I agree that the 'people counteract your action' vs 'people don't' axis and the 'systemic' vs 'atomic' axis are different - but I think that there's a strong correlation between the two. Of course any intervention could have people working to counteract it, but I think these counter-actions are much more likely for systemic-type interventions.
This is because many systemic interventions have the property that, if a large majority of people agreed the intervention was a good idea, it would be easy to accomplish, or would have already been accomplished. This is at least true of systemic interventions that take the form of advocacy for social/political change in democracies - there might be other significant classes of systemic change to which this argument does not apply though - perhaps those where we think that many of those who disagree with us can be easily persuaded, or forced to comply.
This means that it's likely to be the case that the systemic interventions that still need doing must be those that have a significant group of people who disagree with us, and it is these people who are likely to counteract. It is hard to think of ways to campaign for removing rich-world agricultural subsidies in a way that is both effective, and does not invoke counteraction. Drug policy reform would also likely provoke counteraction (and by people who will genuinely believe that they, not we, are the altruists).
But non-systemic interventions seem like they would generally be easier to do in ways that avoid counteraction, because they tend to take the form of atomic improvements rather than sweeping change. I don't think there actually are many, if any, people who will really spend their money attempting to give more people malaria or schistosomiasis as a response to us spending ours the other way.
Having said all this I think this ceiling-cost approach is a very useful one, and systemic changes can be extremely effective. Rather, I just think these are the sorts of reasons that make might make one `suspicious about systemic changes per se.' as you put it.
In many cases a big concern with systemic change is that, especially when political, it involves playing zero-sum, or negative-sum games. For example, if I think that some international legal reform X is useful, but you think it would be detrimental, we might both donate money to campaigns fighting for our side of the issue and cancel each other out, meaning the money is wasted. It would have been better for us to realise this before donating to the political campaigns and give our money elsewhere.
Note this is not the same as just saying that people might disagree on which cause is the most effective. If I think that funding a vaccine program is most effective, and you think that funding a malaria-net program is more effective we can both donate without stopping the other.
Not all systemic change is of this adversarial type, involving campaigning against other people who disagree and will spend money in the other direction. But I think this is a problem which overwhelmingly affects attempts at systemic change rather than atomic change. Systemic change usually involves changing some rules or reforming some institution - which doesn't inherently need to consume lots of resources - unless we need to spend money campaigning against some people on the other side. Conversely, atomic change generally involves interventions which require resources even if everybody agrees it is a good idea (such as buying malaria nets or creating vaccines).
The conclusion here is that when calculating spending money on systemic change, you need to account for other people reacting by spending their money fighting against you - money they might have otherwise spent on something useful.