Table 7.6.

Combination therapies for biothreat bacterial pathogens.

Combination therapeutics		Notes	References
Bacillus anthracis
Antibiotics	AIGIV	Combination therapy with antibiotics and AIGIV is more effective than antibiotics alone in a rabbit model of inhalational anthrax and improved survival compared to the antibiotic treatment alone	[155]
Ciprofloxacin	Clindamycin	Treatment of rabbits with systemic anthrax with clindamycin and ciprofloxacin had improved efficacy compared to monotherapy and could be used to prevent relapse of infection	[156]
Ciprofloxacin	PA IgG antibodies	Combination therapy for anthrax, including antiprotective antigen (PA IgG) antibodies and ciprofloxacin in a rodent anthrax model increased survival significantly compared to ciprofloxacin treatment alone	[157]
Levofloxacin	Raxibacumab	Combination therapy with raxibacumab, an IgG1 monoclonal antibody that binds protective antigen, and the antibiotic levofloxacin provides protection in rabbits late in the disease course	[158]
Oligochlorophen	Antibiotics	Targeting cytoskeletal proteins such as FtsZ with oligochlorophen analogs is a promising new treatment method that has a 10-fold lower development of resistance compared to antibiotics used for anthrax treatment in humans	[159]
Penicillin, meropenem, or rifampin	Linezolid	Treatment of antibiotic-resistant inhalation anthrax with linezolid and penicillin, meropenem, or rifampin had the inhibitory effect on mean lethal factor levels compared to the control groups and successfully treated fluoroquinolone-resistant B. anthracis infection	[160]
Rifampin	Clindamycin	Combination therapy for anthrax with rifampin and clindamycin was shown to be synergistic in vitro	[161]
Brucella spp.
Doxycycline	Rifampin	Successful combination therapies used to treat pulmonary brucellosis in humans is doxycycline and rifampin for 6 weeks	[162]
Burkholderia mallei
Antibiotic	Heat-killed vaccine	Combination of an antibiotic moxifloxacin, azithromycin, or sulfamethoxazole-trimethoprim, and vaccination using heat-killed B. mallei can protect BALB/c mice from lethal glanders infection, potentially by stimulating immune responses, such as gamma interferon, which acts synergistically with antibiotic therapy to inhibit bacterial growth	[163]
Enrofloxacin, trimethoprim, and sulfadiazine	Doxycycline	Successful 12-week combination treatment of parenteral administration of enrofloxacin and trimethoprim with sulfadiazine followed by oral administration of doxycycline eliminated B. mallei from glanderous horses during an outbreak	[164]
Burkholderia pseudomallei
Antibiotics	Farnesol	Combination therapy with farnesol a sesquiterpene alcohol that damages biofilm matrix and interferes with cell wall and peptidoglycan biosynthesis, facilitates antimicrobial penetration, and reduces the minimum biofilm eradication concentration for ceftazidime, amoxicillin, doxycycline, and sulfamethoxazole-trimethoprim in vitro	[165], [166]
Ceftazidime	Avibactam	Avibactam restores susceptibility to ceftazidime for genetically diverse extremely drug resistant isolates of Burkholderia from cystic fibrosis patients by binding PenA and the combination treatment significantly improved survival of larvae infected with the drug resistant isolates	[166]
Ceftazidime	IFN-γ	Interferon gamma–induced reactive oxygen species with ceftazidime leads to synergistic killing of intracellular B. pseudomallei and markedly increases the effectiveness of antimicrobial therapy for the treatment of B. pseudomallei infection in mice	[167], [168]
Clostridium botulinum
Antibody cocktail		BoNT serotypes and subtypes differences present a significant challenge for creating monoclonal antibody treatments for neutralization, by diversifying the V-regions of mAbs and selecting cross reactivity, a combination treatment of three antibodies neutralized BoNT/F1, F2, F4, and F7 in mice and was 150 times more potent than equine antitoxin	[169]
Coxiella burnetii
Doxycycline	Chloroquine	Combination therapy of doxycycline and hydroxychloroquine combination shortened the duration of therapy and reduced the number of relapses in patients with Q fever endocarditis. And a case of Q fever endocarditis with biological prosthetic aortic valve and aortic homograft was successfully treated with doxycycline and chloroquine combination therapy	[170], [171]
Francisella tularensis
Antibiotics	Uptake inhibitors and inflammatory inhibitors	Cytochalasin B, LY294002, wortmannin, nocodazole, MG132, and XVA143 inhibitors reduce F. tularensis update and reduce inflammatory cytokine production and can be used in combination with antibiotics to improve survival of infected mice	[172]
Gentamicin	Membrane antigen immunization	Postexposure immunization with membrane protein fraction antigens and treatment with low-dose gentamicin increased survival of mice and significantly reduced bacterial burdens in the liver and spleen	[173]
Yersinia pestis
Antibiotics	Efflux pump inhibitor	Combination therapy, including antibiotics with an efflux pump inhibitor, would be a novel mechanism to restore the efficacy of the antibiotic in resistant strains of Y. pestis	[174]
Antibody therapy	Corticosteroid	The addition of antiinflammatory methylprednisolone, a corticosteroid, in combination with antibody therapy correlates with improved mouse survival, with reduction in neutrophil and matrix metalloproteinase 9 in the tissue, and the mitigation of tissue damage	[175]
Ciprofloxacin	L-97-1	A novel postexposure medical countermeasure l-97-1, an A1 adenosine receptor antagonist blocks LPS-induced activation of immunomodulatory cytotoxic substance accumulation to prevent acute lung injury, and in combination with ciprofloxacin improves survival of rats following infection with Y. pestis	[176]

AIGIV, anthrax immune globulin intravenous; IFN, interferon; LPS, lipopolysaccharide; PA, protective antigen.