christie AB. Infectious Diseases: epidemiology and clinical practice. Churchill Livingstone, New York 1987;2:997:983-1003.

10. Doganay M, Aydin N. Antimicrobial susceptibility of Bacillus anthracis. Scand J Infect Dis 1991;23:333-335. [PubMed]

11. Friedlander AM. Anthrax-Clinical Features, Pathogenesis, and Potential Biological Warfare Threat. In Current Clinical Topics in Infectious Diseases 2000;20:335 (Remington JS, Swartz MN, eds.) [PubMed]

12. Friedlander AM, Pittman PR, Parker GW. Anthrax vaccine: evidence for safety and efficacy against inhalational anthrax. JAMA 1999;282:2104-2106. [PubMed]

13. Friedlander AM, Welkos SL, Pitt ML, Ezzell JW, Worsham PL, Rose KJ, Ivins BE, Lowe JR, Howe GB, Mikesell P, Lawrence WB. Postexposure prophylaxis against experimental inhalation anthrax. J Infect Dis 1993;167:1239-1242. [PubMed]

14. Gochenour WS Jr., Sawyer WD, Henderson JE, Gleiser CA, Kuehne RW, Tigertt WD. On the recognition and therapy of Simian woolsorter’s disease. J Hyg 1963;61:317-322. [PubMed]

15. Gold H. Anthrax: a report of one hundred seventeen cases. AMA Arch Intern Med 1955;96:387-396. [PubMed]

16. Grinberg LM, Abramova FA, Yampolskaya OV, Walker DH, Smith JH. Quantitative pathology of inhalational anthrax I: quantitative microscopic findings. Mod Pathol 2001;14:482-495. [PubMed]

17. Heine HS, Dicks R, Byrne WR. In vitro activity of daptomycin, sparfloxacin, quinupristin-dalfopristin and other antibiotics against Bacillus anthracis. 40st Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto Can, Sept 17-20, 2000; Abst 517, p167.

18. Heine HS, Dicks R, Andrews G. In vitro activity of oratavancin (LY33328), levofloxacin, meropenem, GAR936 and linezolid against strains of Bacillus anthracis. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, Ill, Dec. 16-19, 2001; Abst E-534, p173.

19. Henderson DW, Peacock S, Belton FC. Observations on the prophylaxis of experimental pulmonary anthrax in the monkey. J Hyg 1956;54:28-36. [PubMed]

20. Inglesby TV, O'Toole T, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, Friedlander AM, Gerberding J, Hauer J, Hughes J, McDade J, Osterholm MT, Parker G, Perl TM, Russell PK, Tonat K. Anthrax as a Biological Weapon, 2002: Updated recommendations for management. JAMA 2002;287:2236-2252. [PubMed]

21. Jernigan JA, Stephens DS, Ashford DA, Omenaca C, Topiel MS, Galbraith M, Tapper M, Fisk TL, Zaki S, Popovic T, Meyer RF, Quinn CP, Harper SA, Fridkin SK, Sejvar JJ, Shepard CW, McConnell M, Guarner J, Shieh WJ, Malecki JM, Gerberding JL, Hughes JM, Perkins BA. Bioterrorism-related inhalational anthrax: the first 10 cases reported in the United States. Emerg Infect Dis 2001; 7:933-944. [PubMed]

22. Lightfoot NF, Scott RJ, Turnbull PC. Antimicrobial susceptibility of Bacillus anthracis. Salisbury Med Bull Suppl 1990;68:95-98.

23. Lincoln RE, Walker JS, Klein F, Haines BW. Anthrax. Advances Vet Sciences 1964;9:327-368.

24. Meselson M, Guillemin J, Hugh-Jones M, Langmuir A, Popova I, Shelokov A, Yampolskaya O. The Sverdlovsk anthrax outbreak of 1979. Science 1994;266:1202-1208. [PubMed]

25. Mikesell P, Hillanbrand DA, Friedlander AM, Bush K. Antibiotic susceptibility profiles and beta-lactamase activity in strains of Bacillus anthracis. Amer Soc Micro Annual Meeting 1992;Abstract A-122.

26. Mohammed J, Marston CK, Popovic T, Weyant RS, Tenover FC. Antimicrobial Susceptibility of Bacillus anthracis. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, Ill, Dec. 16-19, 2001;Abst UL-9.

