It seems like a good idea. After all, combination therapy of antivirals for HIV treatment transformed AIDS from a death sentence into a manageable chronic condition. But bacteria are not viruses.
The scenario in which combining antibiotics makes most sense is when long-term therapy is anticipated—such as for TB treatment. Development of resistance to single agents is almost inevitable, and combination therapy for TB has long been standard.
But for shorter-term treatment the answer is less obvious. The problem is in how resistance develops. Resistance can emerge in two ways: accumulation of mutations in previously-susceptible hosts, or by selection and amplification of small populations that were already resistant. Resistance in HIV or in TB bacteria usually arises by through the first scenario. But resistant bacterial infections are mostly due to resistance genes that were present before the start of antibiotic therapy.
These resistance genes are often carried on mobile genetic elements that move between bacteria, including between commensal and pathogenic bacteria.
Worse, these elements often carry more than one resistance gene. The SCCmec element of S. aureus for example—which converts it into MRSA—often bears resistance elements for tetracycline (tetA), streptomycin (aadD), clindamycin (ermA) as well as methicillin resistance (mecA). Note those transposons (the Tn elements). They enable resistance genes to hop around, increasing the likelihood that they get transferred between strains and species.
From Genetics of Antimicrobial Resistance in Staphylococcus aureus
Or consider this nightmare plasmid, isolated from colistin-resistant E. coli:
From Colistin resistance gene mcr-1 harboured on a multidrug resistant plasmid
In addition to colistin (a last-ditch antibiotic), it encodes resistance to trimethoprim, tetracycline, aminoglycoside, and sulphonamide antibiotics. Treating a patient with two of these antibiotics would provide an immense advantage to strains carrying the plasmid, increasing their relative fitness and allowing them to proliferate. It would increase the chance that the plasmid gets transferred to other bugs.
That’s the theory. There aren’t a whole lot of data addressing the risk of resistance development in combination vs monotherapy. A comprehensive review of the subject finds some evidence that combination therapy reduces the risk of resistance development.
But a couple of meta-analyses (here and here) find that combination therapy imposes a small but significant risk of superinfection by multiply-resistant organisms. That is, you start off infected with a bug that is resistant to one antibiotic, but susceptible to others, and end up with an infection that is resistant to many antibiotics and perhaps susceptible to none—the nightmare scenario.
Combination therapy is quite common in India. There is little evidence of patient benefit, and multi-drug resistance is rampant there. Combination therapy is not necessarily a contributor to MDR—but it hasn’t checked or prevented it either.
Combination antibiotic therapy works great in the test tube
Time-kill kinetics demonstrating growth of organisms in the settings of no drug (circles), addition of drug A (open squares), addition of drug B (triangles), and addition of both drugs A and B (closed squares). From Combination Therapy for Treatment of Infections with Gram-Negative Bacteria.
But bacteria are wily creatures and have a history of outsmarting our best plans. Given the weak evidence of benefit, the increased risk of adverse drug interactions, and the lesser but real risk of selecting nightmare bugs, most infectious disease docs are wary of combination therapy. The current consensus seems to be to use it temporarily until the susceptibilities of the infecting bugs are known, and then to target them with monotherapy.