27. National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard M7-A5. Fifth ed., 2000;20:2.

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29. Pittman PR, Gibbs PH, Cannon TL, Friedlander AM. Anthrax vaccine: short-term safety experience in humans. Vaccine 2001;20:972-978. [PubMed]

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32. Saggar SN, Joseph MM, Bell WJ. Treatment of cutaneous anthrax with a single oral dose of doxycycline. East Afr Med J 1974;51:889-894. [PubMed]

33. Severn M. A fatal case of pulmonary anthrax. Brit Med J 1976;1:748. [PubMed]

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Tables

Table 1. Broth dilution minimum inhibitory concentrations (ug/ml) (Ref 20, 10, 26, 17, 18)

	MIC (ug/ml) (Lightfoot)			MIC (ug/ml) (Doganay)			MIC (ug/ml) (CDC)			MIC (ug/ml) (USAMRIID)
ANTIBIOTIC	Range	MIC50	MIC90	Range	MIC50	MIC90	Range	MIC50	MIC90	Range	MIC50	MIC90
Amikacin				0.03-0.06	0.03	0.06				1-4	2	2
Gentamicin	0.06-0.5	0.125	0.25	0.03-0.25	0.06	0.125				1-4	2	2
Netilmicin				0.015-0.125	0.06	0.125				2-8	2	4
Streptomycin	0.5-4	1	1	1-4	2	4				4-16	4	8
Tobramycin				0.25-1	0.25	1				1-16	2	4
Vancomycin				0.25-1	1	1	0.5-2	2	2	1-4	2	2
Oritavancin										<0.03-1	0.25	0.5
Erythromycin	0.25-1	0.5	1	0.25-1	0.5	1	0.5-1	1	1
Azithromycin				0.5-4	1	4				2-32	8	8
Clarithromycin				0.03-0.25	0.06	0.12				0.25-2	0.5	1
Clindamycin				0.5-1	1	1	<0.5-1	<0.5	1	0.12-1	0.25	0.5
Levofloxacin										0.06-1	0.25	0.5
Ofloxacin				0.03-0.06	0.06	0.06				0.25-2	1	2
Ciprofloxacin	0.03-0.06	0.06	0.06	0.03-0.06	0.03	0.06	0.03-0.12	0.06	0.06	0.06-2	0.25	1
Sparfloxacin										0.12-2	0.5	0.5
Novobiocin										1-4	2	2
Amox/clav (2:1)				0.015-0.015	0.015	0.015				0.5-16	1	2
Amoxicillin	0.03-64	0.06	0.125	0.015-0.03	0.015	0.015				8->64	64	>64
Ampicillin				0.03-0.125	0.03	0.03				4->64	64	>64
Penicillin G	0.015-64	0.06	0.125	0.015-0.03	0.015.	0.015	<0.06-128	<0.06	<0.06	2->64	64	>64
Piperacillin				0.125-0.5	0.25	0.5				16->64	64	>64
Imipenem										<0.03->64	<0.03	0.12
Meropenem										<0.03->64	0.06	0.12
Ceftazidime				128-256	128	256				>64	>64	>64
Cefotaxime				8-32	32	32				16->64	32	>64
Cefotetan										8-32	16	16
Cefuroxime	1-64	32	64	16-64	64	64				16->64	64	>64
Cefazolin				0.015-0.03	0.015	0.015				0.5-8	0.5	1
Ceftriaxone				16-32	16	32	14-32	16	32	16->64	16	64
Aztreonam				>128	>128	>128				>64	>64	>64
Sulfamethoxazole										2->64	>64	>64
Co-trimoxazole				8-16	16	16				2->64	>64	>64
Trimethoprim										>64	>64	>64
Tetracycline	0.06-1.0	0.125	0.125				0.03-0.06	0.03	0.06
Doxycycline										<0.03-0.12	0.06	0.06
Tigecycline										<0.03-0.5	0.12	0.5
Clofazamine										8-64	16	32
Rifampin							<0.25-0.5	<0.25	0.5	<0.03-1	0.5	0.5
Quinupristin-Dalfopristin										0.25-4	1	1
Chloramphenicol	2-4	4	4	1-2	2	2	2-8	4	4	8-64	16	16
Daptomycin										1-4	2	2
Linezolid										1-4	2	4